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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 15  |  Issue : 1  |  Page : 23-28

Are we late in treating with growth hormone short small for gestational age children? Experience of a tertiary care centre


1 Department of Pediatric, Tawam Hospital, Al Ain, UAE
2 Department of Medical Education, University of Health Sciences, Lahore, Pakistan
3 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE
4 Department of Pediatric, Tawam Hospital; Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

Date of Submission15-Jun-2021
Date of Decision10-Jul-2021
Date of Acceptance09-Oct-2021
Date of Web Publication25-Mar-2022

Correspondence Address:
Noura Al Hassani
Department of Pediatric, Division of Endocrinology, Tawam Hospital and College of Medicine and Health Sciences, United Arab Emirates University, P O Box 15258, Tawam Hospital, Al Ain
UAE
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hmj.hmj_33_21

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  Abstract 


Background: Short small for gestational age (SGA) children not showing a catch-up growth by 2–4 years of age is an indication for growth hormone (GH) therapy. Objective: The objective of this study was to evaluate at what age short SGA patients present to our paediatric endocrine clinic and start on GH therapy. In addition, we aim to assess their GH response during the 1st year of therapy. Materials and Methods: This retrospective observational study included 108 'SGA' children with 'short stature' who were managed in the paediatric endocrine clinic at Tawam Hospital within 5 years. Patients' electronic medical records were reviewed and their data were retrieved. Results: The median (interquartile range) age at the time of presentation was 6.8 years (3.3, 10.0), with a statistically significant difference between the non-syndromic and syndromic patients, 7.3 (5.2, 10.7) versus 3.2 (1.8, 5.9) years, respectively, whereas the median age at the time of starting GH treatment was 10.7 years (8.1, 13.6), with 47.4% treated at 5–10 years of age and 42.1% at >10 years of age. The mean (±standard deviation) delta height z-score for all treated patients was 0.58 ± 0.40 at 1 year. There was a significant difference in both the mean height at pre and post 1 year of starting GH treatment between the non-syndromic and syndromic groups (P < 0.0001 and 0.003, respectively). Conclusion: The majority of our short SGA patients presented late and were subsequently treated with GH later than the international consensus or guideline recommendations. There is a need for increased awareness to refer these children earlier for a better outcome.

Keywords: Age, catch-up growth, growth hormone therapy, non-syndromic, short stature, small for gestational age, syndromic


How to cite this article:
AlZaabi S, Anchassi D, Alij D, Alij A, Choudhry K, Narchi H, Al Hassani N. Are we late in treating with growth hormone short small for gestational age children? Experience of a tertiary care centre. Hamdan Med J 2022;15:23-8

How to cite this URL:
AlZaabi S, Anchassi D, Alij D, Alij A, Choudhry K, Narchi H, Al Hassani N. Are we late in treating with growth hormone short small for gestational age children? Experience of a tertiary care centre. Hamdan Med J [serial online] 2022 [cited 2022 May 28];15:23-8. Available from: http://www.hamdanjournal.org/text.asp?2022/15/1/23/340816




  Introduction Top


Small for gestational age (SGA) is defined as birth weight and/or birth length that is <2 standard deviations below the mean for gestational age.[1] It has a worldwide prevalence of 3%–10%,[2],[3],[4] which is an underestimation due to the lack of recording of birth anthropometric data and gestational age in many national databases.[1],[5] Affected infants can be either preterm or full-term and may have associated intrauterine growth retardation. SGA is not a homogeneous group, and the underlying aetiology differs between the different groups. The exact aetiology remains unknown in approximately 40% of the cases, whereas in the remaining 60%, half are related to maternal factors, 5% to foetal reasons and fewer than 5% are caused by placental abnormalities.[2]

In addition to being at higher risk for perinatal morbidity, accelerated progression to puberty, neurocognitive problems, metabolic disease, particularly obesity, impaired insulin sensitivity, type 2 diabetes mellitus and cardiovascular disease later in life, SGA infants are also at a higher risk of persistent short stature.[1],[5] Although up to 90% experience a catch-up growth in the 1st year of life, reaching near completion by the age of 2 years,[2],[6],[7] the remaining 10% may remain short in adulthood.[7],[8] When compared to term SGA infants, most preterm SGA infants have a slower rate of growth with a prolonged catch-up period, taking up to 4 years to achieve a height in the normal range. The majority of the children who fail to catch up in their growth do not have the classical growth hormone (GH) deficiency. They may, instead, have alterations in the GH-insulin-like growth factor 1 (GH-IGF1) axis, including differing degrees of either GH-IGF1 resistance or GH metabolism abnormalities.[9] GH treatment of short children born SGA who did not catch up by 2–4 years of age has been approved by both the US Food and Drug Administration since 2001 and the European Medicines Agency since 2003.[1],[9]

The average age for starting GH therapy in non-syndromic SGA patients is frequently delayed by several years beyond the recommended age of 2–4 years (as per consensus-based guidelines).[6] It has also been shown that this delay is associated with a decreased response to GH.[9] Syndromic SGA patients include Turner syndrome, one of the first conditions treated with GH, the short-stature homeobox-containing gene deficiency, Silver– Russell syndrome More Details, Noonan syndrome, Prader–Willi syndrome as well as achondroplasia.[3]

The main predictive factors of growth response in the short term, in children born SGA, include the shorter height and lighter weight at the start of treatment, shorter mid parental height (MPH), younger age at initiation of GH therapy, the GH dose administered (especially during the 1st year of treatment) and the number of prepubertal years during which the patient was treated with GH.[10]

We have suspected that in our centre, short SGA children present late to the paediatric endocrine clinic, thus delaying GH treatment and potentially affecting their growth response. Furthermore, there is a paucity of information in the literature about the response to GH in syndromic SGA children.

We therefore aimed to evaluate, in a cohort of short SGA patients attending the paediatric endocrinology clinic, their age at the time of presentation and at the time of initiation of GH treatment. We also aimed to assess their GH response after 1 year of therapy, comparing syndromic with non-syndromic groups.


  Materials and Methods Top


This retrospective observational study includes all short SGA children managed in the paediatric endocrine clinic at Tawam Hospital over 5 years (between January 2014 and December 2018). Tawam Hospital, one of the largest hospitals in the United Arab Emirates, is a public tertiary hospital and part of the Abu Dhabi Health Services Company owned by the Health Authority of Abu Dhabi. It has a 469-bed capacity and serves as a regional referral centre for specialised medical care.

We reviewed the electronic medical records of all children <16 years of age and attending our endocrine clinic for short stature, defined as ≤2 standard deviation score (SDS) below the mean for the same age and sex, <3rd percentile or <2 SDS from mid parental height (MPH), using the CDC growth chart. SGA was defined as birth weight and/or birth length <2 SDS for gestational age. Patients who did not fit the definition of short stature and SGA were excluded.

Baseline demographic and clinical characteristics were collected, including nationality, gender, age at presentation, age at starting GH treatment, height and weight z-scores based on the CDC method, presence of dysmorphic features or confirmed syndromes, Tanner stage (prepubertal or pubertal), IGF-1, insulin-like growth factor-binding protein 3 (IGFBP3) and bone age by X-ray.

All height measurements were expressed as z-scores. Delta height z-score was the difference between the z-score at the end of 1 year of treatment with GH and the z-score when therapy was started. IGF-1 and IGFBP3 were measured by immunoassay and were considered low if below the minimum level of gender- and age-matched reference ranges. Bone age was evaluated by the method of Greulich and Pyle and was considered delayed if it was >2 z-scores behind the chronological age.

In our centre, we are following the international guidelines and consensuses in using GH treatment in short SGA who failed to catch up by the age of 2–4 years. The administered dose was 0.03–0.06 mg/kg/day administered daily at bedtime.

Statistical analysis

Continuous variables normally distributed (as per the Shapiro–Wilk test) were reported as mean ± standard deviation (SD) and were compared between the two groups with the unpaired t-test and with the paired t-test for repeated measurements in each child. Variables not normally distributed were reported as the median and interquartile range (25th and 75th percentiles) and were compared with the non-parametric Kruskal–Wallis test. Categorical values were expressed as number and percentage (%) and were compared with the Chi-squared or the Fisher's exact test where appropriate. All associations between the variables and the compared groups that were significant at the P < 0.1 level were entered in a linear logistic regression model to calculate the corrected coefficients for the height z-score change with treatment, after adjusting for confounders. In addition, testing for interaction was also performed between the presence of a syndrome and the significant explanatory variables in the model. The statistical package STATA version 15 (StataCorp, Texas, USA) was used for all calculations, and a two-tailed P < 0.05 defined statistical significance.


  Results Top


During the study period, 1112 patients with confirmed short stature were followed in the paediatric endocrine clinic, of whom 108 (9.7%) were identified to be also SGA [Figure 1].
Figure 1: Study Flowchart

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At their first visit to the paediatric endocrine clinic of these 108 children, 80 (74.1%) were non-syndromic, whereas 28 (25.9%) were syndromic or had dysmorphic features. The median age at presentation of the cohort was 6.8 years, 61% being males and 81% Emirati. Their mean (±SD) weight (Wt) and height (Ht) z-scores at that time were −2.8 ± 1.63 and −2.6 ± 1.04, respectively [Table 1].
Table 1: Demographic and clinical characteristics of the enrolled 108 small for gestational age children at the time of presentation

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In the dysmorphic group of 28 children, 10 had dysmorphic features (where a genetic cause was suspected without any confirmed syndrome), 4 had skeletal dysplasia, another 4 had Russell–Silver syndrome, 2 had chromosome abnormalities and 1 child for each of the following conditions: Blount's disease, CHARGE syndrome, Down syndrome, osteogenesis imperfecta, Robinow syndrome, Rothmund–Thomson syndrome, Stromme syndrome and Williams syndrome.

In comparing the non-syndromic with the syndromic groups [Table 1], there was a statistically significant difference in the median age at presentation, 7.3 years versus 3.2 years (P < 0.001), in the mean Wt z-score (−2.57 ± 1.57 vs. −3.64 ± 1.54; P = 0.002) and the mean Ht z-score (−2.3 ± 0.84 vs. −3.2 ± 1.43; P ≤ 0.001).

The median age at the time of presentation was 6.8 years and at the time of starting GH treatment was 10.7 years. The majority of the children (89.5%) were started on treatment at or after the age of 5 years, with 42.1% being over 10 years of age [Table 2].
Table 2: Age of participants at presentation and at the time of growth treatment

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GH therapy was initiated on 57 (52.8%) of the 108 patients (47 non-syndromic and 10 syndromic); however, only 47 completed 1 year of the GH treatment.

There was a statistically significant difference between the treated non-syndromic and the syndromic groups [Table 3] in their mean Ht at the initiation of treatment and 1 year later (P < 0.0001 and 0.003, respectively). However, there was no significant difference in the delta height z-score (±SD) 1 year post GH treatment (0.56 ± 0.39 vs. 0.71 ± 0.45, P = 0.3).
Table 3: Univariate comparison between the 57 non-syndromic and syndromic small for gestational age children treated with growth hormone (only 47 children completed 1 year of treatment)

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On the other hand, the mean (± SD) delta height z-score for all treated patients was 0.58 ± 0.40, with a statistically significant difference between the mean (±SD) height at pre and post 1 year of GH treatment (−2.79 ± 0.95 and −2.20 ± 0.99, respectively, P < 0.0001). This difference was evident in the non-syndromic group (−2.66 ± 0.97 and −2.10 ± 0.98, respectively, P < 0.0001) and also in the syndromic group (−3.41 ± 0.60 and −2.69 ± 0.92, respectively, P = 0.003).

In the multivariate regression model, neither the age at presentation, the age or the Ht z-score when treatment was initiated nor the presence of a syndrome was statistically significantly associated with the delta height z-score after 1 year of GH therapy [Table 4].
Table 4: Multivariate linear regression model of the delta height (height gain) z-score of 47 small for gestational age children who have completed 1 year of growth hormone treatment

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No serious side effects of GH treatment were observed after 1 year of therapy.


  Discussion Top


Our results showed that our short SGA children's median age at the time of presentation was 6.8 years, their median age at the time of starting GH treatment 10.7 years with 47.4% treated at 5–10 years of age and 42.1% at >10 years of age. This is considered to be delayed treatment compared with the international consensus and guidelines that recommend using GH in such children if they do not show catch-up growth by 2–4 years of age.

Our findings confirm several previous reports. Houk and Lee demonstrated that the average age of GH treatment initiation in short stature children born SGA is typically several years later than the recommended age.[9] Furthermore, in the Pfizer International Growth Database (KIGS), for 1909 children born SGA, the mean age at the start of GH therapy was 9.1 years[11] and the American Norditropin Studies, Web-Enabled Research (the ANSWER Program), has demonstrated that in 360 GH-naïve children born SGA, the mean age at treatment initiation was 8.4 years.[12] Such delays are associated with a significantly reduced growth response as it has been shown that a younger age at GH treatment initiation is associated with greater short-term as well as long-term Ht response and final adult Ht.[9] Therefore, identifying such a group of short SGA children at an earlier age is crucial.

One of the major contributing factors for this delayed presentation to our centre is generally the poor accuracy in the neonatal records of the gestational age as well as the birth weight and length measurements. In addition, the lack of awareness amongst the primary care providers and families about treatable short stature if the child is not catching up in growth by 2–4 years of age is a cause of delay. Moreover, we believe that the delay in treating our short SGA patients might be due to missed follow-up clinic visits, family fear of the side effects of the GH treatment and being more concerned about the other SGA associated comorbidities leading to their perception that the child's height has the least priority.

We found a more significant delay in the age at presentation between the non-syndromic and the syndromic groups. This could result from the finding that syndromic patients had a lower mean Ht and Wt SDS than the non-syndromic group, in addition to aberrations in the GH/IGF-1 axis,[13] leading to early recognition of growth failure and resulting in earlier referral. Furthermore, syndromic children usually tend to have several comorbidities and chronic conditions necessitating more frequent healthcare visits leading to earlier detection of poor liner growth.

Multiple studies have shown that the use of GH in short-born SGA is effective in improving growth velocity and final adult Ht.[1],[4],[6],[14] However, there were no studies specifically comparing the GH response between non-syndromic and syndromic patients. Reassuringly, in our study, we found that the delta height z-score 1-year post GH therapy amongst all treated patients was 0.58 ± 0.40, with no significant difference between both the groups.

Our results demonstrate that none of the following factors was a significant predictor of height post 1 year of GH therapy: age at the time of presentation, age at the time of starting the GH treatment, Ht SDS at the time of treatment or presence of a syndrome. This is in contrast to the findings by Ranke et al., in a study of 613 children born SGA and treated with GH, where the most important predicting factor for the response to treatment after the 1st year of therapy was the GH dose used, followed by age at the time of treatment, Wt SDS and mid-parental height.[15] The absence of predictors in our study could be explained by the small sample, non-compliance to GH treatment and presence of existing comorbidities or chronic illnesses.

This study has some limitations. As it was a single-centre study, generalisations of the findings to different settings cannot be confidently made. The sample size was modest, and the measured outcome was only available after a short course (1 year) of GH therapy. It remains unknown what the long-term effects of GH treatment might have been. Future multicentre studies with larger sample size, a longer period of GH therapy and a longer follow-up are needed.


  Conclusion Top


The majority of the short SGA patients in our study were presented and treated with GH later than the international consensus or guideline recommendations. Nonetheless, there was a good response amongst treated patients, both non-syndromic and syndromic. There is a need to increase the awareness amongst families of affected children, general practitioners, paediatricians and neonatologists to identify short SGA children earlier. This involves regular follow-up of the children's growth parameters, every 3 months in the 1st year of life and every 6 months thereafter. This would allow the identification of those remaining short by 2–4 years of age, leading to early referral to paediatric endocrinology clinics for early GH therapy.

Ethical clearance

The study was approved by the institutional Ethics Committee of Tawam Human Research Ethics Committee (T-HREC) (reference number NAA/ AJ/650).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: A consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007;92:804-10.  Back to cited text no. 1
    
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Arya AD. Small for gestation and growth hormone therapy. Indian J Pediatr 2006;73:73-8.  Back to cited text no. 2
    
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Deodati A, Cianfarani S. The Rationale for Growth Hormone Therapy in Children with Short Stature. J Clin Res Pediatr Endocrinol 2017;9:23-32. doi: 10.4274/jcrpe.2017.S003. Epub 2017 Dec 27. PMID: 29280742; PMCID: PMC5790327.  Back to cited text no. 3
    
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Hwang IT. Efficacy and safety of growth hormone treatment for children born small for gestational age. Korean J Pediatr 2014;57:379-83.  Back to cited text no. 4
    
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Johnston LB. Should recombinant human growth hormone therapy be used in short small for gestational age children? Arch Dis Child 2004;89:740-4.  Back to cited text no. 5
    
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Klein ML, Rapaport R. Growth hormone treatment in children born small for gestational age – Adult height and metabolic consequences. US Endocrinol 2010;6:63.  Back to cited text no. 6
    
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Saenger P, Czernichow P, Hughes I, Reiter EO. Small for gestational age: Short stature and beyond. Endocr Rev 2007;28:219-51.  Back to cited text no. 7
    
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Chatelain P, Carrascosa A, Bona G, Ferrandez-Longas A, Sippell W. Growth Hormone Therapy for Short Children Born Small for Gestational Age. Horm Res 2007;68:300-309. doi: 10.1159/000107935  Back to cited text no. 8
    
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Dahlgren J, Wikland KA; Swedish Study Group for Growth Hormone Treatment. Final height in short children born small for gestational age treated with growth hormone. Pediatr Res 2005;57:216-22.  Back to cited text no. 9
    
10.
Houk CP, Lee PA. Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes. Int J Pediatr Endocrinol 2012;2012:11.  Back to cited text no. 10
    
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Cutfield WS, Lindberg A, Rapaport R, Wajnrajch MP, Saenger P. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res 2006;65 Suppl 3:153-9. doi: 10.1159/000091719. Epub 2006 Apr 10. PMID: 16612129.  Back to cited text no. 11
    
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Ross J, Lee PA, Gut R, Germak J. Factors influencing the one- and two-year growth response in children treated with growth hormone: Analysis from an observational study. Int J Pediatr Endocrinol 2010;2010:494656.  Back to cited text no. 12
    
13.
Şıklar Z, Berberoğlu M. Syndromic disorders with short stature. J Clin Res Pediatr Endocrinol 2014;6:1-8.  Back to cited text no. 13
    
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de Zegher F, Albertsson-Wikland K, Wollmann HA, Chatelain P, Chaussain JL, Löfström A, et al. Growth hormone treatment of short children born small for gestational age: Growth responses with continuous and discontinuous regimens over 6 years. J Clin Endocrinol Metab 2000;85:2816-21.  Back to cited text no. 14
    
15.
Ranke MB, Lindberg A, Cowell CT, Wikland KA, Reiter EO, Wilton P, et al. Prediction of response to growth hormone treatment in short children born small for gestational age: Analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 2003;88:125-31.  Back to cited text no. 15
    


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