Recombinant human growth hormone (rhGH) is an approved and effective treatment for short children born small for gestational age (SGA). Prevalence of children eligible for treatment as SGA is reported to be 1:1800. The latest data from the National Registry of Growth Hormone therapy (RNAOC) showed that the number of children treated with SGA indication is still small (prevalence 0.37/100,000) and these children are significantly less reported than those treated for growth hormone deficiency (GHD), although GHD prevalence is 1:4000–1:10,000. This means that many short children born SGA are still not properly identified, and therefore not treated with rhGH, or misdiagnosed as GHD. This article provides some practical tools for the identification of children eligible for rhGH treatment.
Hinweise
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Abkürzungen
GHD
Growth hormone deficiency
rhGH
recombinant human growth hormone
RNAOC
National Registry of Growth Hormone therapy
SGA
Small for gestational age
Background
To born small for gestational age (SGA) is considered the main reason for short stature in 10% of short adults.
Children born SGA should be 2% of the population by definition (− 2 SDS correspond to the 2nd percentile). Actually, some population studies have shown different prevalence: 3.1% in Finland out of 1,390,165 singletons, 5.5% in Sweden out of 3650 healthy full-term children (37–43 gestational weeks) (of which 1.6% SGA only for weight, 2.4% SGA only for length, 1.5% SGA both for weight and length), 3.5% in Japan on 27,228 children (3.4% in term children, 5.5% in preterm children; 1.2% SGA only for weight, 1.5% SGA only for length, 0.8% SGA both in weight and length) [1].
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Catch-up growth is more pronounced during the first 6 months and is usually completed in the first 2 years of life (although preterm born SGA catch-up growth is completed also beyond the first 2 years of life, beyond age 6 years and sometimes in adolescence). Previous studies found that 8–12% of SGA children will have a short stature at 2 years of life and these children have a higher risk of short stature later in life [2, 3].
Recombinant human growth hormone (rhGH) is an approved and effective treatment for short children born SGA [4]. Although long-term treatment with rhGH can increase adult height, since SGA children are increasingly recognized as a heterogeneous group in which multiple mechanisms of growth retardation and metabolic disturbances could be causative, it has to be kept in mind – and shared with parents prior to treatment – that the response to rhGH therapy is highly variable and additional studies are needed to identify the responders [5].
SGA children do not need to be deficient in growth hormone (GH) in order to qualify for, or benefit from, rhGH therapy: in fact, the vast majority of SGA children demonstrate GH levels in the normal range, but appear to have low normal circulating IGF-I concentrations. Moreover, SGA children with GH deficiency need higher than replacement dose of rhGH for optimum growth response (0,035 mg/kg/day), probably because of some IGF-I resistance [6]. Assessment of the GH-IGF-I axis may be required if growth velocity is persistently reduced and signs of GH deficiency or hypopituitarism are present.
With the limits of a mechanistic calculus, considering a minimum prevalence of 2% children born SGA for weight and/or length, the hypothetical prevalence of short children born SGA at the age of 2 years would be 0.24% (1:417). Only one Japanese study [1] verified the prevalence of children with short stature born SGA by studying an entire cohort of nearly 30,000 children born during a three-year period and re-evaluated at 3 years of life: the prevalence was found to be 0.06% (1:1800) (notably greater in preterm births < 34 SGA, 0.39%, 1:256). Although considerably lower than the hypothetical one, this prevalence far exceeds the estimated prevalence of GHD (1:4000–1:10,000).
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Although rhGH treatment is not mandatory in every child born SGA without catch-up growth, and parents need to be informed about the variability of response to therapy, we believe that in Italy many short children born SGA are still not properly identified and therefore rhGH treatment is not offered as an option.
Aim of this article is to describe the situation of rhGH prescriptions in short children born SGA in Italy and to provide practical tools for pediatricians to identify children eligible for rhGH treatment according to Italian regulation.
Main text
Treatment with rhGH has been approved in 2009 by the Italian Medicines Agency (AIFA) for the treatment of children with short stature born SGA and is then reimbursed by the Italian National Health System (Servizio Sanitario Nazionale – SSN) according to the Note #39 on the use of drugs.
This treatment was approved in 2001 from the American Food and Drug Administration (FDA), in 2003 from the European European Agency for the Evaluation of Medicinal Products (EMEA) and in 2008 from the Ministry of Labor and of Welfare in Japan; eligibility criteria are slightly different from each other.
According to the latest version (2014) of the Note #39 of AIFA [7], to access treatment with rhGH in individuals born SGA it is necessary to meet all the following criteria (Fig. 1):
birth weight ≤ − 2 standard deviations score (SDS) (<3rd percentile) and/or length at birth ≤ − 2 SDS for gestational age according to Bertino charts [8];
age at the start of GH therapy equal to or greater than 4 years;
height less than or equal to − 2.5 SDS;
growth velocity lower than 50th percentile.
Fig. 1
Flow chart to verify the eligibility of a child born SGA for rhGH treatment7
×
In previous regulations, rhGH was provided only for short children born SGA for weight (not for length) and Gagliardi charts had to be used. Bertino charts are the most recent and methodologically more accurate, which differentiate neonatal weights and lengths not only based on sex but also on birth order.
The latest data from the National Registry of Growth Hormone therapy (RNAOC) showed only 311 rhGH prescriptions based on SGA indication versus 3942 based on GHD indication on the overall population of 4584 subjects taking rhGH in childhood in Italy [9]. Moreover, a subanalysis on Registry data, showed that the prevalence of SGA treated patients in 2017 was 0.37/100,000 (1.79/100,000 when considering the 0–15 years population) which is extremely lower than expected, with a stable incidence of new treated patient over the last 7 years (0.42/100,000 per year) (Table 1).
Table 1
Prevalence and incidence of rhGH treatment in SGA patients in Italy from 2011 to 2017, according to the National Registry of Growth Hormone therapy data
Year
2011
2012
2013
2014
2015
2016
2017
Mean
±DS
Prevalence
SGA treated patients (n)
54
68
65
70
108
140
155
Prevalence (per 100,000 general population/year)
0.37
0.47
0.44
0.28
0.22
0.27
0.37
0.35
0.09
Prevalence (per 100,000 0–15 years population/year)
0.61
0.76
0.72
0.78
1.22
1.60
1.79
1.07
0.47
Incidence
New SGA treated patients (n)
39
29
30
30
47
49
39
Incidence (per 100,000 general population/year)
0.37
0.27
0.22
0.28
0.44
0.47
0.38
0.35
0.09
Incidence (per 100,000 0–15 years population/year)
0.44
0.33
0.27
0.34
0.53
0.56
0.45
0.42
0.11
In order not to lose short children born SGA, it would be appropriate for primary care pediatricians to identify their own SGA patients since the first medical encounter and to monitor them over time.
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Remarkably, the definition of SGA used in neonatology might sometimes be different from the one reported here (<− 2 SDS): the definition of <10th percentile is broadly used to increase sensitivity for hypoglycemic screening and/or other charts may be used. Therefore, SGA definition needs to be re-evaluated.
Pediatricians can use Bertino charts [8] or, more precisely, directly verify the SDS on the website (http://www.inescharts.com) designed by scientific societies (Italian Society of Pediatric Endocrinology and Diabetology – SIEDP, Italian Society of Neonatology – SIN, Italian Society of Medical Statistics and Clinical Epidemiology – SISMEC); however, to facilitate the identification of SGA children, we propose to use two simple tables (Table 2 for weights and Table 3 for lengths): if the weight or the length of a baby is under the data reported in the Tables, it might be SGA therefore an exact calculation is needed through the aforementioned website to confirm it (data in the Tables are referred to a gestational age of X week + 6 days, which is the highest in the gestational week, in order not to lose data, with the exclusion of 42 weeks + 3 days which is the maximum included in Bertino charts).
Table 2
Weight (in grams) that might be ≤ − 2 SDS according to Bertino charts based on gestational age, sex and birth order calculated based on the formula: \( \mathrm{SDS}=\frac{{\left(\frac{y}{\mathrm{M}\left(\mathrm{t}\right)}\right)}^{\mathrm{L}\left(\mathrm{t}\right)}-1}{\mathrm{S}\left(\mathrm{t}\right)\times \mathrm{L}\left(\mathrm{t}\right)} \)
Gestational age
Firstborn males
Not-firstborn males
Firstborn females
Not-firstborn females
23
379
397
355
373
24
408
429
381
402
25
449
472
418
441
26
501
527
466
492
27
566
597
527
557
28
647
681
602
636
29
745
784
693
732
30
861
906
803
847
31
999
1049
933
983
32
1160
1217
1085
1142
33
1345
1409
1260
1324
34
1552
1625
1457
1529
35
1779
1860
1672
1753
36
2015
2105
1896
1986
37
2244
2344
2114
2213
38
2448
2555
2306
2414
39
2606
2720
2456
2570
40
2711
2830
2555
2673
41
2767
2889
2606
2729
42
2782
2905
2619
2742
Table 3
Length (in centimeters) that might be ≤ − 2 SDS according to Bertino charts based on gestational age, sex and birth order calculated based on the formula: \( \mathrm{SDS}=\frac{{\left(\frac{y}{\mathrm{M}\left(\mathrm{t}\right)}\right)}^{\mathrm{L}\left(\mathrm{t}\right)}-1}{\mathrm{S}\left(\mathrm{t}\right)\times \mathrm{L}\left(\mathrm{t}\right)} \)
Gestational age
Firstborn males
Not-firstborn males
Firstborn females
Not-firstborn females
23
26.3
26.6
25.8
26.1
24
27.4
27.7
26.9
27.2
25
28.6
28.9
28.1
28.3
26
29.8
30.1
29.3
29.5
27
31.1
31.4
30.5
30.8
28
32.4
32.7
31.8
32.1
29
33.7
34.1
33.1
33.4
30
35.1
35.5
34.5
34.8
31
36.5
36.9
35.9
36.2
32
38.0
38.4
37.3
37.7
33
39.5
39.8
38.7
39.1
34
40.9
41.3
40.1
40.5
35
42.3
42.7
41.5
41.9
36
43.6
44.0
42.8
43.2
37
44.8
45.2
44.0
44.4
38
45.8
46.3
45.0
45.4
39
46.7
47.1
45.8
46.3
40
47.3
47.8
46.4
46.9
41
47.8
48.2
46.9
47.4
42
48.0
48.4
47.1
47.5
If the child born SGA has a height lower than − 2.5 SDS at 4 years and growth rate is <50th percentile, there is an indication to start treatment with rhGH and the child must be sent to a pediatric endocrinology center (rhGH prescription is subject to a therapeutic plan, signed by specialized centers which are identified by Regions and Autonomous Provinces). To calculate height SDS, pediatricians can use the Growth Calculator distributed by SIEDP on the website http://www.weboriented.it/gh4/; however, to facilitate the identification of short children we propose to use Table 4. For practical purposes, it may be useful to remind that a growth rate of 7 cm in the previous year is equal to the 50th percentile according to Tanner charts.
Table 4
Height (in centimeters) equal to −2.5 SDS at 4 years of age (Cacciari charts [10] for Italian children or WHO charts [11] for other backgrounds)
Males
Females
Cacciari charts
91.97
91.55
WHO < 5 years charts
92.85
92
Conclusions
In conclusion, data suggest that SGA children with short stature are under recognized and frequently miss an opportunity of treatment in Italy. We strongly encourage the use of these simple and time-sparing tables for the identification and appropriate care of SGA children.
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Acknowledgments
Not applicable.
Ethics approval and consent to participate
Not needed.
Consent for publication
Not needed.
Competing interests
The authors declare that they have no competing interests.
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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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