Early Growth Hormone Initiation Leads to Favorable Long-Term Growth Outcomes in Children Born Small for Gestational Age

Anders Juul; Philippe Backeljauw; Marco Cappa; Alberto Pietropoli; Nicky Kelepouris; Agnès Linglart; Roland Pfäffle; Mitchell Geffner

Disclosures

J Clin Endocrinol Metab. 2023;108(5):1043-1052.

Abstract and Introduction

Abstract

Context: Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed.

Objective: We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA.

Methods: Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated.

Results: The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported.

Conclusion: Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

Introduction

Growth hormone (GH) therapy is widely used for the treatment of short stature in children with a number of disorders, including GH deficiency (GHD), Turner syndrome, Prader-Willi syndrome, Noonan syndrome, idiopathic short stature (ISS), chronic renal failure, short stature homeobox containing gene deficiency, and short children born small for gestational age (SGA). According to consensus guidelines, newborns with a birth weight and/or length standard deviation score (SDS) of <−2 for gestational age are considered SGA.^[1] Although most infants born SGA show early spontaneous catch-up growth, short stature persists into childhood and adulthood in approximately 10% of patients.^[2] GH therapy is approved for the treatment of children born SGA who fail to show spontaneous catch-up growth by 2 to 4 years of age in the USA,^[3] or by 4 years of age or later in Europe.^[4] The effectiveness of GH treatment for improving growth outcomes in children born SGA has been well documented.^[5–9]

A consensus statement on the management of short children born SGA recommends starting GH therapy at a young age,^[1] and in patients born SGA with Silver–Russell syndrome, initiation of GH treatment at age 2 to 4 years is recommended.^[10] However, real-world data indicate that the initiation of GH treatment in SGA patients is often delayed. In the observational NordiNet® International Outcome Study (IOS), the mean age at GH treatment start was 8.5 years in France,^[11] 7.7 years in Germany, and 7.1 years in the UK.^[12] Early age at GH treatment initiation has been shown to be an important predictor of growth response in patients born SGA^[13] and there is evidence that starting GH therapy at an early age is associated with improved height outcomes.^[14] Accordingly, greater gains in height standard deviation score (HSDS) have been observed among GH-treated children born SGA aged <4 years compared with older patients.^[15]

However, few studies have examined the short- and long-term effects of initiating GH treatment in children born SGA who are <4 years of age, compared with those initiating later.^[15–17] The NordiNet® IOS and American Norditropin Studies: Web-Enabled Research (ANSWER) Program are international, multicenter, observational studies that assessed the long-term effectiveness and safety of somatropin (Norditropin®; Novo Nordisk A/S, Copenhagen, Denmark) in pediatric and adult patients. This paper reports an analysis from the NordiNet® IOS and the ANSWER Program registries, which assessed whether patient age at GH therapy initiation impacts long-term growth outcomes and safety in short children born SGA.

1 2 3 4 5

Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Patient characteristics at birth and at GH therapy initiation (EAS, N = 3318)
	Age group at GH therapy initiation
	2 to <4 years N = 356		4 to <6 years N = 1048		≥6 years N = 1914
	n		n		n
Characteristics at birth
Male, n (%)	356	193 (54.2)	1048	604 (57.6)	1914	1083 (56.6)
Born preterm^a, n (%)	349	138 (38.9)	1032	378 (36.4)	1864	539 (28.4)
Birth length SDS^b, mean (SD)	276	−2.92 (1.53)	881	−2.77 (1.31)	1596	−2.52 (1.42)
Birth weight SDS^b, mean (SD)	377	−2.32 (1.25)	1013	−2.15 (1.09)	1815	−1.98 (1.15)
Target height SDS^c, mean (SD)	320	−0.58 (1.02)	977	−0.86 (0.93)	1771	−1.00 (0.92)
Characteristics at GH therapy initiation
Age (years) at GH therapy initiation, mean (SD)	356	3.23 (0.56)	1048	4.90 (0.58)	1914	9.25 (2.21)
HSDS^c, mean (SD)	356	−3.27 (1.10)	1048	−3.07 (0.91)	1914	−2.82 (0.78)
BMI SDS^c, mean (SD)	355	−1.04 (1.56)	1043	−0.79 (1.23)	1907	−0.92 (1.23)
BA/CA, mean (SD)	151	0.68 (0.23)	518	0.71 (0.21)	1096	0.82 (0.15)
IGF-I SDS^d, mean (SD)	188	0.20 (1.24)	618	−0.12 (1.22)	1095	−1.18 (1.46)
GH peak (mg/mL), mean (SD)	70	13.21 (9.73)	200	15.91 (15.28)	391	14.22 (10.80)

Data are presented for the EAS (n = 3318).
Abbreviations: BA, bone age; BMI, body mass index; CA, chronological age; EAS, effectiveness analysis set; GH, growth hormone; HSDS, height standard deviation score; IGF-I, insulin-like growth factor I; n, number of patients with available data; SD, standard deviation; SDS, standard deviation score.
^aPreterm was defined as <37 weeks' gestation.
^bCalculated using Usher and MacLean reference data (19).
^cHSDS and BMI SDS were calculated using national reference data for patients in NordiNet® IOS and using Centers for Disease Control and Prevention national reference growth charts for patients in the ANSWER Program (20).
^dCalculated using Brabant et al reference data (21).

Table 2. Reasons for treatment discontinuation (EAS, N = 3318)
	Total	Age group at GH therapy initiation
	Total	2 to <4 years N = 356	4 to <6 years N = 1048	≥6 years N = 1914
Any reason	3318 (100%)	356 (100%)	1048 (100%)	1914 (100%)
Reason not recorded^a	2758 (83.1%)	319 (89.6%)	948 (90.5%)	1491 (77.9%)
Adult height reached/growth plate fusion	180 (5.4%)	7 (2.0%)	27 (2.6%)	146 (7.6%)
Low height velocity	62 (1.9%)	3 (0.8%)	10 (1.0%)	49 (2.6%)
Patient choice	82 (2.5%)	6 (1.7%)	15 (1.4%)	61 (3.2%)
Switch to another product	44 (1.3%)	8 (2.3%)	10 (1.0%)	26 (1.4%)
Inadequate response to GH	27 (0.8%)	4 (1.1%)	5 (0.5%)	18 (0.9%)
Off-treatment evaluation	27 (0.8%)	1 (0.8%)	13 (1.2%)	11 (0.6%)
No funds for GH treatment	17 (0.5%)	1 (0.3%)	0 (0.0%)	16 (0.8%)
Poor compliance	15 (0.5%)	0 (0.0%)	3 (0.3%)	12 (0.6%)

Data are presented as n (%). Reasons for discontinuation with >10 patients in the total EAS are presented. Reasons affecting <10 patients included: AE/ADR including death (n = 5), inter-current event/injury (n = 6), and suspected non-compliance (n = 5).
Abbreviations: ADR, adverse drug reaction; AE, adverse event; EAS, effectiveness analysis set; GH, growth hormone.
^aIncluding patients who reached the end of the study and may have continued to receive further GH therapy outside of the study.

Table 3. Frequently reported adverse drug reactions (FAS, N = 5643)
	Age group at GH therapy initiation
	2 to <4 years N = 519	4 to <6 years N = 1420	≥6 years N = 3648
Patient-years	2303.5	6429.9	12 090.7
Any ADR, n patients (%)	8 (1.5)	25 (1.8)	41 (1.1)
Nonserious ADR, n patients (%)
Total	5 (1.0)	20 (1.4)	29 (0.8)
Headache	1 (0.2)	8 (0.6)	10 (0.3)
Injection-site reaction	0 (0.0)	0 (0.0)	6 (0.2)
Arthralgia	0 (0.0)	3 (0.2)	2 (0.6)
Hypothyroidism	0 (0.0)	2 (0.1)	2 (0.6)
Scoliosis	0 (0.0)	1 (0.1)	2 (0.6)
Serious ADR, n patients (%)
Total	4 (0.8)	5 (0.4)	13 (0.4)
Epiphysiolysis	2 (0.4)	0 (0.0)	2 (0.6)
Headache	0 (0.0)	1 (0.1)	2 (0.6)
Type 2 diabetes mellitus	0 (0.0)	2 (0.1)	0 (0.0)
Tonsillar hypertrophy	2 (0.4)	0 (0.0)	0 (0.0)
Increased intracranial pressure	0 (0.0)	0 (0.0)	2 (0.6)

ADRs occurring in ≥2 patients are presented.
Abbreviations: ADR, adverse drug reaction; FAS, full analysis set; GH, growth hormone.

Authors and Disclosures

Anders Juul^1,2, Philippe Backeljauw³, Marco Cappa⁴, Alberto Pietropoli⁵, Nicky Kelepouris⁶, Agnès Linglart⁷, Roland Pfäffle⁸ and Mitchell Geffner⁹

¹Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, 2100 Copenhagen, Denmark
²Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
³Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
⁴Unit of Endocrinology, Bambino Gesù Children's Hospital, IRCCS, 00165 Roma, Italy
⁵Novo Nordisk Health Care AG, Global Medical Affairs Biopharm, 8058 Zurich, Switzerland
⁶Novo Nordisk Inc., Clinical, Medical and Regulatory Biopharm-RED, Plainsboro, NJ 08536, USA
⁷AP-HP, Paris Saclay University, INSERM, Physiologie et Physiopathologie Endocriniennes, Endocrinology and Diabetology for Children, Bicêtre Paris Saclay Hospital, 94270 Le Kremlin-Bicetre, France
⁸University of Leipzig, Medical Faculty, University Hospital for Children and Adolescents, Center for Pediatric Research, Liebigstr.19, 04103 Leipzig, Germany
⁹The Saban Research Institute and the Center for Endocrinology, Diabetes and Metabolism, Children's Hospital, Los Angeles, CA 90027, USA

Correspondence
Mitchell Geffner, MD, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #61, Los Angeles, CA 90027, USA. Email: mgeffner@chla.usc.edu.

Author Contributions
All authors were involved in conducting this study and data collection, and in drafting, critical revision, and final approval of the version of the paper to be published. All authors agree to be accountable for all aspects of the work. All authors affirm that the work submitted for publication is original and has not been published (other than as an abstract or preprint in any language or format) or submitted elsewhere for print or electronic publication consideration.

Disclosures
The authors declare the following conflicts of interest in relation to this article: A.J. has received speaker fees from Ferring, IPSEN, and Novo Nordisk, and an unrestricted grant from Novo Nordisk for the North European SGA study (NESGAS). P.B. has been a consultant for Ascendis Pharma, BioMarin, Endo Pharmaceuticals, Ipsen, Jupiter/Cavalry Bioventures, Novartis/Sandoz, and Novo Nordisk, and currently receives research support from Ipsen, Novartis, and Novo Nordisk. M.C. has nothing to declare. A.P. is an employee of Novo Nordisk Health Care AG. N.K. is an employee of Novo Nordisk Inc and holds stocks in Novo Nordisk and Pfizer. A.L. has received speaker fees from Alexion, Sandoz, Novo Nordisk, and Pfizer, and consultant fees from Merck Serono. R.P. has received speaker fees from Novo Nordisk, Sandoz, Merck Serono, Pfizer, and Ferring, and currently receives research support from Novo Nordisk, Novartis, and Pfizer. M.G. has a research contract with Novo Nordisk, receives consultant fees from Adrenas, Eton Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, and Pfizer, receives royalties from McGraw-Hill and UpToDate, and serves on a data safety monitoring board for Ascendis.