Abstract
Introduction: Although the clinical benefits of long-term recombinant human growth hormone (rhGH) therapy have been well demonstrated in children born small for gestational age (SGA), little is known about the outcomes of this therapy in children born with very low birth weight (VLBW). This study aimed to report the short- and long-term response to rhGH therapy in a cohort of VLBW patients, comparing subgroups according to size, gestational age (GA), and causal factors associated with VLBW. Methods: We describe 33 patients born at VLBW treated with rhGH; 16 also received GnRHa. Medical records were analyzed at baseline and after 1 year of rhGH treatment. Data on the adult height SDS from 23 patients were also collected. Growth velocities and height SDS changes were calculated, along with the differences between the observed and predicted growth velocities. Results: The first-year growth velocity (7.5 ± 2.1 cm/year) was aligned with prediction models for SGA children. After 1 year of rhGH treatment, height SDS improved from −3.0 ± 1.1 to −2.6 ± 1.3, with no differences among subgroups. Among patients reaching adult height, 73.9% remained short (−2.5 ± 1.3) after long-term therapy (6.7 ± 3.3 years). The initial height SDS, height SDS change in the first year of treatment, and target height SDS were key independent predictors of height gain. Conclusion: The response to rhGH treatment was suboptimal in the VLBW group, independent of the size, GA, or etiological diagnosis. However, adult height may be improved in patients receiving rhGH treatment. This underscores the need for tailored protocols and further investigations to optimize outcomes in this population.
Journal Section:
Clinical Practice Committee Publication
References
1.
Blencowe
H
, Krasevec
J
, de Onis
M
, Black
RE
, An
X
, Stevens
GA
, et al. National, regional, and worldwide estimates of low birthweight in 2015, with trends from 2000: a systematic analysis
. Lancet Glob Health
. 2019
;7
(7
):e849
–60
. 2.
Victora
JD
, Silveira
MF
, Tonial
CT
, Victora
CG
, Barros
FC
, Horta
BL
, et al. Prevalence, mortality and risk factors associated with very low birth weight preterm infants: an analysis of 33 years
. J Pediatr
. 2020
;96
(3
):327
–32
. 3.
Michaelis
IA
, Krägeloh-Mann
I
, Manyisane
N
, Mazinu
MC
, Jordaan
ER
. Prospective cohort study of mortality in very low birthweight infants in a single centre in the Eastern Cape province, South Africa
. BMJ Paediatr Open
. 2021
;5
(1
):e000918
. 4.
Chung
SH
, Bae
CW
. Improvement in the survival rates of very low birth weight infants after the establishment of the Korean neonatal network: comparison between the 2000s and 2010s
. J Korean Med Sci
. 2017
;32
(8
):1228
–34
. 5.
WHO, Making every baby count: audit and review of stillbirths and neonatal deaths
. 2016
, World Health Organization
: Geneva
.6.
WHO, International Classification of Diseases, Tenth Revision
. Clinical modification (ICD-10-CM)
. 2021
.7.
Hokken-Koelega
ACS
, van der Steen
M
, Boguszewski
MCS
, Cianfarani
S
, Dahlgren
J
, Horikawa
R
, et al. International consensus guideline on small for gestational age: etiology and management from infancy to early adulthood
. Endocr Rev
. 2023
;44
(3
):539
–65
. 8.
Marks
KA
, Reichman
B
, Lusky
A
, Zmora
E
; Israel Neonatal Network
. Fetal growth and postnatal growth failure in very-low-birthweight infants
. Acta Paediatr
. 2006
;95
(2
):236
–42
. 9.
Takayanagi
T
, Shichijo
A
, Egashira
M
, Egashira
T
, Mizukami
T
. Extrauterine growth restriction was associated with short stature and thinness in very low birthweight infants at around six years of age
. Acta Paediatr
. 2019
;108
(1
):112
–7
. 10.
Peila
C
, Spada
E
, Deantoni
S
, Iuliano
E
, Moro
GE
, Giribaldi
M
, et al. The “fortilat” randomized clinical trial follow-up: neurodevelopmental outcome at 18 Months of age
. Nutrients
. 2020
;12
(12
):3807
. 11.
Crump
C
. An overview of adult health outcomes after preterm birth
. Early Hum Dev
. 2020
;150
:105187
. 12.
Yun
J
, Jung
YH
, Shin
SH
, Song
IG
, Lee
YA
, Shin
CH
, et al. Impact of very preterm birth and post-discharge growth on cardiometabolic outcomes at school age: a retrospective cohort study
. BMC Pediatr
. 2021
;21
(1
):373
. 13.
de Mendonça
ELSS
, de Lima Macêna
M
, Bueno
NB
, de Oliveira
ACM
, Mello
CS
. Premature birth, low birth weight, small for gestational age and chronic non-communicable diseases in adult life: a systematic review with meta-analysis
. Early Hum Dev
. 2020
;149
:105154
. 14.
Van de Pol
C
, Allegaert
K
. Growth patterns and body composition in former extremely low birth weight (ELBW) neonates until adulthood: a systematic review
. Eur J Pediatr
. 2020
;179
(5
):757
–71
. 15.
Hollanders
JJ
, Schaëfer
N
, van der Pal
SM
, Oosterlaan
J
, Rotteveel
J
, Finken
MJJ
, et al. Long-term neurodevelopmental and functional outcomes of infants born very preterm and/or with a very low birth weight
. Neonatology
. 2019
;115
(4
):310
–9
. 16.
Arai
S
, Sato
Y
, Muramatsu
H
, Yamamoto
H
, Aoki
F
, Okai
Y
, et al. Risk factors for absence of catch-up growth in small for gestational age very low-birthweight infants
. Pediatr Int
. 2019
;61
(9
):889
–94
. 17.
Hollanders
JJ
, van der Pal
SM
, van Dommelen
P
, Rotteveel
J
, Finken
MJJ
. Growth pattern and final height of very preterm vs. very low birth weight infants
. Pediatr Res
. 2017
;82
(2
):317
–23
. 18.
Itabashi
K
, Mishina
J
, Tada
H
, Sakurai
M
, Nanri
Y
, Hirohata
Y
. Longitudinal follow-up of height up to five years of age in infants born preterm small for gestational age; comparison to full-term small for gestational age infants
. Early Hum Dev
. 2007
;83
(5
):327
–33
. 19.
Jamshed
S
, Khan
F
, Chohan
SK
, Bano
Z
, Shahnawaz
S
, Anwar
A
, et al. Frequency of normal birth length and its determinants: a cross-sectional study in newborns
. Cureus
. 2020
;12
(9
):e10556
. 20.
Mallia
T
, Grech
A
, Hili
A
, Calleja-Agius
J
, Pace
NP
. Genetic determinants of low birth weight
. Minerva Ginecol
. 2017
;69
(6
):631
–43
. 21.
Yaghootkar
H
, Freathy
RM
. Genetic origins of low birth weight
. Curr Opin Clin Nutr Metab Care
. 2012
;15
(3
):258
–64
. 22.
Homma
TK
, Freire
BL
, Honjo Kawahira
RS
, Dauber
A
, Funari
MFA
, Lerario
AM
, et al. Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing
. J Pediatr
. 2019
;215
:192
–8
. 23.
Freire
BL
, Homma
TK
, Funari
MFA
, Lerario
AM
, Vasques
GA
, Malaquias
AC
, et al. Multigene sequencing analysis of children born small for gestational age with isolated short stature
. J Clin Endocrinol Metab
. 2019
;104
(6
):2023
–30
. 24.
Freire
BL
, Homma
TK
, Lerario
AM
, Seo
GH
, Han
H
, de Assis Funari
MF
, et al. High frequency of genetic/epigenetic disorders in short stature children born with very low birth weight
. Am J Med Genet
. 2022
;188
(9
):2599
–604
. 25.
Collett-Solberg
PF
, Ambler
G
, Backeljauw
PF
, Bidlingmaier
M
, Biller
BMK
, Boguszewski
MCS
, et al. Diagnosis, genetics, and therapy of short stature in children: a growth hormone research society international perspective
. Horm Res Paediatr
. 2019
;92
(1
):1
–14
. 26.
Upners
EN
, Raket
LL
, Petersen
JH
, Thankamony
A
, Roche
E
, Shaikh
G
, et al. Timing of puberty, pubertal growth, and adult height in short children born small for gestational age treated with growth hormone
. J Clin Endocrinol Metab
. 2022
;107
(8
):2286
–95
. 27.
Kum
CD
, Rho
JG
, Park
HK
, Lee
HS
, Hwang
JS
. Factors influencing growth hormone therapy effect during the prepubertal period in small for gestational age children without catch-up growth
. Ann Pediatr Endocrinol Metab
. 2021
;26
(1
):31
–7
. 28.
Wu
W
, Gong
C
, Li
Y
, Hu
Y
, Gong
H
, Fu
J
, et al. Long-term efficacy and safety of recombinant human growth hormone in children born small for gestational age
. Horm Metab Res
. 2023
;55
(9
):599
–609
. 29.
Lapeyre
D
, Klosowski
S
, Liska
A
, Zaoui
C
, Gremillet
C
, Truffert
P
. [Very preterm infant (<32 weeks) vs very low birth weight newborns (1500 grammes): comparison of two cohorts]
. Arch Pediatr
. 2004
;11
(5
):412
–6
. 30.
Berndt
C
, Schweizer
R
, Ranke
MB
, Binder
G
, Martin
DD
. Height, muscle, fat and bone response to growth hormone in short children with very low birth weight born appropriate for gestational age and small for gestational age
. Horm Res Paediatr
. 2014
;82
(2
):81
–8
. 31.
Kuczmarski
RJ
, Ogden
CL
, Guo
SS
, Grummer-Strawn
LM
, Flegal
KM
, Mei
Z
, et al. 2000 CDC Growth Charts for the United States: methods and development
. Vital Health Stat
. 2002
;11
(246
):1
–190
.32.
Fredriks
AM
, van Buuren
S
, van Heel
WJM
, Dijkman-Neerincx
RHM
, Verloove-Vanhorick
SP
, Wit
JM
. Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders
. Arch Dis Child
. 2005
;90
(8
):807
–12
. 33.
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
(1
):125
–31
. 34.
Tauber
M
, Ester
W
, Auriol
F
, Molinas
C
, Fauvel
J
, Caliebe
J
, et al. GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism
. Clin Endocrinol
. 2007
;67
(3
):457
–61
. 35.
Straetemans
S
, Thomas
M
, Craen
M
, Rooman
R
, De Schepper
J
; BESPEED
. Poor growth response during the first year of growth hormone treatment in short prepubertal children with growth hormone deficiency and born small for gestational age: a comparison of different criteria
. Int J Pediatr Endocrinol
. 2018
;2018
:9
. 36.
Boguszewski
MC
, Mericq
V
, Bergada
I
, Damiani
D
, Belgorosky
A
, Gunczler
P
, et al. Latin American consensus: children born small for gestational age
. BMC Pediatr
. 2011
;11
:66
. 37.
Lee
PA
, Chernausek
SD
, Hokken-Koelega
ACS
, Czernichow
P
; International Small for Gestational Age Advisory Board
. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001
. Pediatrics
. 2003
;111
(6 Pt 1
):1253
–61
. 38.
Aycan
Z
, Araslı Yılmaz
A
, Yel
S
, Savaş-Erdeve
Ş
, Çetinkaya
S
. Evaluation of growth hormone results in different diagnosis and trend over 10 Year of follow-up: a single center experience
. J Clin Res Pediatr Endocrinol
. 2021
;13
(3
):332
–41
. 39.
Beisti Ortego
A
, Fuertes Rodrigo
C
, Ferrer Lozano
M
, Labarta Aizpun
JI
, de Arriba Muñoz
A
. Adult height in short children born small for gestational age treated with growth hormone
. Med Clin
. 2020
;154
(8
):289
–94
. 40.
Boguszewski
MC
, Lindberg
A
, Wollmann
HA
. Three-year growth response to growth hormone treatment in very young children born small for gestational age-data from KIGS
. J Clin Endocrinol Metab
. 2014
;99
(8
):2683
–8
. 41.
Maiorana
A
, Cianfarani
S
. Impact of growth hormone therapy on adult height of children born small for gestational age
. Pediatrics
. 2009
;124
(3
):e519
–31
. 42.
Bannink
E
, Djurhuus
CB
, Christensen
T
, Jøns
K
, Hokken-Koelega
A
. Adult height and health-related quality of life after growth hormone therapy in small for gestational age subjects
. J Med Econ
. 2010
;13
(2
):221
–7
. 43.
Boguszewski
MCDS
, Cardoso-Demartini
ADA
. Management of endocrine disease: growth and growth hormone therapy in short children born preterm
. Eur J Endocrinol
. 2017
;176
(3
):R111
–22
. 44.
Adler
E
, Lambert
AS
, Bouvattier
C
, Thomas-Teinturier
C
, Rothenbuhler
A
, de Boissieu
P
, et al. Determinants of final height in patients born small for gestational age treated with recombinant growth hormone
. Horm Res Paediatr
. 2021
;94
(1–2
):52
–62
. 45.
Renes
JS
, Willemsen
RH
, Mulder
JC
, Bakker-van Waarde
WM
, Rotteveel
J
, Oostdijk
W
, et al. New insights into factors influencing adult height in short SGA children: results of a large multicentre growth hormone trial
. Clin Endocrinol
. 2015
;82
(6
):854
–61
. 46.
Ranke
MB
, Lindberg
A
; KIGS International Board
. Height at start, first-year growth response and cause of shortness at birth are major determinants of adult height outcomes of short children born small for gestational age and Silver-Russell syndrome treated with growth hormone: analysis of data from KIGS
. Horm Res Paediatr
. 2010
;74
(4
):259
–66
. 47.
Juul
A
, Backeljauw
P
, Cappa
M
, Pietropoli
A
, Kelepouris
N
, Linglart
A
, et al. Early growth hormone initiation leads to favorable long-term growth outcomes in children born small for gestational age
. J Clin Endocrinol Metab
. 2023
;108
(5
):1043
–52
. 48.
Boguszewski
MCS
, Carlsson
M
, Lindberg
A
, Dahlgren
J
, Aydin
F
, Camacho-Hübner
C
, et al. Near-adult height after growth hormone treatment in children born prematurely-data from KIGS
. J Clin Endocrinol Metab
. 2020
;105
(7
):dgaa203
. 49.
Smeets
CC
, Zandwijken
GRJ
, Renes
JS
, Hokken-Koelega
ACS
. Long-term results of GH treatment in silver-russell syndrome (SRS): do they benefit the same as non-SRS short-SGA
. J Clin Endocrinol Metab
. 2016
;101
(5
):2105
–12
. 50.
Binder
G
, Liebl
M
, Woelfle
J
, Eggermann
T
, Blumenstock
G
, Schweizer
R
. Adult height and epigenotype in children with Silver-Russell syndrome treated with GH
. Horm Res Paediatr
. 2013
;80
(3
):193
–200
. 51.
Ertl
DA
, de Nanclares
GP
, Jüppner
H
, Hanna
P
, Pagnano
A
, Pereda
A
, et al. Recombinant growth hormone improves growth and adult height in patients with maternal inactivating GNAS mutations
. Eur J Endocrinol
. 2023
;189
(1
):123
–31
. 52.
Giabicani
E
, Willems
M
, Steunou
V
, Chantot-Bastaraud
S
, Thibaud
N
, Abi Habib
W
, et al. Increasing knowledge in IGF1R defects: lessons from 35 new patients
. J Med Genet
. 2020
;57
(3
):160
–8
. 53.
Walenkamp
MJE
, Robers
JML
, Wit
JM
, Zandwijken
GRJ
, van Duyvenvoorde
HA
, Oostdijk
W
, et al. Phenotypic features and response to GH treatment of patients with a molecular defect of the IGF-1 receptor
. J Clin Endocrinol Metab
. 2019
;104
(8
):3157
–71
. 54.
Malaquias
AC
, Noronha
RM
, Souza
TTO
, Homma
TK
, Funari
MFA
, Yamamoto
GL
, et al. Impact of growth hormone therapy on adult height in patients with PTPN11 mutations related to noonan syndrome
. Horm Res Paediatr
. 2019
;91
(4
):252
–61
. 55.
Arroyo Ruiz
R
, Ballester Pérez
A
, Leiva-Gea
I
, Martínez-Aedo
M
, López-Siguero
JP
. Factors influencing height gain in children born small for gestational age treated with recombinant growth hormone: what extent is puberty involved
. Ther Adv Endocrinol Metab
. 2022
;13
:20420188221083534
. 56.
Al Khalifah
RA
, Alhakami
A
, AlRuthia
Y
, Al Sarraj
HZ
, Abulqasim
J
, Al-Rasheedi
A
, et al. The long-term growth, cost-effectiveness, and glycemic effects of growth hormone therapy on children born small for gestational age over 10 years: a retrospective cohort study
. J Pediatr Endocrinol Metab
. 2022
;35
(11
):1357
–68
. 57.
Coutant
R
, Leheup
B
, Nicolino
M
, Salles
JP
. Growth hormone dose modulation and final height in short children born small for gestational age: French real-life data
. Horm Res Paediatr
. 2023
;96
(5
):495
–508
. 58.
Maghnie
M
, Ranke
MB
, Geffner
ME
, Vlachopapadopoulou
E
, Ibáñez
L
, Carlsson
M
, et al. Safety and efficacy of pediatric growth hormone therapy: results from the full KIGS cohort
. J Clin Endocrinol Metab
. 2022
;107
(12
):3287
–301
. 59.
Lee
HS
, Kum
CD
, Rho
JG
, Hwang
JS
. Long-term effectiveness of growth hormone therapy in children born small for gestational age: an analysis of LG growth study data
. PLoS One
. 2022
;17
(4
):e0266329
. 60.
Chen
SC
, Bryce
J
, Chen
M
, Charmandari
E
, Choi
JH
, Dou
X
, et al. Development of a minimum dataset for the monitoring of recombinant human growth hormone therapy in children with growth hormone deficiency: a GloBE-reg initiative
. Horm Res Paediatr
. 2024
;97
(4
):365
–73
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