Abstract
Introduction: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH. Materials and Methods: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy. Results: We included 252 patients with an average birth length of −2.0 ± 0.7 SD and birth weight of −1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from −2.2 ± 0.9 SD to −1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively). Conclusion: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment.
References
1.
Saenger
P
, Czernichow
P
, Hughes
I
, Reiter
EO
. Small for gestational age: short stature and beyond
. Endocr Rev
. 2007 Apr 1
;28
(2
):219
–51
. .2.
Zeve
D
, Regelmann
MO
, Holzman
IR
, Rapaport
R
. Small at birth, but how small? The definition of SGA revisited
. Horm Res Paediatr
. 2016
;86
(5
):357
–60
. .3.
WHO
. Aspects of low birth weight. Report of the expert committee of maternal child health
. WHO Tech Rep
. 1961
;217
:3
—16
.4.
Marzouk
A
, Filipovic-Pierucci
A
, Baud
O
, Tsatsaris
V
, Ego
A
, Charles
M-A
, et al. Prenatal and post-natal cost of small for gestational age infants: a national study
. BMC Health Serv Res
. 2017 Mar 21
;17
(1
):221
. .5.
Hokken-Koelega
ACS
, De Ridder
MAJ
, Lemmen
RJ
, Hartog
HD
, De Muinck Keizer-Schrama
SMPF
, Drop
SLS
. Children born small for gestational age: do they catch up?
Pediatr Res
. 1995 Aug
;38
(2
):267
–71
. .6.
Karlberg
J
, Albertsson-Wikland
K
. Growth in full-term small-for-gestational-age infants: from birth to final height
. Pediatr Res
. 1995 Nov
;38
(5
):733
–9
. .7.
Gibson
AT
, Carney
S
, Cavazzoni
E
, Wales
JK
. Neonatal and post-natal growth
. Horm Res
. 2000
;53
(Suppl 1
):42
–9
. .8.
Cooke
RWI
, Foulder-Hughes
L
. Growth impairment in the very preterm and cognitive and motor performance at 7 years
. Arch Dis Child
. 2003 Jun
;88
(6
):482
–7
. .9.
Barker
DJ
. The fetal origins of coronary heart disease
. Acta Paediatr Suppl
. 1997 Jul
;422
:78
–82
. .10.
McIntire
DD
, Bloom
SL
, Casey
BM
, Leveno
KJ
. Birth weight in relation to morbidity and mortality among newborn infants
. N Engl J Med
. 1999 Apr 22
;340
(16
):1234
–8
. .11.
Leger
J
, Levy-Marchal
C
, Bloch
J
, Pinet
A
, Chevenne
D
, Porquet
D
, et al. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study
. BMJ
. 1997 Aug 9
;315
(7104
):341
–7
. .12.
Leger
J
, Limoni
C
, Collin
D
, Czernichow
P
. Prediction factors in the determination of final height in subjects born small for gestational age
. Pediatr Res
. 1998 Jun
;43
(6
):808
–12
. .13.
Sas
T
, de Waal
W
, Mulder
P
, Houdijk
M
, Jansen
M
, Reeser
M
, et al. Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial
. J Clin Endocrinol Metab
. 1999 Sep
;84
(9
):3064
–70
. .14.
Boguszewski
M
, Albertsson-Wikland
K
, Aronsson
S
, Gustafsson
J
, Hagenäs
L
, Westgren
U
, et al. Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial
. Acta Paediatr
. 1998 Mar
;87
(3
):257
–63
.15.
Van Pareren
Y
, Mulder
P
, Houdijk
M
, Jansen
M
, Reeser
M
, Hokken-Koelega
A
. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial
. J Clin Endocrinol Metab
. 2003 Aug
;88
(8
):3584
–90
. .16.
Carel
J-C
, Chatelain
P
, Rochiccioli
P
, Chaussain
J-L
. Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study
. J Clin Endocrinol Metab
. 2003 Apr
;88
(4
):1587
–93
. .17.
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 Feb
;57
(2
):216
–22
. .18.
Butenandt
O
, Lang
G
. Recombinant human growth hormone in short children born small for gestational age. German Study Group
. J Pediatr Endocrinol Metab
. 1997 Jun
;10
(3
):275
–82
.19.
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 Aug
;85
(8
):2816
–21
. .20.
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 Jan 1
;88
(1
):125
–31
. .21.
Lem
AJ
, van der Kaay
DCM
, de Ridder
MAJ
, Bakker-van Waarde
WM
, van der Hulst
FJPCM
, Mulder
JC
, et al. Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial
. J Clin Endocrinol Metab
. 2012 Nov
;97
(11
):4096
–105
. .22.
van der Steen
M
, Lem
AJ
, van der Kaay
DCM
, Hokken-Koèelega
ACS
. Puberty and pubertal growth in GH-treated SGA children: effects of 2 years of GnRHa nersus No GnRHa
. J Clin Endocrinol Metab
. 2016 May
;101
(5
):2005
–12
. .23.
Mamelle
N
, Munoz
F
, Martin
JL
, Laumon
B
, Grandjean
H
. [Fetal growth from the AUDIPOG study. II. Application for the diagnosis of intrauterine growth retardation]
. J Gynecol Obstet Biol Reprod (Paris)
. 1996
;25
(1
):71
–7
.24.
Sempé
M
, Pédron
G
, Roy-Pernot
MP
. Auxologie: méthode et séquences
. Paris
: Theraplix
; 1979
.25.
Hermanussen
M
, Cole
J
. The calculation of target height reconsidered
. Horm Res
. 2003
;59
(4
):180
–3
. .26.
Alberti
C
, Chevenne
D
, Mercat
I
, Josserand
E
, Armoogum-Boizeau
P
, Tichet
J
, et al. Serum concentrations of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio, and markers of bone turnover: reference values for French children and adolescents and z-score comparability with other references
. Clin Chem
. 2011 Oct
;57
(10
):1424
–35
. .27.
Greulich
WW
, Pyle
S
. Radiographic atlas of skeletal development of the hand and wrist
. Stanford University Press
; 1959
. p. 272
.28.
Carel
J-C
, Eugster
EA
, Rogol
A
, Ghizzoni
L
, Palmert
MR
. Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children
. Pediatrics
. 2009 Apr 1
;123
(4
):e752
–62
. .29.
de Zegher
F
, Ong
KK
, Ibáñez
L
, Dunger
DB
. Growth hormone therapy in short children born small for gestational age
. Horm Res
. 2006
;65
(Suppl 3
):145
–52
. .30.
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 Mar
;92
(3
):804
–10
. .31.
van Dijk
M
, Bannink
EMN
, van Pareren
YK
, Mulder
PGH
, Hokken-Koelega
ACS
. Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls
. J Clin Endocrinol Metab
. 2007 Jan
;92
(1
):160
–5
. .32.
Thomas
M
, Beckers
D
, Brachet
C
, Dotremont
H
, Lebrethon
M-C
, Lysy
P
, et al. Adult height after growth hormone treatment at pubertal onset in short adolescents born small for gestational age: results from a Belgian Registry-Based Study
. Int J Endocrinol
. 2018
;2018
:6421243
. .33.
Maiorana
A
, Cianfarani
S
. Impact of growth hormone therapy on adult height of children born small for gestational age
. Pediatrics
. 2009 Sep
;124
(3
):e519
–31
. .34.
Luo
ZC
, Albertsson-Wikland
K
, Karlberg
J
. Length and body mass index at birth and target height influences on patterns of postnatal growth in children born small for gestational age
. Pediatrics
. 1998 Dec
;102
(6
):E72
. .35.
Cianfarani
S
, Ladaki
C
, Geremia
C
. Hormonal regulation of postnatal growth in children born small for gestational age
. Horm Res
. 2006
;65 Suppl 3
(Suppl 3
):70
–4
. .36.
de Zegher
F
, Hokken-Koelega
A
. Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term
. Pediatrics
. 2005 Apr
;115
(4
):e458
–62
. .37.
Verkauskiene
R
, Petraitiene
I
, Albertsson Wikland
K
. Puberty in children born small for gestational age
. Horm Res Paediatr
. 2013
;80
(2
):69
–77
. .38.
Kamp
GA
, Mul
D
, Waelkens
JJ
, Jansen
M
, Delemarre-van de Waal
HA
, Verhoeven-Wind
L
, et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation
. J Clin Endocrinol Metab
. 2001 Jul
;86
(7
):2969
–75
. .39.
van Gool
SA
, Kamp
GA
, Visser-van Balen
H
, Mul
D
, Waelkens
JJJ
, Jansen
M
, et al. Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty
. J Clin Endocrinol Metab
. 2007 Apr
;92
(4
):1402
–8
. .40.
van der Steen
M
, Lem
AJ
, van der Kaay
DCM
, Bakker-van Waarde
WM
, van der Hulst
FJPCM
, Neijens
FS
, et al. Metabolic health in short children born small for gestational age treated with growth hormone and gonadotropin-releasing hormone analog: results of a randomized, dose-response trial
. J Clin Endocrinol Metab
. 2015 Oct
;100
(10
):3725
–34
. .41.
Goedegebuure
WJ
, van der Steen
M
, de With
JL
, Hokken-Koelega
A
. Cognition, health-related quality of life, and psychosocial functioning after GH/GnRHa treatment in young adults born SGA
. J Clin Endocrinol Metab
. 2018 Nov 1
;103
(11
):3931
–8
. .42.
van der Steen
M
, Lem
AJ
, van der Kaay
DCM
, Hokken-Koèelega
ACS
. Puberty and pubertal growth in GH-treated SGA children: effects of 2 years of GnRHa versus No GnRHa
. J Clin Endocrinol Metab
. 2016 May
;101
(5
):2005
–12
. .43.
Chan
JM
, Stampfer
MJ
, Ma
J
, Gann
P
, Gaziano
JM
, Pollak
M
, et al. Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer
. J Natl Cancer Inst
. 2002 Jul 17
;94
(14
):1099
–106
. .44.
Cohen
P
, Rogol
AD
, Howard
CP
, Bright
GM
, Kappelgaard
A-M
, Rosenfeld
RG
, et al. Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study
. J Clin Endocrinol Metab
. 2007 Jul
;92
(7
):2480
–6
. .45.
Sas
T
, Mulder
P
, Hokken-Koelega
A
. Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency
. J Clin Endocrinol Metab
. 2000 Oct
;85
(10
):3786
–92
. .46.
Willemsen
RH
, Arends
NJT
, Bakker-van Waarde
WM
, Jansen
M
, van Mil
EGAH
, 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 (Oxf)
. 2007 Oct
;67
(4
):485
–92
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