EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
Abdel Wahab et al
INSULIN-LIKE GROWTH FACTOR I AND VASCULAR ENDOTHELIAL
GROWTH FACTOR AS PREDICTIVE FACTORS IN RETINOPATHY OF
PREMATURITY AND OTHER COMPLICATIONS OF PREMATURE BIRTH
By
Walid Abdel Wahab1,4, Walid Niazy Hassan2 , Ahmed Mahfuz3,4
Departments of Pediatrics1, Biochemistry2, and Community Medicine3, College of
Medicine, King Khalid University, Abha, Saudi Arabia, and Aseer Regional
Committee of Neonatal Care4
ABSTRACT:
Background: Insulin-like growth factor I (IGF-I) and vascular endothelial growth
factor (VEGF) are necessary for normal development of retinal blood vessels in mice
and humans. We conducted a prospective study measuring serum levels of IGF-I and
VEGF in preterm infants who developed complications of prematurity such as
retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and
necrotizing enterocolitis (NEC). Also to evaluate their value in the prediction of those
complications.
Methods: A sample of 62 preterm infants who developed morbidity of prematurity
such as ROP (n=31), BPD (n=18) and NEC (n=13) were included in the study. This
group consist of 33 male and 29 female, their gestational age was less than 33 weeks
(range: 25-32), and their mean birth weight was 961.7 g (range: 640-1200 g). Of the
31 infants with ROP, 19 had non-proliferative ROP and 12 had proliferative ROP.
Twenty two preterm infants with no ROP, BPD or NEC of matched age and sex were
enrolled in the study as a control group. Serum levels of IFG-I were measured by
using radioimmunoassay while, serum VEGF levels were determined by enzyme
linked immunosorbent assay (ELISA).
Results: Serum levels of IGF-I were significantly lower (p < 0.001) in preterm infants
with complications of premature birth than in the control group, however serum levels
of VEGF were significantly higher (p < 0.001) in patients than in the controls. Among
infants complicated with ROP, serum levels of IGF-I were significantly lower (p<
0.001) in patients with non-proliferative ROP than in those with proliferative ROP.
We found that serum levels of VEGF were significantly higher (p< 0.001) in infants
who had proliferative ROP than in those with non-proliferative disease. In BPD
group, serum levels of IGF-I were significantly lower in patients than in the controls,
while serum levels of VEGF were significantly higher in infants with BPD than in
those without this morbidity. Serum levels of IGF-I were significantly lower (p<
0.001) in patients with NEC than in the control group. There was a significant positive
correlation between IGF-I and VEGF (r= + 0.736; p<0.05).
Conclusion: Low serum IGF-I levels predict an increased risk of ROP as well as
other complications of premature birth such as BPD and NEC. Replacement of IGF-I
to levels found in utero may prevent those complications. High serum VEGF levels
predict retinal neovascularization or phase II ROP and carry poor prognosis. AntiVEGF therapy may be a promising strategy for treating retinal neovascular
proliferation which can cause blindness.
KEYWORDS:
Preterm infants
Vascular endothelial growth factor
27
Insulin-like growth factor I
Retinopathy of prematurity.
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
Abdel Wahab et al
Bronchopulmonary dysplasia
(BPD) is a significant health problem
in preterm infants. It is characterized
by arrested alveolar development.
Mechanism that regulate alveolar
development
remains
poorly
understood. Even less is known about
regulation of the growth and
development of pulmonary vasculature7. BPD and necrotizing enterocolitis (NEC) are known serious
complications of premature birth. IGFI is necessary for the development of
nerve, muscle, bone, liver, lung, eye
and other body tissues8. IGF-I
enhances
fetal
growth
and
gastrointestinal development in sheep9.
INTRODUCTION:
Retinopathy of prematurity
(ROP) is a blinding disease, initiated
by lack of retinal vascular growth after
preterm birth1. The greatest risk factors
for development of ROP are low birth
weight and low gestational age
although the pathogenesis of ROP is
multifactorial2.
There are both oxygenregulated and non oxygen-regulated
factors, which contribute to normal
vascular development and retinal
neovascularization. A critical non
oxygen-regulated growth factor is
insulin-like growth factor I (IGF-I) and
one important oxygen- regulated factor
is vascular endothelial growth factor
(VEGF)3.
The aim of the study was to
mesure serum levels of IGF-I and
VEGF in preterm infants who
developed
complications
of
prematurity such as ROP, BPD and
NEC. Also to evaluate their value in
the prediction of those complications.
Pathologically, ROP consists of
two phases, the first phase (nonproliferative), and the second phase
(retinal neovascularization or proliferative) ROP3.
SUBJECTS AND METHODS:
This study was conducted at
neonatal intensive care units of Abha
General and Aseer Central Hospitals,
Southwestern of Saudi Arabia between
January, 2004 to June 2006. A sample
of sixty two Preterm infants who
developed morbidity of prematurity
such as ROP, BPD and NEC were
included in the study. This group
consist of 33 male and 29 female, their
gestational age was less than 33 weeks
(range: 25-32), and their mean birth
weight was 961.7 g (range: 640-1200
g). Twenty two preterm infants with no
ROP, BPD or NEC of matched age and
sex were enrolled in the study as a
control group.
The first phase of ROP in
preterm infants consists of cessation of
the normal retinal vascular growth
which would occur in utero, as well as
loss of some of the developed vessels.
IGF-I is essential for normal retinal
vascular development and lack of IGFI is associated with lack of vascular
growth and subsequent initiation of
ROP, so IFG-I has a critical role in the
development of phase I of ROP. The
second phase of ROP, retinal
neovascularization, (proliferative ROP)
is hypoxia induced and VEGF plays a
role in the genesis of this phase3.
Recent experimental studies suggest
that growth factors such as VEGF and
IGF-I can play an important role in the
development of ROP, but clinical
implications of these findings remain
unclear4,5,6.
INCLUSION CRITERIA OF THE
PATINETS:
(A) Patients with ROP:
ROP was classified according
to the International Classification of
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EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
ROP (ICROP)10 and subdivided into
stage 1 (demarcation line), stage 2
(ridge), stage 3 (ridge with extraretinal
fibrovascular proliferations), stage 4
(subtotal retinal detachment), and stage
5 (total retinal detachment). Nonproliferative ROP was defined as stage
1 and 2, however, stage 3 and 4 are
considered as proliferative ROP11. The
preterm infants were evaluated
according to the protocol of screening
of ROP12. Initial examination was
performed by 31 weeks postmenstrual
or 4 weeks chronological age, which is
later. Follow up fundus examinations
once or twice a week until the eyes
were fully vascularized or until the
condition was stable. Diagnosis of
ROP was done by consultant
ophthalmologist by using indirect
ophthalmoscopy.
Abdel Wahab et al
with corticosteroids had been reported
to alter serum IGF-I in neonates16.
Venous blood samples (1 ml)
were obtained from both patients and
control groups. Sera were separated
and stored at -800C until the assay.
IGF-I assay
Serum levels of IGF-I were
measured by using radioimmunoassay
[RIA] (Mediagnost GmbH, Tuingen,
Germany). As the presence of IGF-Ibinding proteins in the serum interferes
in the RIA procedure, these proteins
were removed. Serum samples were
extracted with formic acid and acetone
as described previously 17. Because this
extraction method does not eliminate
all IGF-I-binding proteins present in
the serum acid-acetone extracts were
subjected to cryoprecipitation, a
procedure described previously 17. The
mean recoveries of iodinated IGF-I
added to the serum were 90.5%. The
Tris-neutralized serum extracts were
diluted with RIA buffer containing
0.02% protamine sulfate and 0.05%
Tween-20. Diluted seum extracts
(1:50) were used in this RIA. The
purified recombinant human IGF-I
preparation purchased from Amgen,
Inc. (Thousand Oaks, CA) was used as
the reference preparation, and human
IGF-I (A52–8MH-144; Eli Lilly &
(B) Patients with BPD:
Bronchopulmonary dysplasia
and chronic lung disease (CLD) are
still
used
in
the
literature
interchangeably, however, CLD is
considered as stage IV of BPD
according to Northway stages of
BPD13. Diagnosis of BPD was based
on the typical appearance of BPD on
serial chest radiographs13. Diagnosis of
CLD was based on the need of preterm
infants for oxygen supplementation at
36 weeks postconception14. Patients
with BPD who enrolled in the study
had stage II or III.
Co., Indianapolis, IN) was
iodinated and used as trace. Antiserum
prepared against human IGF-I was
used in this RIA. All serum extracts
were included in the same assay to
avoid interassay variability and IGF-I
was measured in duplicate by a IGF
radioimmunoassy of around 250-fold
excess of IGF17.
(C) Patients with NEC:
Diagnosis of NEC was done
according to modified Bell’s criteria
and staging for NEC. It depends on
clinical, radiological and laboratory
findings15.
Preterm infants with congenital
anomalies or had been given corticosteroids for more than 14 days were
excluded from the study. Treatment
VEGF assay
Serum VEGF levels were
determined using a sensitive sandwich
ELISA (R&D Systems, Minneapolis,
29
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
MN, USA). A quantitative enzyme
immunoassay was performed using
micro-well plates pre-coated with
monoclonal antibody. For each study
participant, 100 µl of serum or
standards were added to the wells and
the unbound materials were washed
off. An enzyme-linked polyclonal
antibody that is specific for human
VEGF was added, and unbound
antibody was removed by washing the
plate.
Tetramethylbenzidine and
hydrogen peroxide was added to the
wells, developed, and read on a microplate spectrophotometer at 450-nm
wavelength. All analyses were
performed in duplicate. Concentrations
were expressed in pg/ml. The detection
limit of the VEGF assay was 9 pg/ml.
Abdel Wahab et al
III (n = 18) and the third group had
necrotizing enterocolitis (n = 13). Of
the 31 patients with ROP, 19 had nonproliferative (stage I & II) ROP and 12
had proliferative (stage III & IV) ROP.
No infant developed ROP stage V.
Characteristics of patients and controls
are shown in table 1.
Serum levels of IGF-I were
significantly lower (p < 0.001) in
preterm infants with complications of
premature birth than in the control
group, however serum levels of VEGF
were significantly higher (p < 0.001) in
patients than in the controls (figure 1).
Among infants complicated with ROP,
serum levels
of
IGF-I were
significantly lower (p< 0.001) in
patients with non-proliferative ROP
than in those with proliferative ROP.
We found that serum levels of VEGF
were significantly higher (p< 0.001) in
infants who had proliferative ROP than
in those with non-proliferative disease
as shown in table 2.
Statistical analysis:
Values were expressed as mean
+ standard deviation (SD). The
significance of comparison between
mean values of two groups was
evaluated by student t-test. However,
the significance of comparison
between more than one group was
performed by ANOVA for parametric
continuous variables. Simple Pearson
correlation coefficient was calculated
to quantify the correlation between
serum levels IGF-I and VEGF in
preterm infants with ROP. Significant
differences were denoted by p < 0.05.
Statistical analysis was performed by
using the (SPSS) software.
RESULTS:
We studied 62 preterm infants
with complications of premature birth
in addition to 22 preterm neonates of
matched gestational age and sex
(without complications) as a control
group.
Preterm
infants
with
complications of prematurity were
divided into 3 groups; the first group
developed retinopathy of prematurity
(n = 31), the second group had
bronchopulmonary dysplasia stage II &
In BPD group, serum levels of
IGF-I were significantly lower in
patients than in the control group.
Serum levels of VEGF were
significantly higher in infants with
BPD than in those without this
morbidity (figure 2).
Figure 3 shows the serum
levels of IGF-I and VEGF in preterm
infants who developed NEC. Serum
levels of IGF-I were significantly
lower (p< 0.001) in patients with NEC
than in the control group. Regarding
serum levels of VEGF, we found no
significant difference between patients
and controls.
There was a significant positive
correlation between IGF-I and VEGF
(r= + 0.736; p<0.05) in preterm infants
with ROP..
30
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
Abdel Wahab et al
Table 1. Characteristics of patients and controls
NonProliferative
BPD
proliferative
ROP
(Stage II &III)
ROP (Stage I, II) (Stage III, IV)
(n = 18)
(n = 19)
(n = 12)
Gestational age, weeks
Mean + SD
Range
Birth weight, gram
(Mean + SD)
Sex;
Male, n (%)
Female, n (%)
28.5 + 1.5
26-31
26.9 + 1.0
25-29
28.5 + 1.3
26-30
971.8 + 155.5
842.1 + 142.9
10 (53)
9 (47)
7 (58)
5 (42)
NEC
(n = 13)
Controls
(n = 22)
28.5 + 1.8
26-33
28.9 + 1.7
26-32
958.3 + 153.5 1006.5+ 176.6
9 (50)
9 (50)
994.3 + 203.7
7 (54)
6 (46)
70
*
60
Serum level
50
40
Control
Patients
30
*
20
10
0
IGF-1 (mg/L)
VEGF (Pg/ml)
Figure 1. Serum levels of IGF-I and VEGF in preterm infants with complications
(ROP, BPD, NEC) (n = 62) and controls (n = 22). * p < 0.001
Table 2: Serum levels of IGF-I and VEGF in preterm infants with ROP and controls
IGF-I (ug / L)
VEGF (Pg / ml)
Non-proliferative
ROP (Stage I, II)
(n = 19)
Proliferative ROP
(Stage III, IV)
(n = 12)
Controls
(n = 22)
11.2 + 3.8
49.2 + 4.1
20.8 + 2.5
77.9 + 7.2
40.8 + 3.5*
32.7 + 5.4*
Values are mean + SD ; * p < 0.001
31
12 (55)
10 (45)
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
70
Abdel Wahab et al
*
60
serum levels
50
40
30
Control
BPD
*
20
10
0
IGF-1 (mg/L)
VEGF (Pg/ml)
Figure 2. Serum levels of IGF-I and VEGF in preterm infants with BPD (Stage II
&III) (n = 18) and controls (n = 22). * p < 0.001
50
**
45
40
Serum level
35
30
25
Control
*
NEC
20
15
10
5
0
IGF-1 (mg/L)
VEGF (Pg/ml)
Figure 3. Serum levels of IGF-I and VEGF in preterm infants with NEC
(n = 13) and controls (n = 22). * p < 0.001, **p = 0.04
significantly lower in patients with
non-proliferative than in those with
proliferative ROP. The critical role of
IGF-I system in retinal vascular
development had been confirmed in a
clinical study done by Hellstrom and
his colleagues where patients with
defects in IGF-I or IGF-I receptor gene
DISCUSSION:
Our study showed that serum
concentrations
of
IGF-I
were
significantly lower in preterm infants
with ROP than in those without this
complication. These data are in
consistent with the results of studies
done by Smith18 and Lofqvist19. We
found that serum levels of IGF-I were
32
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
were found to have a reduced number
of retinal vascular branching points20.
Abdel Wahab et al
confirming the central role of VEGF in
neovascular eye disease25-27. Our data
showed that serum levels of VEGF
were statistically higher in preterm
infants with ROP than in those without
the disease. Also we found higher
serum concentrations of VEGF in
infants with proliferative than those
with non-prolifrative ROP and these
findings are in accordance with the
results of study that was conducted by
Brady-MacCreery28.
Our
results
support the role of VEGF in the
genesis of ROP especially the
proliferative phase of the disease.
Smith reviewed the significant
role of low serum IGF-I concentration
in the genesis of ROP. Since the
proliferative phase of ROP is induced
by retinal hypoxia consequent to the
retinal vascular growth arrest of the
first phase in which low serum IGF-I
concentration plays a pivotal role,
Smith proposed that the second
proliferative phase would not occur if
the first phase was prevented3. Our
results support that in preterm infants,
early restoration of IGF-I to levels
similar to those present in utero might
prevent ROP by promoting normal
vascular development. This perhaps
could be accomplished by assuring
sufficient nutrient intake.
We found a significant positive
correlation between serum levels of
IGF-I and VEGF in preterm infants
with ROP. Also we noticed that serum
levels of IGF-I were significantly
higher in patients with proliferative
than in those with non-proliferative
ROP. These findings indicate that IGFI is important and VEGF alone may
not be sufficient for promoting
vigorous retinal angiogenesis.
IGF-I is a nutrient-dependent
factor (e.g. diary products and
germinated barley), insufficient intake
of nutrients will result in a further
decline of this peptide. Sufficient
nutrient intake during pregnancy is
important to reduce the risk of ROP21.
Early breast feeding may be
particularly beneficial at it has been
shown that breast milk contains
available amount of IGF-I22.
Alexander in his study tried
administration of insulin-like growth
factor binding protein-3 (IGFBP-3) to
preterm babies and found that it
stabilized the existing vessels in the
retina, also block the neovascularization. So administration of this
protein to preterm infants might
prevent ROP damage23.
In
murine
mouse
of
retinopathy, it was shown that IGF-I
enhances the production of VEGF by
using IGF-I receptor antagonism which
inhibited retinal neovascularization by
decreasing the expression of both
VEGF and VEGF receptors29. Also
IGF-I regulates VEGF stimulation of
Akt / PKB (protein-kinase B) phosphorylation, which is central in the
signaling pathway of cell proliferation30.
Chronic lung disease is
considered as stage IV of BPD
according to Northway stages of
BPD13. Our study showed that serum
concentrations
of
IGF-I
were
significantly lower in preterm babies
who developed BPD (stage II or III)
than in those without this complication.
These results are in consistent with
In the mouse, retinal hypoxia
stimulates an increase in the expression
of VEGF before the development of
neovascularization4,24. Other investigators have also shown that VEGF is
associated with ocular neovascularization in other animal models,
33
EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008
those of studies done by Pierce31,
Chetty32 and Capoluongo33. We found
that serum levels of VEGF were
significantly higher in patients with
BPD (stage II or III) than in preterm
infants without this morbidity. Lung
blood vessels actively promote alveolar
growth during development and
contribute to the maintenance of
alveolar
structures
throughout
postnatal
life.
Disruption
of
angiogenesis impairs alveolarization
and preservation of vascular growth
and endothelial survival promotes
growth and sustains the architecture of
the distal airspace7.
Abdel Wahab et al
and gut of the preterm infants so could
prevent BPD and NEC.
High serum VEGF levels predict
retinal neovascularization or phase II
ROP and carry poor prognosis. AntiVEGF therapy may be a promising
strategy for treating retinal neovascular
proliferation
which
can
cause
blindness.
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464-9
‫ ومعامل نمو األوعية الدموية كعوامل تنبؤ فى‬1-‫”معامل النمو المماثل لألنسولين‬
“‫األطفال الخدج المصابين باعتالل شبكية العين ومضاعفات الوالدة المبكرة‬
3
‫أحمد محفوظ‬.‫د‬.‫ أ‬,2‫ وليد نيا زى‬.‫ د‬.‫أ‬,1‫وليد عبد الوهاب عيد‬.‫د‬
‫المملكة‬-‫ أبها‬-‫جامعة الملك خالد‬-‫ كلية الطب‬-3‫ الصحة العامة‬,2‫ الكيمياء الحيوية‬,1‫طب األطفال‬
‫العربية السعودية‬
:‫خلفية وهدف البحث‬
‫يعتبر مرض اعتالل شبكية العين فى األطفال الخدج (غير مكتملي العمر الرحمي) من‬
‫ ومعامل نمو‬1-‫ معامل النمو المماثل لألنسولين‬.‫األمراض الخطيرة التى قد تؤدى إلى العمى‬
‫ والهدف من وراء‬.‫األوعية الدموية ضروريين لنمو وتطور األوعية الدموية بشبكية العين‬
‫البحث هو قياس مستوى هذان العامالن فى دم األطفال الخدج المصابين بمضاعفات الوالدة‬
‫المبكرة ومنها اعتالل شبكية العين و اعتالل الرئة والقصيبات الهوائية وأيضا االلتهاب المعوي‬
.‫المتحلل وكذلك التعرف على دورهم في التنبؤبتلك المضاعفات‬
:‫طريقة البحث‬
‫ أسبوع وكانت‬32-25 ‫ تراوحت أعمارهم الحملية بين‬, ‫ طفال خديجا‬62 ‫شملت الدراسة‬
:‫ قسم هؤالء األطفال إلى ثالث مجموعات‬.‫ جرام‬1200-640 ‫أوزانهم عند الوالدة بين‬
18 ‫ طفال مصابا باعتالل الشبكية و المجموعة الثانية وشملت‬31 ‫المجموعة األولى وشملت‬
‫ طفال‬13 ‫طفال مصابا باعتالل الرئة والقصيبات الهوائية والمجموعة الثالثة والتى احتوت على‬
36
‫‪Abdel Wahab et al‬‬
‫‪EL-MINIA MED., BULL., VOL. 19, NO. 1, JAN., 2008‬‬
‫مصابا بااللتهاب المعوي المتحلل‪ .‬كما اشتملت الدراسة على عدد ‪ 22‬طفال من األطفال الخدج‬
‫الغير مصابين بمضاعفات الخداجة ولهم نفس الجنس والسن كمجموعة ضابطة‪ .‬من بين األطفال‬
‫المصابين باعتالل شبكية العين ‪ ,‬كان هناك عدد ‪ 19‬طفال مصابا بدرجة متوسطة من اعتالل‬
‫الشبكية و ‪ 12‬طفال مصابا بدرجة شديدة من المرض‪.‬‬
‫تم قياس مستوى معامل النمو المماثل لألنسولين‪ 1-‬ومعامل نمو األوعية الدموية فى الدم لكال‬
‫المجموعتين التجريبية والضابطة بواسطة اختبار اإلشعاع المناعي‪.‬‬
‫نتائج البحث‪:‬‬
‫أظهرت الدراسة انخفاض مستوى معامل النمو المماثل لألنسولين‪ 1-‬فى دم األطفال المصابون‬
‫بمضاعفات الخداجة عند مقارنتهم بالمجموعة الضابطة‪ .‬وكان هذا االنخفاض أكبر فى األطفال‬
‫المصابين بدرجة متوسطة من اعتالل الشبكية عن اآلخرين المصابين بالدرجة الشديدة من‬
‫االعتالل‪ .‬كما أظهرت النتائج ارتفاع مستوى معامل نمو األوعية الدموية فى دم األطفال‬
‫المصابون بمضاعفات الخداجة عن أطفال المجموعة الضابطة‪ ,‬وكانت نسبة االرتفاع أكبر فى‬
‫األطفال المصابين بدرجة متقدمة من اعتالل الشبكية عن األطفال المصابين بدرجة متوسطة من‬
‫هذا المرض‪.‬وكانت لكل تلك الفروق دالالت إحصائية واضحة‪ .‬فى هذه الدراسة الحظنا وجود‬
‫عالقة إيجابية ذات داللة إحصائية بين مستوى معاملي النمو فى مجموعة األطفال المصابين‬
‫باعتالل شبكية العين‪.‬‬
‫اإلستنتاجات‪:‬‬
‫انخفاض مستوى معامل النمو المماثل لألنسولين‪ 1-‬فى األطفال المصابين باعتالل الشبكية له‬
‫أهمية فى توقع حدوث المرض لذا معالجة هذا اإلنخفاض قد يمنع حدوث االعتالل ومضاعفاته‬
‫كما انه يساعد على منع مضاعفات الخداجة األخرى‪ .‬ارتفاع مستوى معامل نمو األوعية‬
‫الدموية فى األطفال المصابين بدرجة متقدمة من اعتالل شبكية العين يشير إلى دوره فى تحديد‬
‫األطفال المعرضين لحدوث المضاعفات وإعطاء الدواء المضاد لعامل نمو األوعية الدموية فى‬
‫تلك المرحلة من اعتالل الشبكية قد يكون له دور فى المستقبل فى منع حدوث العمى عند هؤالء‬
‫األطفال‪.‬‬
‫‪37‬‬