The Impact of Growth and Growth Factors for Vascular and Neural Development in Preterms

Despite significant improvement in neonatal intensive care the number of preterm children with severe visual impairment is increasing. Retinopathy of prematurity (ROP) is a major
cause of blindness in children in the developed and developing world, despite current
treatment of late-stage ROP. Approximately 40% of perinatal blindness can be attributed to
ROP. A recent Swedish study demonstrated that one third of the boys born below 25 weeks of
gestational age became visually impaired or blind due to ROP and/or cerebral dysfunction
(Jacobson et al. 2009).
Angiogenesis is a complex process involving changes in many metabolic pathways. Our
research group has found a strong association between the circulating growth factor Insulinlike
growth factor 1 (IGF-I), postnatal growth and development of vascular and neural
elements in preterm infants. Ours and others findings on this topic will be presented in detail
below.
IGF-I and foetal growth
IGF-I is a polypeptide, which resembles insulin in its molecular structure. In humans IGF-I is
primarily produced by hepatocytes in the liver and the production is regulated by pituitary
growth hormone. IGF-I exists extra-cellular and is bound to and controlled by six insulin-like
growth factor binding proteins. Seventy-five percent of the IGF-I is bound to insulin-like
growth factor binding protein 3 (IGFBP-3) together with an acid labile subunit (ALS). The
insulin-like growth factor binding proteins can either inhibit, or potentiate cellular IGF-I
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responses, and influence distribution and elimination of IGF-I. The cellular actions of IGF-I
are mediated through binding of IGF-I to the IGF-I receptor, which is located on the surface
of different cell types in all tissues. IGF-I can also bind to the insulin receptor, but at a much
lower affinity than insulin.
IGF-I is of major importance for foetal growth and is synthesized by all foetal tissues early in
gestation, and the placenta is actively involved in regulating circulatory foetal levels of IGF-I.
Concentrations of foetal IGF-I are closely related to placental transfer of nutrients. The
disruption of placental nutrient supply as well as amniotic supply at birth is followed by a
rapid decline in levels of IGF-I. During pregnancy thyroxine plays a more important role than
pituitary growth hormone in the regulation of foetal IGF-I, but after birth IGF-I is regulated
by pituitary growth hormone.
IGF-I is related to nutrition, birth weight and gestational age (Hellström et al. 2003) .
Nutrition is an important environmental factor influencing IGF-I levels. At very preterm birth
the IGF-I levels of the newborn decrease abruptly, and do not reach normal intrauterine values
for several weeks/months (Engström et al. 2005), in contrast to term infants who restore their
serum levels of IGF-I in a few days. A recent study found a dramatic decrease in the
circulating serum levels of IGF-I and its major binding protein, IGFBP-3 in very preterm
infants and that inflammation at birth with increased cord levels of pro-inflammatory
cytokines was associated with a decrease in IGF-I (Hansen-Pupp et al. 2007). The important
role of nutrition for the foetal IGF-I levels was demonstrated in an animal study of foetuses of
pregnant rats, who were fasted during the last days of gestation, and the serum IGF-I levels
were 30 % lower than in the control foetuses (Davenport et al 1990).
IGF-I and brain development
IGF-I acts directly on the brain and promotes differentiation, proliferation and maturation of
progenitors of neural stem cells, and has anti-apoptotic properties (Ye & D’Ercole 2006).
Oligodendrocyte maturation is crucial for myelination as mentioned above, and several
studies on mice and other rodents have shown an important role of IGF-I in differentiation of
oligodendrocyte progenitor cells (Ye & D’Ercole 2006). In vitro, IGF-I has been found to
promote remyelination and cerebellar Purkinje cell development. In addition, a relationship
has recently been shown in preterm infants between cerebellar volume and serum IGF-I
(unpublished data).
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IGF-I may also play an important role in the stimulation of postnatal brain growth. Overexpression
of IGF-I in mice stimulated the brain growth and ameliorated the brain growth
even in the face of under-nutrition, and IGF-I protected myelination in cases with undernutritional
insults. A relationship between low circulating levels of IGF-I, the development of
ROP, and poor development of head circumference in preterm infants has also been
documented (Löfqvist et al. 2006). IGF-I is essential for the development of normal
vascularisation of the human retina as mentioned above (Hellström et al. 2001, Hellström et
al. 2002), and promotes the angiogenesis in the brain (Lopez-Lopez et al. 2004). In the study
by Lopez-Lopez and co-workers (2004) systemic injections of IGF-I in adult mice increased
the brain vessel density.
A gender difference in IGF-I levels, where boys had lower levels than girls, has been shown
in preterm (GA < 32 weeks) infants (Engström et al. 2005).
IGF-I and retinal development in prematurity
Ocular growth is influenced by IGF-I and treatment with IGF-I increases the ocular axial eye
length in patients with short axial lengths due to growth hormone insensitivity (Laron
syndrome).
In infants born prematurely the retina is not fully vascularised. The more premature the child,
the larger is the avascular area. The sudden loss of nutrition and growth factors necessary for
normal growth at preterm birth causes the vascular growth that would normally occur in utero
to slow down or cease. In addition, the relative hyperoxia of the extra-uterine milieu together
with supplemental oxygen cause a regression of already developed retinal vessel. IGF-I is
necessary for normal development of retinal blood vessels (Hellström et al. 2002).
Preterm birth is associated with a rapid fall in IGF-I, and the baby often suffers from
immaturity, poor nutrition, acidosis, hypothyroxemia and sepsis which all may further reduce
the IGF-I levels. When the neural elements of the retina mature and need more oxygen, poor
vascularisation leads to hypoxia and production of vascular endothelial growth factor
(VEGF). If sufficient IGF-I is not available VEGF is accumulated, as a minimum level of
IGF-I is required for VEGF to induce vessel growth. When the IGF-I levels slowly increase
when the infant matures, and IGF-I reaches the minimum level for VEGF to promote vessel
growth, an excessive and uncontrolled neovascularisation may take place, see figure 1. The
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serum levels of IGF-I during the first weeks of life in the babies are inversely correlated with
the severity of ROP (Hellström et al. 2003).
In an experimental study on neonatal mice it was recently shown that exogenous administered
IGF-I attenuated retinopathy and improved weight gain as well as maturation
(Vanhaesenbrouck et al. 2009).
Hök Wikstrand et al (2009) recently demonstrated that preterm children had reduced neuronal
rim area of the optic disc and that this finding was associated with both low birth weight and
poor early postnatal growth. This indicates that early weight gain is important for neural
development of the visual system in preterm children. The same authors also found in preterm
infants that poor visual acuity and visual perception was correlated with poor early weight
gain and that the infants with hyperopia at school age had low neonatal serum IGF-1 levels
(Hök et al. 2010).
Figure 1. Schematic representation of IGF-I/VEGF control of blood vessel development in
ROP. (A) In utero, VEGF is found at the growing front of vessels. IGF-I is sufficient to allow
vessel growth. (B) With premature birth, IGF-I is not maintained at in utero levels, and
vascular growth ceases. (C) As the premature infant matures, the developing but nonvascularized
retina becomes hypoxic. VEGF increases in retina and vitreous. With
maturation, IGF-I level slowly increases. (D) When the IGF-I level increases, with high
VEGF levels in the vitreous, endothelial cell survival and proliferation driven by VEGF may
proceed. NV ensues at the demarcation line, extending into the vitreous, leading to retinal
detachment and blindness can occur. (Hellström et al 2001).
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Program to predict severe ROP
An association between poor postnatal growth and later development of ROP has earlier been
reported (Wallace et al. 2000).
Hellström and co-workers have recently developed a web-based program to predict which
children are at risk of developing the most severe form of ROP. This program named
WINROP combines in a highly novel way the use of neonatal data (weight) and biomarkers
(serum IGF-I levels) with statistical monitoring (Löfqvist et al. 2006). Löfqvist and coworkers
(2006) have verified the program’s ability to provide early and accurate identification
of children with the greatest risk of developing the disease ROP in a new follow-up study of
extremely preterm children (Löfqvist et al. 2009).
A further development and significant simplification of this program has resulted in
monitoring of the children’s postnatal weight gain only in order to predict the development of
severe ROP. This simplified approach was recently published and confirmed that WINROP
correctly identified the very premature children at high risk of developing severe ROP
(approx. 15%) and also correctly excluded those children who did not develop the disease
(approximately 75%) (Löfqvist et al. 2009).
In addition, we have successfully validated WINROP in cooperation with the
neonatal/ophthalmology wards at Brigham and Women in Boston (Wu et al. 2010) and at the
Departments of Ophthalmology and Pediatrics, Hospital de Clínicas de Porto Alegre, Federal
University of Rio Grande do Sul, Brazil (Hård et al. 2010).
WINROP provides a tool to identify infants at risk for sight threatening ROP. We believe that
additional NICU data from developing countries will help in modifying the algorithm for
these populations. The close association between poor neonatal weight development and ROP
indicates that optimizing growth may be one way to reduce ROP.
Conclusions
In summary, for decades neonatal intensive care has focused on survival of the most
immature babies. The time has now come to find ways to optimize weight development and
normalize growth of vital structures such as vessels and neurons.
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