Nutrition, insulin-like growth factor-1 and retinopathy of prematurity

SUMMARY Retinopathy of prematurity is a potentially blinding disease starting with impaired retinal vessel growth in the neonatal period. Weeks to months later, peripheral retinal hypoxia induces pathologic neo-vascularization that may lead to retinal detachment and blindness. Current treatment strategies target late stage disease and it would be advantageous if retinopathy of prematurity could be prevented. Poor general growth after very preterm birth is a universal problem associated with increased risk of retinopathy. Loss of the maternal–fetal interaction results not only in loss of nutrients but also of other factors provided in utero. The importance of nutrition and factors such as insulin-like growth factor-1 and ω -3 long chain fatty acids for proper retinal vascularization has been defined in animal studies. Increasing evidence of the applicability of these findings to human infants is accumulating. This review focuses on factors essential for neonatal growth and possible strategies to improve growth and prevent retinopathy.


Introduction
For very preterm infants, the third trimester intrauterine milieu is replaced by an extrauterine environment for which they are poorly adjusted.At this stage, the central nervous system including the retina normally undergoes intense neurovascular growth and remodeling.In recent years, a strong association has been found between low serum insulin-like growth factor-1 (IGF-1) levels and poor weight gain during the first weeks of life and later retinopathy of prematurity (ROP).This review will explore the relationship between nutrition and these variables and possible therapeutic interventions to prevent ROP.

Retinopathy of prematurity
In the first phase of ROP there is retardation of retinal vessel growth and destruction of already formed vessels. 1 The first sign of transition to the second phase of ROP is a demarcation line between vascularized and avascular retina.With increasing severity, this line becomes a ridge 2 mainly composed of astrocyte precursors, possibly due to increased cell division or interrupted migration. 3Interestingly, hypoxic retinal ganglion cells secrete semaphorin 3A which directs vessels away from the hypoxic area. 4In severe ROP, uncontrolled growth of abnormal blood vessels into the vitreous may lead to retinal detachment and blindness.Treatment with laser or off-label use of anti-VEGF (vascular endothelial growth factor) molecules targets late stage disease at risk for retinal detachment but is only partially effective in preventing blindness and not effective at increasing the number of patients with good visual acuity.

Insulin like growth factor-1
IGF-1, which is nutrition dependent, is essential for brain, muscle, bone and vascular growth and remodeling pre-and postnatally, mediated mainly through the IGF-1 receptor (IGF-1R) and regulated by at least six IGF-binding proteins (BPs).IGFBP-1 and IGFBP-3 appear to be the most important for fetal growth regulation.IGFBP-1 reduces the availability of IGF in serum and is associated with growth inhibition. 5However, some isoforms of IGFBP-1 with less affinity for IGF-1 are found in amniotic fluid and in serum of mid-gestational fetuses 6 and have weaker growth-inhibiting or -promoting effects. 5IGFBP-3 binds IGF-1 with the acid labile subunit (ALS) in a ternary complex, prolonging half-life in the circulation.IGFBP-3 also has other IGF-1-independent protective actions on neurons and vessels. 7,8ring the third trimester, IGF-1 serum levels normally increase two-to three-fold. 9Rare human IGF-1 gene defects cause both pre-and postnatal growth retardation, sensorineural deafness, microcephaly, intellectual deficit and later adiposity. 10The importance of IGF-1 for fetal and neonatal growth was shown in studies of IGF-1 knock-out mice that had a birth weight of 60% of normal and growth retardation after birth resulting in mice with 30% of normal weight after 8 weeks. 11,12Circulating IGF-1 is mainly produced by the liver, but IGF-1 is also secreted by almost all cells at some time during development.The roles of circulating versus locally secreted IGF-1 in somatic and brain growth are only partly known.
To address this problem, mouse models were developed that lack either liver-derived IGF-1 or IGF-1 produced in other organs.Without liver-derived IGF-1, but with normal expression in non-hepatic tissue, growth is not affected, suggesting that growth is mediated by autocrine/paracrine actions of IGF-1 as well as by non-liver sources of circulating IGF-1. 13owever, when IGF-1 production in all organs except liver is blocked, endocrine IGF-1 then plays a very significant role in mouse growth.The authors propose that the actions of circulating and local IGF-1 are largely interchangeable, so that mice maintaining either appear normal. 14 mice, IGF-1 half-life in serum varies with binding.In the ternary complex (IGF-1/ IGFBP-3/ALS) IGF-1 half-life was 10-16 h; in the binary complex (IGFBP-3) it was 30-60 min and for free IGF-1 it was 10 min. 15w information about the roles and mechanisms of IGF-1 actions in the central nervous system has emerged.IGF-1 is expressed by all cells in the brain with the highest expression in the perinatal period. 16In addition, circulating IGF-1 enters the brain through the bloodbrain barrier, corresponding to the blood-retina barrier in the eye, through a transport mechanism mediated by astrocytes.Central nervous system IGF-1 entry is dependent on neuronal activity and directed to activated areas. 17In the developing brain, IGF-1 regulates glucose metabolism by mechanisms similar to those by which insulin controls peripheral glucose utilization. 18IGF-1 has profound effects on neuronal differentiation, growth and neuronal plasticity, thus influencing the cellular substrate for cognition. 19ring pregnancy, the mother provides oxygen and essential nutrients to the fetus via the placenta, regulating fetal growth.IGF-1 levels in fetal serum (obtained at cordocentesis) increase with gestation and correlate with fetal size. 9,20

Normal fetal retinal vascularization
Retinal vascularization starts at ~12 weeks of gestational age at the optic nerve.The area immediately anterior to the vasculature is densely populated with astrocyte precursors, which first appear in the optic nerve and retina at 8 weeks and extend to the retinal periphery at 28 weeks with reduced density by 32 weeks. 21Astrocytes are intimately associated with blood vessels during vascularization which initially occurs by vasculogenesis or blood vessel formation from vascular precursor cells which are restricted to the central two-thirds of the retina. 22The expansion of the vascular network then proceeds through angiogenesis or budding from formed vessels.Increased metabolic demands of the maturing retinal neurons anterior to the vascular front result in an expanding wave of 'physiological hypoxia', which induces expression of vascular endothelial growth factor (VEGF), which stimulates vascular growth, and the wave moves forward. 23In the retina, IGF-1 controls VEGF-mediated vascular growth 24 by controlling the MAPK and Akt pathways, critical to endothelial cell proliferation and survival, possibly by mediating a switch from antiangiogenic to angiogenic VEGF isoforms. 25A minimum level of IGF-1 is needed for maximum VEGF signaling of Akt and MAPK. 24

Animal studies
Rodents have commonly been used for studies of oxygen-induced retinopathy (OIR) in the neonatal period.Mice and rats are born with almost avascular retinas (similar to a human of gestational age 5 months) and retinal vascularization mainly takes place during the first weeks of life.Exposure of mice or rat pups with incomplete retinal vascularization to high oxygen levels results in loss of retinal vessels followed by pathologic neo-vascularization after return to room air. 26 1956 the Swede Bo Hellström reported that poor nutrition in mouse pups resulted in poor weight gain and also in slightly reduced growth of retinal vessels.Exposure to 98-100% oxygen almost completely stopped vessel outgrowth irrespective of the state of nutrition.Poor neonatal growth followed by later catch-up growth, which is common in preterm infants, appeared to be associated with increased risk of retinopathy in mice, as had been noted in 1953 by Lubchenco in infants. 27Poorly fed newborn mice exposed to 10 days of oxygen, then returned to room air for 10 days, developed pathological neovascularization in only two out of 12 pups, whereas 12 out of 12 pups that were undernourished during oxygen exposure but received a normal diet thereafter had extra-retinal neovascularization. 28terestingly, in a rat OIR model, starvation affected the outgrowth of the vasculature more than growth of the retina, resulting in a smaller ratio of vascularized-to-total retina.Underfed pups also developed more neovascularization than well-fed pups.A smaller area of normal vascularization was associated with higher incidence and severity of abnormal neovascularization.This study agrees with other reports that the size of the peripheral avascular zone determines the incidence of, and severity of, neo-vascularization in rats exposed to variable oxygen. 29,30idosis in the neonatal period results in acidosis-induced retinopathy (AIR), similar to OIR.AIR also results in more neo-vascularization in underfed versus normally fed rat pups. 31Recently, OIR in mice with poor weight gain showed a delayed onset and prolonged course of neovascularization and VEGF expression. 32F-1 knock-out mice lack IGF-1 both before and after birth and have impaired retinal vessel growth.24 Vanhaesebrouck et al. 33 showed that postnatal undernutrition in wild type OIR mice was associated with reduced weight gain, low serum IGF-1 and more severe neovascularization compared with normally fed peers.Importantly, when underfed mice were treated with recombinant human (rh) IGF-1, growth and maturation increased and OIR decreased.33 This agrees with the finding that IGF-1 ameliorates growth in states of undernutrition by improving food utilization. 34

Clinical studies
For the newborn infant, normal weight gain after birth indicates health.Unfortunately, postnatal growth retardation is a major problem in very preterm infants (normalized for gestational age and sex) resulting in lower-weight standard deviation score (SDS) at discharge versus SDS at birth. 357][38][39] In the Swedish national EXPRESS study of infants with gestational age <27 weeks, weight SDS at 36 weeks of postmenstrual age was highly negatively associated with proliferative ROP 40 (Fig. 1 41,42 ).
Serum concentrations of IGF-1 fall sharply after very preterm birth.In two studies of 136 infants with gestational age between 24 and 32 weeks at birth, the decreased level and duration of low IGF-1 values during 30-33 weeks of postmenstrual age were correlated with ROP severity (Fig. 2). 41,42

The screening algorithm 'WINROP'
Current screening for ROP is based on gestational age and birth weight.Since the vast majority (~90%) of infants who undergo repeated painful examinations for ROP require no treatment, better selection of infants at risk is urgently needed.Since weight gain and serum IGF-1 levels are associated with later ROP we developed the ROP prediction algorithm Weight IGF-1 Neonatal ROP (WINROP).WINROP was constructed to detect deviations between the rate of weight and serum IGF-1 gain of 13 infants with proliferative ROP versus 38 infants with no or mild ROP using online statistical surveillance (www.winrop.com). 43n alarm is shown when the accumulated deviation reaches a certain level before a PMA of 33 weeks.Since serial blood tests are needed for IGF-1 analyses and weight gain reflects IGF-1 levels, we tested whether WINROP could predict ROP using weight gain alone.Infants with hydrocephalus were excluded since their weights partly reflected accumulation of fluid in the head.In this retrospective study of 353 infants with weekly weights, but no IGF-1 values, WINROP correctly identified all infants with later proliferative ROP with sensitivity of 100%.Specificity was 84.5%.5][46][47][48] WINROP has provided new information concerning the importance of early postnatal weight gain, which gives us a better understanding of ROP pathogenesis and allows modification of traditional screening for both low and 6.Why is it so hard to achieve good neonatal growth in very preterm infants?
Very preterm infants frequently become growth-restricted after birth and nutritional strategies to improve growth have not been optimized.The recommended amounts of nutrients are seldom given.In addition, the optimal growth velocity is not known and currently recommended rates of growth appear to be too low.In the US multicenter Extremely Low Gestational Age Newborn (ELGAN) study of 1506 infants born between 23 and 27 6 / 7 gestational weeks, less nutrition was provided than was recommended.Although current growth velocity goals were reached, 75% of the infants had a weight below the 10th centile at 28 days compared to 18% at birth (Fig. 3). 49Ehrenkranz et al. 50followed the weight gain of 1660 infants with birth weight of 501-1500 g.Most of the infants born at gestational age 24-29 weeks had not achieved the median birth weight of the reference fetuses of the same PMA at discharge.Infants with major morbidities grew even more slowly than healthier infants. 50The etiology of the postnatal growth restriction in pre-term infants is multifactorial and only partly known.The following contributing factors will be discussed: • increased frequency of intrauterine growth restriction • oxygen treatment.

Intrauterine growth restriction
Intrauterine growth restriction increases the risk of preterm birth as demonstrated in the ELGAN study where 18% of infants were growth-restricted (weight <10th centile) already at birth. 49

Increased metabolic rate
The postnatal metabolic rate of the preterm infant is higher than that of a fetus in utero surrounded by its mother with a metabolic rate similar to hers.In mammals, small size is associated with increased metabolism presumably to compensate for heat loss through a relatively larger surface area.Preterm infants undergo a prolonged adaptation to an extrauterine metabolism appropriate for size resulting in increased calorie demands compared to those of a fetus of the same age. 51Energy requirements are also higher in infants with diseases associated with preterm birth such as chronic lung disease. 52

Insufficient nutrition
Premature birth results in loss of the placenta, the amnion and amniotic fluid which is rich in nutrients and growth factors including IGF-1.Amniotic fluid is normally swallowed by the fetus and contributes to fetal growth. 53,54After very preterm birth, immaturity of the gastrointestinal tract including the liver and pancreas and other organs prevents sufficient enteral feeding which is important for gut maturation. 55Total parenteral nutrition contains some basic nutrients but lacks other factors, many probably unknown, which are normally provided in utero.

Low serum IGF-1 concentrations
IGF-1 serum levels fall rapidly after preterm birth, due to loss of the maternal-fetal interaction.Since liver IGF-1 synthesis is mainly regulated by energy and amino acid availability, low serum levels are a natural consequence of the poor initial nutrient intake of most very preterm infants.However, other factors may contribute to low circulating IGF-1.Since neuronal activity in the brain has been found to result in the passage of IGF-1 from the circulation to the brain 17 and preterm birth exposes the infant to light and visual stimulation as well as other sensory stimulation earlier than normally, one might speculate that the passage of IGF-1 from the circulation into the brain is increased compared to intrauterine.

ω-3 polyunsaturated fatty acids
During the third trimester, a massive transfer of long chain polyunsaturated fatty acids (LCPUFAs) from the mother to the fetus takes place.Docosahexaenoic acid (DHA), an ω-3-LCPUFA derived from cold water algae and oily fish, is the predominant fatty acid of membrane phospholipids in the brain gray matter and the retina, and the only ω-3-LCPUFA present in significant amounts in the brain.In the third trimester, there is a massive placental transfer of DHA from the mother to the fetus during the time of rapid formation of synapses and dendritic spines and development of retinal photoreceptor cells. 56The lipid bilayers of rod photoreceptors are made up of phosphoglycerides with >50% DHA.Absolute accretion of DHA in the brain is greater before than after term birth. 57Since the capacity to synthesize DHA is very limited in humans, especially in infants, it needs to be provided in the diet. 58,59HA is not merely a structural component of cell membranes but is essential for proper function of membranes.Dietary DHA is needed for optimal functional maturation of the retina and visual cortex and prevents photoreceptor apoptosis during early development (in vitro) and during oxidative stress. 60,61DHA is a major component at the synaptic site, modulating the uptake and release of neurotransmitters.
At preterm birth, DHA provided via the placenta is no longer available and the infant's reserves are insufficient. 57In a study of infants with gestational age 24-29 6 / 7 weeks, the blood DHA level at birth was 6.9 ± 0.2 mol% with little variation between gestational ages and similar to those found in term infants.Parenteral lipid infusion with soybean-oil based Intralipid (Fresenius Kabi, Bad Homburg, Germany) was started day 2 and most infants still received some parenteral nutrition at 2 weeks of age.The meanDHA level fell by ~40% at week 1 and then remained low for at least 4 weeks postnatally (Fig. 4).Later full enteral feeding with breast milk or DHA-supplemented formula could not overcome the blood DHA deficit after birth. 62 mice with OIR (75% oxygen days P7-12), the pups of dams fed a diet rich in ω-3 LCPUFAs compared to those fed a diet rich in ω-6-LCPUFAs had the same degree of vascular development at P6 and vaso-obliteration at P12, but had less avascular retinal area from P13 to P17 and less pathologic neovascularization at P17, indicating that ω-3-PUFA increased revascularization of avascular retina, suppressing neovascularization. 63 the retina, ω-6-PUFA increases activated microglial production of tumour necrosis factorα, whereas this production is reduced by elevated ω-3 possibly due to the protective effects of the ω-3 PUFA-derived resolvins and neuroprotectins. 63ω-3-PUFA also directly suppresses neovascularization through the anti-angiogenic effect of the 5-lipoxygenasederived DHA metabolite 4-hydroxy-DHA, mediated through the peroxisome proliferatoractivated receptor (PPAR)-γ receptor.Administration of ω-3PUFAs exclusively during the neovascular stage, at P14-17 strongly decreased the neovascular activity of the retina via PPAR-γ-dependent reduction of inflammatory mediators and attenuation of endothelial cell activation. 64,65 a recent Polish study, infants with birth weight <1250 g born before gestational age 32 weeks, needing total parenteral nutrition from day 1, received a lipid emulsion consisting of equal parts of 20% Clinoleic (soy bean and olive oil) (Baxter SA, Norfolk UK) and 10% Omegaven [with fish oil (DHA)] (Fresenius Kabi AG).A historic control group received Clinoleic only.The frequency of retinopathy in the two groups was similar, 32.5 versus 36.3%.However, regression of disease was more frequent in the Omegaven-treated group and fewer needed laser treatment. 66enty years ago, Martinez suggested that parenteral lipids and milk formulas should be enriched with DHA to provide 0.5-1.0% of total fatty acids, with preterm infants especially sensitive to the effect of dietary fatty acid imbalances. 67Nowadays formulas for enteral use in preterm infants are commonly DHA-supplemented.However, for parenteral use during the first weeks of life, Intralipid is the most used lipid source, resulting in severe DHA deficiency during the first postnatal week. 62The newer emulsion Clinoleic contains even less DHA than Intralipid (0.23% versus 0.34%). 68

Parenteral nutrition, breast milk and formula
Normally, loss of the placenta and amnion is immediately followed by ingestion of mother's colostrum and milk which provides unique nutrients including DHA 69 and hormones and growth factors including IGF-1. 70Colostrum contains very high concentrations of IGF-1 which decline during the first days of life. 71Very preterm infants often require more nutrients than can be provided by enteral feeding during the first postnatal weeks and parenteral nutrition in the neonatal period is frequently performed.Duration of parenteral nutrition has been recognized as a risk factor for ROP. 72Contradictory results have been reported regarding breast-feeding and ROP risk possibly partly due to differences in study design.Protective effects have been found in some studies [73][74][75][76] whereas other authors reported no association between human milk feedings and ROP. 77Current recommendations of mother's milk as the best source of nutrition for preterm infants precludes randomized controlled trials comparing breast milk and formulas.

Inositol
Inositol insufficiency is associated with ROP. 78This carbohydrate is present in high concentrations in breast milk 79 and lower serum levels in preterm infants are found after prolonged parenteral nutrition. 80Administration of inositol to infants with respiratory distress syndrome, who received parenteral nutrition during the first week of life, is associated with decreased incidence of ROP. 81

Vitamin E
Preterm infants have an immature antioxidant system and are susceptible to oxidative stress.Vitamin E, a free radical scavenger, was tested to prevent ROP. 82High doses of vitamin E tended to decrease ROP and blindness but to increase the risk of sepsis. 83However, current enteral and parenteral nutrition options result in less vitamin E provided than recommended for very low birth weight infants. 73

Oxygen treatment
Hyperoxia is clearly a risk factor for ROP.Fluctuating oxygen levels appear to be as harmful or more than constant hyperoxia. 84Interestingly, rat pups exposed to hyperoxia interrupted by clustered episodes of hypoxia not only developed severe OIR but also low body weight and low systemic IGF-1 levels. 85

Possible therapeutic interventions to prevent ROP 10.1. Increased and optimized nutrition
Inappropriate fear of early amino acid administration stemming from a time when the first generation of amino acid solutions induced adverse reactions has resulted in early protein deficits in preterm infants.High doses of amino acids early are effective and safe.Early aggressive nutrition with amino acids and lipids is associated with higher levels of IGF-1 and IGFBP-3 at 40 weeks of PMA which are negatively associated with ROP. 86However, in a study of infants with gestational age <31 weeks, nutrient intake during the initial postnatal phase of growth retardation did not affect either serum IGF-1 or growth, but in the subsequent phase of catch-up growth starting ~30 weeks PMA, both serum IGF-1 and circulating IGF-1 were modified by nutrient intake.During the whole period, serum IGF-1 was associated with growth.The most immature infants experienced a more pronounced decrease in weight SDS and the growth retardation phase was prolonged although this could not be explained by lower accumulated nutritional intake. 87Thus, the most immature infants appear to have impaired ability to utilize the nutrients provided.After increased nutrition regimens, Kaempf et al. 88 noted an increase in hyperglycaemia and insulin use, which was associated with more proliferative ROP (4% in 2001 versus 9% in 2009).0][91] Not only more nutrition, but also more appropriate composition of nutrient solutions with factors essential for normal development such as DHA, vitamin E and inositol might help prevent ROP.

Supplementation with IGF-1
Since low serum IGF-1 in very preterm infants is strongly associated with poor weight gain and ROP and other morbidities, and since supplementation with IGF-1 in experimental studies improves growth and prevents ROP, 72 supplementation with IGF-1 might be used to improve postnatal growth and outcome.At present, a phase II study known as Insulin-Like Growth Factor 1 (IGF-1) in the prevention of Complications of Preterm Birth (ClinicalTrials.gov Id:NCT01096784) is recruiting patients in Sweden. 92

Conclusion
In order to achieve better early growth and prevention of ROP, possible preventive measures that need further evaluation include better nutrition, supplementation with IGF-1 and nutritive factors found to be missing in very preterm infants such as DHA, vitamin E and inositol.Longitudinal development of serum insulin-like growth factor-1 (IGF-1) in relation to chronologic age in infants with different retinopathy of prematurity (ROP) stages (n = 136). 41,42high risk infants.Alarms usually occur during the first month after birth whereas proliferative ROP develops weeks to months later.This suggests that interventions to improve growth in the early neonatal period might help prevent ROP.Docosahexaenoic acid (DHA) levels in preterm infants decrease soon after birth and plateau by the first postnatal week. 62