Eva Engström

Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: Direct correlation with clinical retinopathy of prematurity

Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low levels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As IGF-I increases to a critical level, retinal neovascularization is triggered. These data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease.

Early Weight Gain Predicts Retinopathy in Preterm Infants: New, Simple, Efficient Approach to Screening

BACKGROUND. The risk for sight-threatening retinopathy of prematurity is predicted by using gestational age and/or weight at birth. All infants below a threshold undergo serial ophthalmologic examinations for identification of those who would benefit from treatment (∼10%). We hypothesized that factoring in postnatal weight gain could identify children at risk for sight-threatening retinopathy of prematurity more specifically and earlier. METHODS. Weekly weights from birth to postmenstrual week 36 were retrospectively entered into a surveillance system that gave an alarm when the rate of weight gain decreased to a certain level. For all children (N = 354) screened and/or treated for retinopathy of prematurity at Sahlgrenska University Hospital in 2004–2007, weekly weights were recorded. One child was excluded because of known nonphysiologic weight gain (hydrocephalus). RESULTS. For 127 (36%) of 353 children, no alarm was given; for 40%, alarm at low risk was given after postmenstrual week 32. None of those children developed retinopathy of prematurity requiring treatment. Of the remaining 24% of children who received alarm at high or low risk before 32 postmenstrual weeks, 41% developed proliferative retinopathy of prematurity and 29% were treated because of sight-threatening disease. The median time from alarm to treatment was 9 weeks. CONCLUSIONS. The weight, insulin-like growth factor, neonatal retinopathy of prematurity algorithm detected early 100% of infants who developed retinopathy of prematurity requiring treatment and correctly predicted the majority who did not require treatment. With this simple postnatal evaluation, costly stressful eye examinations can be markedly reduced (∼75% of infants). In addition, early identification of children at risk may lead to the initiation of interventions and possibly prevent sight-threatening retinopathy of prematurity.

Postnatal Head Growth Deficit Among Premature Infants Parallels Retinopathy of Prematurity and Insulin-like Growth Factor-1 Deficit

BACKGROUND. We hypothesized that in premature infants, retinal vascular growth retardation between birth and postmenstrual age of ∼30 to 32 weeks that initiates retinopathy of prematurity is paralleled by brain growth retardation. METHODS. In a prospective longitudinal study, we measured postnatal head growth, retinopathy of prematurity stage, protein and energy intake, severity of illness and serum insulin-like growth factor-1 levels in 58 preterm infants (mean gestational age at birth: 27.6 weeks) from birth until postmenstrual age of ∼40 weeks. RESULTS. Premature infant head growth decelerates dramatically after birth until postmenstrual age of ∼30 weeks. Head growth retardation coincides with retinal vascular growth suppression. Accelerated growth follows between post menstrual ages of ∼30 to 32 weeks and ∼40 weeks. The degree of head growth retardation up to postmenstrual age of 31 weeks corresponds to the degree of retinopathy of prematurity and to the degree of suppression of serum levels of insulin-like growth factor-1. At postmenstrual age of 31 weeks, if a child’s head circumference SD is below −2.5, then the probability of also developing at least stage 3 retinopathy of prematurity increases fivefold compared with head circumference above −2.5 SD (32% vs 6%) suggesting parallel processes in brain and retina. Serum insulin-like growth factor-1 levels correlate positively with head circumference SD score and with the degree of retinopathy of prematurity. CONCLUSIONS. The correlation between head and retinal growth is consistent with insulin growth factor-1 being one of the postnatal growth factors involved in this multifactorial process and also suggests that factors that contribute to retinopathy of prematurity during this critical period may also affect neurological dysfunction. Additional studies are required to establish this connection.

Growth in Very Preterm Children: A Longitudinal Study

The knowledge about the long-term growth of very preterm children in relation to gestational age at birth is incomplete. Therefore, a retrospective study of longitudinal growth from birth to 7 y of age in 52 of 56 surviving children who were born at a gestational age of <29 wk between 1988 and 1991 to mothers resident in the city of Göteborg, Sweden, was performed. A majority of the children had an initial decrease in weight during the first months of life, followed by an increase, with a maximum weight gain occurring at 36–40 wk postmenstrual age. After a period of decreased weight and length velocity, a second increase in weight velocity was demonstrated from 6 mo to 2 y of corrected age. A corresponding increase in length velocity was found from 2 to 12 mo of corrected age. A later catch-up growth period was found at 4-5 y of age. At 7 y of age, all but two had reached the normal height range of the population. This long-term catch-up in height was established later in those who were born at an earlier gestational age. We conclude that all preterm infants had an initial period of poor growth, which rendered them growth retarded during the first years of life. It took approximately 4-7 y to overcome what the very preterm child lost in growth during the first months of life. However, as a group, they did reach normal height, weight, and weight for height before puberty.

The role of maternal factors, postnatal nutrition, weight gain, and gender in regulation of serum IGF-I among preterm infants

IGF-I is important for somatic growth and development of the human fetus and neonate. IGF-I also plays an important role in normal vascularization of human retina, as it has been suggested that insufficient IGF-I may be a factor in the development of retinopathy of prematurity. The principal regulator of the bioavailability of IGF-I in the circulation is IGF binding protein 3 (IGFBP-3). The aim of this study was to study factors associated with postnatal serum concentrations of IGF-I and of IGFBP-3 in preterm infants from birth to an age corresponding to 40 wk postmenstruation. We conducted a prospective, longitudinal study in which we measured serum IGF-I and IGFBP-3 concentrations in 76 preterm infants from birth (postmenstrual ages 23–32 wk) until discharge from hospital around 40 wk. Information regarding nutrition, weight gain, maternal factors, and treatment with corticosteroids were collected weekly. Variables found to be associated with postnatal change over time of serum IGF-I and IGFBP-3 were postmenstrual age (p < 0.001), weight gain (standard deviation score) (p < 0.001), and enteral intake of protein (p < 0.001). Male gender was associated with lower IGF-I levels (p < 0.001). The relationship between protein intake and IGF-I (and also between protein intake and IGFBP-3) was positive, as was the relationship between weight gain and IGF-I (and between weight gain and IGFBP-3). These results indicate that the degree of prematurity, low enteral protein intake, male gender, and slow weight gain are associated with a slower postnatal increase of IGF-I in preterm infants.

Nutrient intakes independently affect growth in extremely preterm infants: results from a population-based study

To explore associations between energy and macronutrient intakes and early growth in extremely low gestational age (ELGA) infants.

A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants

In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 μg/kg. The study was conducted at Queen Silvia Childrens Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26–29) and birth weight 1022 g (810–1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12–28) and 771 (651–1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25–59) and 838 (754–1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59–1.42) and 0.87 (0.85–0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated.

Fresh-Frozen Plasma as a Source of Exogenous Insulin-Like Growth Factor-I in the Extremely Preterm Infant

CONTEXT Preterm birth is followed by a decrease in circulatory levels of IGF-I and IGF binding protein (IGFBP)-3, proteins with important neurogenic and angiogenic properties. OBJECTIVE Our objective was to evaluate the effects of iv administration of fresh-frozen plasma (FFP) from adult donors on circulatory levels of IGF-I and IGFBP-3 in extremely preterm infants. DESIGN, SETTING, AND PATIENTS A prospective cohort study was performed in 20 extremely preterm infants [mean (SD) gestational age 25.3 (1.3) wk] with clinical requirement of FFP during the first postnatal week. Sampling was performed before initiation of transfusion, directly after, and at 6, 12, 24, and 48 h after completed FFP transfusion. MAIN OUTCOME MEASURES Concentrations of IGF-I and IGFBP-3 before and after transfusion of FFP were determined. RESULTS FFP with a mean (SD) volume of 11 ml/kg (3.1) was administered at a median postnatal age of 2 d (range 1-7). Mean (SD) IGF-I and IGFBP-3 concentrations in administered FFP were 130 (39) and 2840 microg/liter (615), respectively. Immediately after FFP transfusion, mean (SD) concentrations of IGF-I increased by 133% from 11 (6.4) to 25 microg/liter (9.3) (P < 0.001) and IGFBP-3 by 61% from 815 (451) to 1311 microg/liter (508) (P < 0.001). Concentrations of IGF-I and IGFBP-3 remained higher at 6 (P < 0.001, P = 0.009) and 12 h (P = 0.017, P = 0.018), respectively, as compared with concentrations before FFP transfusion. Typical half-life of administrated IGF-I was 3.4 h for a 1-kg infant. CONCLUSION Transfusion of FFP to extremely preterm infants during the first postnatal week elevates levels of IGF-I and IGFBP-3.

Proliferative Retinopathy Is Associated with Impaired Increase in BDNF and RANTES Expression Levels after Preterm Birth

Background: Extremely preterm delivery is, amongst other complications, associated with retinopathy of prematurity (ROP). Untreated, ROP can progress to visual impairment and blindness due to an overgrowth of new vessels in the retina and vitreous cavity. Objective: The aim of this study was to identify cytokine markers within the first weeks of life that could be used to predict the risk for development of ROP later in life. Methods: Serum levels of 27 different cytokines in infants born at gestational weeks 23–30 were analyzed using a multiplex immunoassay method and compared between infants who did not develop ROP and infants who later developed proliferative ROP. In addition, mRNA levels of brain-derived neurotrophic factor (BDNF) in retinas from mice exposed to hyperoxia were analyzed using quantitative real-time PCR. Results: At birth, serum levels of IL-5 were higher in infants with no ROP compared to infants with proliferative ROP. 10–14 days after birth, serum levels of BDNF and RANTES were lower in infants who later developed proliferative ROP compared to infants who did not develop ROP. Furthermore, mRNA expression levels of BDNF in retinas from mice exposed to hyperoxia were significantly lower at postnatal day 15 compared to retinas from mice in room air. Conclusions: These results indicate that BDNF and RANTES may be important factors in the selective vulnerability of ROP development in preterm infants.

Low postnatal serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD)

Aim:  To characterize postnatal changes in serum insulin‐like growth factor‐1 (IGF‐I) in relation to development of bronchopulmonary dysplasia (BPD) in very preterm infants.