Anna-Lena Hård

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.

Visual function in school-aged children born before 29 weeks of gestation: a population-based study

The aim of this study was to assess visual function, including visual perception, in a geographically‐based population of school‐aged children, with a median age of 7.2 years (range 5.1 to 9.3 years), born before 29 weeks of gestation to mothers living in Göteborg, Sweden. Fifty‐one preterm children participated in the study, six of whom had known brain lesions. Visual acuity, visual fields, stereoacuity, and visual perception were tested. The Test of Visual Perceptual Skills —Revised (TVPS‐R, Gardner 1996) was used to measure visual perception, and the results were compared with those of 50 term (control) subjects. Six percent of the preterm children were visually impaired, with a visual acuity of less than 0.3 (6/18), while 42% of all the preterm children and 34% of those without known brain lesions had a total score below the 5th centile of the reference material for the test, compared with 14% of the control subjects. In conclusion, visual‐perceptual problems seem to be common among very preterm children and should be screened for and assessed before the children start school.

New insights into the development of retinopathy of prematurity - importance of early weight gain

Evidence is accumulating that one of the strongest predictors of retinopathy of prematurity (ROP), in addition to low gestational age, is poor weight gain during the first weeks of life. In infants born preterm, the retina is not fully vascularised. The more premature the child, the larger is the avascular area. In response to hypoxia, vascular endothelial growth factor (VEGF) is secreted. For appropriate VEGF‐induced vessel growth, sufficient levels of insulin‐like growth factor I (IGF‐I) in serum are necessary. IGF‐I is a peptide, related to nutrition supply, which is essential for both pre‐ and post‐natal general growth as well as for growth of the retinal vasculature. In prematurely born infants, serum levels are closely related to gestational age and are lower in more prematurely born infants. At preterm birth the placental supply of nutrients is lost, growth factors are suddenly reduced and general as well as vascular growth slows down or ceases. In addition, the relative hyperoxia of the extra‐uterine milieu, together with supplemental oxygen, causes a regression of already developed retinal vessels. Postnatal growth retardation is a major problem in very preterm infants. Both poor early weight gain and low serum levels of IGF‐I during the first weeks/months of life have been found to be correlated with severity of ROP.

On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment - a review.

Off‐label intravitreal use of the vascular endothelial growth factor (VEGF) antibody bevacizumab for retinopathy of prematurity (ROP) increases despite lack of studies on safety, pharmacokinetics and dosage in developing individuals. Systemic absorption has been considered negligible. A literature search was performed with emphasis on potential adverse systemic effects in developing individuals.

Ocular fundus abnormalities in children born before 29 weeks of gestation: A population-based study

Purpose: Preterm birth has been found to be associated with increased morbidity of the central nervous and vascular tissues. To investigate the influence of preterm birth on the optic disc and retinal vessels, we examined the ocular fundus in school-aged children born very preterm.Methods: A prospective, population-based study was performed in 50 very preterm children (median age 7 years, range 5–9 years) with a median gestational age at birth of 27 weeks (range 24–28 weeks) and a median birth weight of 1055 g (range 450–1520 g). The ocular fundus was examined by ophthalmoscopy in 50 children, and the optic nerve and retinal vessel morphology was evaluated by digital image analysis of ocular fundus photographs in 45 of these children.Results: The median optic disc area was significantly smaller (p = 0.0002) in the preterm children compared with a reference group. There was no difference in cup area and, consequently, the rim area was significantly smaller (p = 0.0002) in the preterm children. Children with early signs of brain lesions commonly had a rim area below the median of the reference group. Preterm children also commonly had an abnormal retinal vascular pattern that was independent of a previous history of retinopathy of prematurity.Conclusion: Very preterm birth was associated with subnormal optic disc and rim areas and an abnormal vascular pattern. The findings clearly demonstrate the effect of preterm birth on the development of these structures. The long term clinical prognosis of these findings has yet to be determined.

Predicting Proliferative Retinopathy in a Brazilian Population of Preterm Infants With the Screening Algorithm WINROP

OBJECTIVE To retrospectively validate the WINROP (weight, insulinlike growth factor I, neonatal, retinopathy of prematurity [ROP]) algorithm in a Brazilian population. WINROP aims to predict ROP and is based on longitudinal weight measurements from birth until postmenstrual age 36 weeks. WINROP has predicted 100% of severe ROP in 3 neonatal intensive care unit settings in the United States and Sweden. METHODS In children admitted to the neonatal intensive care unit at Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, from April 2002 to October 2008, weight measurements had been recorded once a week for children screened for ROP, 366 of whom had a gestational age of 32 weeks or less. The participating children had a median gestational age of 30 weeks (range, 24-32 weeks) at birth and their median birth weight was 1215 g (range, 505-2000 g). RESULTS For 192 of 366 children (53%), no alarm or low-risk alarm after postmenstrual age 32 weeks occurred. Of these, 190 of 192 did not develop proliferative disease. Two boys with severe sepsis who were treated for ROP received low-risk alarms at postmenstrual age 33 and 34 weeks, respectively. The remaining 174 children (47%) received high- or low-risk alarms before or at 32 weeks. Of these infants, 21 (12%) developed proliferative ROP. CONCLUSIONS In this Brazilian population, WINROP, with limited information on specific gestational age and date of weight measurement, detected early 90.5% of infants who developed stage 3 ROP and correctly predicted the majority who did not. Adjustments to the algorithm for specific neonatal intensive care unit populations may improve the results for specific preterm populations.

Prediction of Retinopathy of Prematurity Using the Screening Algorithm WINROP in a Mexican Population of Preterm Infants

OBJECTIVE To retrospectively validate the WINROP (weight, insulin-like growth factor I, neonatal, retinopathy of prematurity [ROP]) algorithm in identification of type 1 ROP in a Mexican population of preterm infants. METHODS In infants admitted to the neonatal intensive care unit at Hospital Civil de Guadalajara from 2005 to 2010, weight measurements had been recorded once weekly for 192 very preterm infants (gestational age [GA] <32 weeks) and for 160 moderately preterm infants (GA ≥32 weeks). Repeated eye examinations had been performed and maximal ROP stage had been recorded. Data are part of a case-control database for severe ROP risk factors. RESULTS Type 1 ROP was found in 51.0% of very preterm and 35.6% of moderately preterm infants. The WINROP algorithm correctly identified type 1 ROP in 84.7% of very preterm infants but in only 5.3% of moderately preterm infants. For infants with GA less than 32 weeks, the specificity was 26.6%, and for those with GA 32 weeks or more, it was 88.3%. CONCLUSIONS In this Mexican population of preterm infants, WINROP detected type 1 ROP early in 84.7% of very preterm infants and correctly identified 26.6% of infants who did not develop type 1 ROP. Uncertainties in dating of pregnancies and differences in postnatal conditions may be factors explaining the different outcomes of WINROP in this population.