Aimon Niklasson

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.

Swedish population-based longitudinal reference values from birth to 18 years of age for height, weight and head circumference

This study aimed to update growth reference values for height, weight and head circumference in order to reflect the changes in body size in the Swedish population during the past two decades. The data came from a large longitudinal growth study on 3650 full‐term healthy Swedish children who were born between 1973 and 1975. All of these 1801 girls and 1849 boys had longitudinal data for height and weight from birth to final height. Comparison with previous Swedish growth reference values based on children born between 1955 and 1958 revealed that there have been secular changes in body size. For instance, at 18 y of age, the updated height and weight reference values are 180.4 cm for males and 167.7 cm for females, i.e. 1.9 cm taller and 5.7 kg heavier for males and 2.3 cm taller and 3.4kg heavier for females compared with the previous reference values.

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.

Cerebral palsy in preterm infants: a population-based case-control study of antenatal and intrapartal risk factors

Previous studies have indicated that foetomaternal infection increases the risk of spastic cerebral palsy (CP) in term infants, whereas this association appears to be less evident in preterm infants. The aim of this study was to analyse infection‐related risk factors for spastic CP in preterm infants. A population‐based series of preterm infants with spastic CP, 91 very preterm (>32wk) and 57 moderately preterm (32–36 wk), born in 1983–90, were included and matched with a control group (n= 296). In total, 154 maternal, antenatal and intrapartal variables were retrieved from obstetric records. In the entire group, histological chorioamnionitis/pyelonephritis, long interval between rupture of membranes and birth, admission‐delivery interval >4 h and Apgar scores of >7 at 1 min just significantly increased the risk of CP, and Apgar scores of >7 at 5 and 10 min were strongly associated with an increased risk. Abruptio placentae, Apgar scores >7 at 1 min and pathological non‐stress test (reason for delivery) were significant risk factors of CP only in the moderately preterm and hemiplegic groups, whereas fever before delivery was a significant risk factor in the very preterm and spastic diplegic groups. Antibiotics during pregnancy was associated with CP only in the spastic diplegic CP group.

Postnatal growth and health in children born after cryopreservation as embryos

BACKGROUND There is uncertainty about the health of children born from in-vitro fertilisation (IVF) with cryopreserved embryos. We investigated the postnatal growth and health (up to 18 months) of these children compared with those born after standard IVF with fresh embryos and those from spontaneous pregnancies. METHODS 255 children from cryopreserved embryos were matched by maternal age, parity, single or twin pregnancy, and date of delivery with 255 children born after IVF with fresh embryos, and 252 children from spontaneous pregnancies. The main endpoint was growth; secondary endpoints were the prevalence of chronic illness, major malformations, cumulative incidence of common diseases, and development during the first 18 months. Growth was assessed by comparison with standard Swedish growth charts and by standard deviation scores. FINDINGS Growth features were similar for both singletons and twins in the three groups. There were 6 (2.4%) of 255, 9 (3.5%) of 255, and 8 (3.2%) of 252 major malformations in the cryopreserved group, standard IVF, and spontaneous groups, respectively (p=0.6 between the cryopreserved and standard IVF group). The prevalence of chronic diseases did not differ between the three groups, with 18.0%, 15.3%, and 16.7% of children with a chronic illness in the cryopreserved group, standard IVF, and spontaneous groups, respectively. INTERPRETATION The cryopreservation process does not adversely affect the growth and health of children during infancy and early childhood. Minor handicaps, behavioural disturbances, learning difficulties, and dysfunction of attention and perception cannot be ruled out at this age.

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.

Medical follow-up study of 5-year-old ICSI children

Children born after intracytoplasmic sperm injection (ICSI) are still a matter of concern. The purposes of the present study were to investigate the physical outcome in 5-year-old children born after ICSI and compare them with children born after spontaneous conception. Three hundred singleton children from Belgium, Sweden and the USA, born after ICSI, were matched by maternal age, child age and gender. In one centre, matching was also performed for maternal education. The main end-point was growth. Secondary end-points were general health, e.g. common diseases, chronic illnesses, surgical interventions and physical/neurological examinations. Standard deviation scores assessed growth. Growth assessed as stature at follow-up was similar in the two groups, despite a higher rate of preterm birth and low birth weight in the ICSI children. Common diseases and chronic illnesses occurred at similar rates in both groups. More ICSI children underwent surgical interventions and required other therapy e. g. physiotherapy and dietary therapy. Physical/neurological examinations revealed few abnormalities in either group. In conclusion, infertility treatment by ICSI does not adversely affect growth during childhood. The childrens general health seems satisfactory.

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.

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.