Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies.

Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity.

Postnatal systemic inflammation and neuro-ophthalmologic dysfunctions in extremely low gestational age children.

AIM: Compared to infants born at term, children born very preterm are at increased risk of visual dysfunctions and neonatal systemic inflammation. Here, we explore whether these two propensities are related. METHODS: As part of the ELGAN study, the concentrations of 16 mediators of inflammation were measured in blood obtained on postnatal days 1, 7, 14, 21 and 28 from 1062 children born before the 28th week of gestation. Presence of visual field deficit, strabismus and/or impaired visual fixation was recorded at age two. The concentrations of each protein were divided into quartiles within gestational week categories. We calculated odds ratios with 99% confidence intervals for having each disorder comparing children with concentration in the top quartile of each protein to children whose concentration was in the lower quartiles on the corresponding day. Analyses were adjusted for gestational age and birth weight Z-score. RESULTS: Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation. No association was found between strabismus and any inflammatory mediator. CONCLUSION: None of the three neuro-ophthalmologic dysfunctions assessed at two years appears to be associated with systemic inflammation measured the first four postnatal weeks.

Antenatal glucocorticoids and neonatal inflammation-associated proteins.

BACKGROUND: To date, studies of the relationship between antenatal glucocorticoids (AGC) and neonatal inflammation in preterm newborns have been largely limited to umbilical cord blood specimens. AIM: To explore the association between exposure to antenatal glucocorticoids and concentrations of inflammation-related proteins in whole blood collected from very preterm newborns at multiple times during the first postnatal month. METHODS: We measured the protein concentrations on postnatal day 1 (N=1118), day 7 (N=1138), day 14 (N=1030), day 21 (N=936) and day 28 (N=877) from infants born before the 28th week of gestation and explored the relationship between antenatal steroid receipt and protein concentrations in the highest and lowest quartiles. The creation of multinomial logistic regression models (adjusted for potential confounders) allowed us calculate odds ratios and 95% confidence intervals. RESULTS: Twenty of 420 assessments [21 (proteins)×2 (exposure levels: partial and full)×2 (quartile levels: top and bottom)×5 (days)] were statistically significant without any cohesive pattern. CONCLUSION: Among infants born before 28 weeks of gestational age, neither full, nor partial courses of antenatal glucocorticoids have a sustained anti-inflammatory effect.

Self-development groups reduce medical school stress: a controlled intervention study.

BACKGROUND: High stress levels and mental health problems are common among medical students and there is a lack of studies on group interventions that aim to reduce such distress during medical school. METHODS: A full class of students (n = 129) participated in group sessions during their third year of medical school in Bergen, Norway. The subsequent third-year class (n = 152) acted as control group, in order to create a quasi-experimental design. Two types of group intervention sessions were offered to the first class. One option was self-development groups led by trained group psychotherapists. Alternatively, students could choose discussion groups that focused on themes of special relevance to doctors, led by experienced general practitioners. The intervention comprised of 12 weekly group sessions each lasting 90 minutes. Data were gathered before the intervention (T1), and three months post intervention (T2). Distress was measured using the Perceived Medical School Stress (PMSS) and Symptom Check List-5 (SCL-5) assessments. RESULTS: The intervention group showed a significant reduction in PMSS over the observation period. The subsequent year control group stayed on the same PMSS levels over the similar period. The intervention was a significant predictor of PMSS reduction in a multiple regression analysis adjusted for age and sex, beta = -1.93 (-3.47 to -0.38), P = 0.02. When we analysed the effects of self-development and discussion groups with the control group as reference, self-development group was the only significant predictor of PMSS reduction, beta = -2.18 (-4.03 to -0.33), P = 0.02. There was no interaction with gender in our analysis. This implicates no significant difference between men and women concerning the effect of the self-development group. There was no reduction in general mental distress (SCL-5) over this period. CONCLUSION: A three-month follow-up showed that the intervention had a positive effect on perceived medical school stress among the students, and further analyses showed this was due to participation in self-development groups.

Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation.

Purpose: To assess the association between systemic levels of inflammation-associated proteins and severe retinopathy of prematurity (ROP) in extremely preterm infants. Methods: We collected whole blood on filter paper on postnatal days 1, 7, 14, 21, and 28 from 1205 infants born before the 28th week of gestation, and measured the concentrations of 27 inflammation-associated, angiogenic, and neurotrophic proteins. We calculated odds ratios with 95% confidence intervals for the association between top quartile concentrations of each protein and prethreshold ROP. Results: During the first three weeks after birth, high concentrations of VEGF-R1, myeloperoxidase (MPO), IL-8, intercellular adhesion molecule (ICAM)-1, matrix metalloproteinase 9, erythropoietin, TNF-α, and basic fibroblast growth factor were associated with an increased risk for prethreshold ROP. On day 28, high levels of serum amyloid A, MPO, IL-6, TNF-α, TNF-R1/-R2, IL-8, and ICAM-1 were associated with an increased risk. Top quartile concentrations of the proinflammatory cytokines TNF-α and IL-6 were associated with increased risks of ROP when levels of neuroprotective proteins and growth factors, including BDNF, insulin-like growth factor 1, IGFBP-1, VEGFR-1 and -2, ANG-1 and PlGF, were not in the top quartile. In contrast, high concentrations of NT-4 and BDNF appeared protective only in infants without elevated inflammatory mediators. Conclusions: Systemic inflammation during the first postnatal month was associated with an increased risk of prethreshold ROP. Elevated concentrations of growth factors, angiogenic proteins, and neurotrophins appeared to modulate this risk, and were capable of reducing the risk even in the absence of systemic inflammation.

Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns.

OBJECTIVE: To explore the association between concentrations of endogenous erythropoietin (EPO) in blood the first 2 weeks of life and neonatal disorders in extremely low gestational age newborns (ELGANs). DESIGN: Prospective cohort study. SETTING: Neonatal care units at 14 participating hospitals in the USA. PATIENTS: 867 children born before the 28th week of gestation from the ELGAN study cohort. MAIN OUTCOME MEASURES: EPO blood concentrations were measured on postnatal days 1, 7 and 14. The following neonatal characteristics and disorders were registered: blood gases, early and late respiratory dysfunction, pulmonary deterioration, retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and bronchopulmonary dysplasia (BPD). We calculated the gestational age-adjusted ORs for having each disorder associated with an EPO blood concentration in the highest or lowest quartile, compared with infants whose EPO concentration was in the middle two quartiles on the corresponding day. RESULTS: Newborns whose day-1 EPO was in the highest quartile were at increased risk for early and persistent respiratory dysfunction during the first 2 weeks of life, and NEC requiring surgery. The lowest EPO quartile on day 1 was associated with a decreased risk of moderate BPD. The association between low EPO and decreased risk of respiratory complications persisted on day 7. On day 14, being in the highest EPO quartile was associated with increased risk of ROP, and BPD not requiring ventilation assistance. CONCLUSIONS: EPO blood concentrations in extremely preterm newborns during the first 2 weeks of life convey information about increased risks of bowel, lung and retinal diseases.

Antecedents and correlates of visual field deficits in children born extremely preterm.

AIM: We sought to identify the antecedents and correlates of visual field deficits (VFDs) at age 2 years among infants born before the 28th week of gestation. METHODS: The visual fields of 1023 infants were assessed by confrontation at age 2 years. We compared the ante-and postnatal characteristics and exposures of the 65 infants with a VFD to their peers who did not have a VFD. We used time-oriented logistic regression risk models to assess the associations of potential antecedents and correlates with a VFD. RESULTS: In the final regression model, VFD was associated with maternal consumption of aspirin during the current pregnancy, recurring/persistent acidemia during the first 3 postnatal days, cerebral ventriculomegaly seen on neonatal ultrasound, prethreshold retinopathy of prematurity (ROP), and supplemental oxygen and ventilator dependence at 36 weeks post-menstrual age. Birth before the 27th week was also associated with increased risk, but its significance was diminished by the addition of postnatal variables. CONCLUSION: In this sample of extremely preterm born infants, antenatal as well as early and late postnatal characteristics and exposures are associated with an increased risk of having a VFD. Our study adds to our knowledge about the complex etiology of visual deficits of prematurity, and supports a multifactorial cause of these deficits.

Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.

BACKGROUND: We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). METHODS: Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. RESULTS: Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. CONCLUSION: hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.