Brigitte Koller

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

IMPORTANCE Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. OBJECTIVE To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. DESIGN, SETTING, AND PARTICIPANTS A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. INTERVENTIONS Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. MAIN OUTCOMES AND MEASURES The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. RESULTS At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). CONCLUSIONS AND RELEVANCE In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00413946.

Safety of Early High-Dose Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants.

OBJECTIVE To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. STUDY DESIGN Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. RESULTS There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. CONCLUSIONS Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. TRIAL REGISTRATION ClinicalTrials.gov: NCT00413946.

Minimally invasive, imaging guided virtual autopsy compared to conventional autopsy in foetal, newborn and infant cases: study protocol for the paediatric virtual autopsy trial.

BackgroundIn light of declining autopsy rates around the world, post-mortem MR imaging is a promising alternative to conventional autopsy in the investigation of infant death. A major drawback of this non-invasive autopsy approach is the fact that histopathological and microbiological examination of the tissue is not possible. The objective of this prospective study is to compare the performance of minimally invasive, virtual autopsy, including CT-guided biopsy, with conventional autopsy procedures in a paediatric population.Methods/DesignFoetuses, newborns and infants that are referred for autopsy at three different institutions associated with the University of Zurich will be eligible for recruitment. All bodies will be examined with a commercial CT and a 3 Tesla MRI scanner, masked to the results of conventional autopsy. After cross-sectional imaging, CT-guided tissue sampling will be performed by a multifunctional robotic system (Virtobot) allowing for automated post-mortem biopsies. Virtual autopsy results will be classified with regards to the likely final diagnosis and major pathological findings and compared to the results of conventional autopsy, which remains the diagnostic gold standard.DiscussionThere is an urgent need for the development of alternative post-mortem examination methods, not only as a counselling tool for families and as a quality control measure for clinical diagnosis and treatment but also as an instrument to advance medical knowledge and clinical practice. This interdisciplinary study will determine whether virtual autopsy will narrow the gap in information between non-invasive and traditional autopsy procedures.Trial RegistrationClinicalTrials.gov: NCT01888380

Functional brain maturation assessed during early life correlates with anatomical brain maturation at term-equivalent age in preterm infants

Background:Amplitude-integrated electroencephalogram (aEEG) is a reliable monitoring tool for electrocortical activity with good predictive value in preterm infants. Magnetic resonance imaging (MRI) is a good neuroimaging tool to detect brain lesions and to evaluate brain maturation. We hypothesized that early aEEG measures, recorded over the first 3 d of life in very preterm infants, correlate with brain maturation and injury score assessed by conventional MRI at term-equivalent age.Methods:Thirty-nine infants born at a mean (range) gestational age (GA) of 29.5 (27.0–31.9) wk and birth weight 1,230 (680–2,020) g had continuous aEEG during the first postnatal 72–84 h. aEEG maturity scores and average maximum and minimum amplitudes were evaluated. Conventional brain MRI was performed at 41.2 (37.1–44.1) wk postmenstrual age (PMA) on a 3T GE system and scored qualitatively for injury and maturation.Results:The average aEEG total maturity score and its cycling subscore were positively and significantly associated with the total MRI maturation score after adjustment for GA, morphine sedation, and PMA at MRI examination. No association was found between the aEEG measures and the MRI injury scores.Conclusion:Early aEEG maturity seems to relate to structural MRI brain maturation at term-equivalent age in preterm infants.

Randomized controlled trials in very preterm infants: does inclusion in the study result in any long-term benefit?

Background: Since the introduction of randomized controlled trials (RCT) in clinical research, there has been discussion of whether enrolled patients have worse or better outcomes than comparable non-participants. Objective: To investigate whether very preterm infants randomized to a placebo group in an RCT have equivalent neurodevelopmental outcomes to infants who were eligible but not randomized (eligible NR). Methods: In the course of an RCT investigating the neuroprotective effect of early high-dose erythropoietin on the neurodevelopment of very preterm infants, the outcome data of 72 infants randomized to placebo were retrospectively compared with those of 108 eligible NR infants. Our primary outcome measures were the mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development II at 24 months of corrected age. The outcomes of the two groups were considered equivalent if the confidence intervals (CIs) of their mean differences fitted within our ±5-point margin of equivalence. Results: Except for a higher socioeconomic status of the trial participants, both groups were balanced for most perinatal variables. The mean difference (90% CI) between the eligible NR and the placebo group was -2.1 (-6.1 and 1.9) points for the MDI and -0.8 (-4.2 and 2.5) points for the PDI. After adjusting for the socioeconomic status, maternal age and child age at follow-up, the mean difference for the MDI was -0.5 (-4.3 and 3.4) points. Conclusions: Our results indicate that the participation of very preterm infants in an RCT is associated with equivalent long-term outcomes compared to non-participating infants.

Urinary Erythropoietin Concentrations after Early Short-Term Infusion of High-Dose Recombinant Epo for Neuroprotection in Preterm Neonates

Background: High-dose recombinant human erythropoietin (rEpo) has first been administered in clinical trials for neuroprotection in very preterm neonates at high risk of brain injury and in (near-) term neonates with hypoxic-ischemic encephalopathy. However, recent trials in adults raised concerns about the safety of high-dose rEpo for neuro- and cardioprotection. Objectives: To evaluate the putative accumulation or renal leakage of Epo as a function of developmental stage after repetitive early short-term infusion of high-dose rEpo (3 × 3,000 U/kg within 42 h after birth; NCT00413946) for neuroprotection in very preterm infants. Methods: Epo concentrations were measured using the ELISA technique in the first two consecutive urine specimens after each rEpo infusion. Results: Renal Epo excretion was significantly higher in preterm infants with gestational ages <29 weeks than in more mature infants and reached up to 23% of the administered rEpo within 8 h after each infusion. The urinary Epo concentration did not increase after three repetitive infusions of high-dose rEpo. The ratio of urinary Epo to total protein concentrations was the same in infants with gestational ages <29 weeks and in those with gestational ages ≥29 weeks. Conclusions: Our data suggest that the higher renal Epo excretion in more immature infants may be attributed to a higher glomerular filtration leakage due to the lower maturation of the kidneys and argue against saturation kinetics after multiple doses of 3,000 U/kg rEpo. This information should be considered in future trials on the use of rEpo for neuroprotection in neonates.

Placebo by Proxy in Neonatal Randomized Controlled Trials: Does It Matter?

Placebo effects emerging from the expectations of relatives, also known as placebo by proxy, have seldom been explored. The aim of this study was to investigate whether in a randomized controlled trial (RCT) there is a clinically relevant difference in long-term outcome between very preterm infants whose parents assume that verum (PAV) had been administered and very preterm infants whose parents assume that placebo (PAP) had been administered. The difference between the PAV and PAP infants with respect to the primary outcome–IQ at 5 years of age–was considered clinically irrelevant if the confidence interval (CI) for the mean difference resided within our pre-specified ±5-point equivalence margins. When adjusted for the effects of verum/placebo, socioeconomic status (SES), head circumference and sepsis, the CI was [−3.04, 5.67] points in favor of the PAV group. Consequently, our study did not show equivalence between the PAV and PAP groups, with respect to the pre-specified margins of equivalence. Therefore, our findings suggest that there is a small, but clinically irrelevant degree to which a preterm infant’s response to therapy is affected by its parents’ expectations, however, additional large-scale studies are needed to confirm this conjecture.

PS-051 Randomised Controlled Trials In Very Preterm Infants: Does Inclusion In The Study Result In Any Long-term Benefit?

Background Since the introduction of randomised controlled trials (RCT) in clinical research, there has been discussion of whether enrolled patients have worse or better outcomes than comparable nonparticipants. Objective To investigate whether very preterm infants randomised to a placebo group in a RCT have equivalent neurodevelopmental outcomes to infants who were eligible but not randomised (eligible NR). Methods In the course of an RCT investigating the neuroprotective effect of early high dose erythropoietin on the neurodevelopment of very preterm infants, the outcome data of 72 infants randomised to placebo were compared with those of 108 eligible NR infants. Our primary outcome measures were the mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development II at 24 months corrected age. The outcomes of the two groups were considered equivalent if the confidence intervals of their mean differences fitted within our ± 5 point margin of equivalence. Results Except for a higher socioeconomic status of the trial participants, both groups were balanced for most perinatal variables. The mean difference (90% CI) between the placebo and the eligible NR group was -2.1 (-6.1 and 1.9) points for the MDI and -0.8 (-4.2 and 2.5) points for the PDI (in favour of the placebo group). After adjusting for the socioeconomic status, maternal age and child age at follow-up, the mean difference for the MDI was -0.5 (-4.3 and 3.4) points. Conclusions Our results indicate that the participation of very preterm infants in an RCT is associated with equivalent long-term outcomes compared to non-participating infants.

56 Safety of High-Dose Erythopoietin for Neuroprotection in Preterm Infants

Background Erythropoietin has been shown to be protective against hypoxic-ischaemic and inflammatory injuries in cell culture, animal models of brain injury, and in clinical trials in human adults. A multicentre randomized placebo-controlled trial was started to investigate whether early administration of high dose recombinant human erythropoietin (rhEpo) in very preterm infants improves neuro-developmental outcome at 24 months. Aim Interim analysis of neonatal complications until discharge from hospital. Results 395 preterm infants were recruited in 5 centres. 206 infants had received (n t ) 3,000 U/kg body weight rhEpo, and 189 infants NaCl 0.9% intravenously at 3, 12–18 and 36–42 hours after birth. Abstract 56 Table 1 EPO (n=206) Placebo (n=189) p GA (wks); mean (SD) 29.3 (1.6) 29.3 (1.6) 0.99 BW (g); mean (SD) 1232 (373) 1231 (314) 0.99 Death n (%) 12 (5.9) 11 (5.9) 0.99 Severe adverse events SAEs n 46 45 0.82 Bronchoplumonary dysplasia n (%) 21 (10.8) 24 (13.5) 0.53 Retinopathy of prematurity n (%) 12 (6.4) 14 (8.3) 0.64 Intraventricular haemorrhage n (%) 38 (18.4) 28 (14.8) 0.41 Haemangioma n infants (%) 35 (17.0) 34 (18.0) 0.89 Haematocrit day 7–10, mean (SD) 47.3 (7.9) 44.8 (7.1) 0.002 Conclusions No significant adverse effects of early high-dose rhEpo treatment in very preterm infants were identified. The neuroprotective effect will be evaluated in 24 months.