Creative music therapy for long-term neurodevelopment in extremely preterm infants: Results of a feasibility trial.

AIM: We tested the feasibility of a future randomised clinical trial (RCT) in which Creative Music Therapy (CMT), a family-integrating individualised approach in neonatal care, could improve neurodevelopment in extremely preterm infants (EPTs). METHODS: In this feasibility trial, 12 EPTs received CMT, while the remaining 19 received standard neonatal care. Socio-demographic data and perinatal complications were compared between groups as risk factors. Bayley Scales of Infant and Toddler Development at 2-year follow-up (FU2) and KABC-II-Kaufman Assessment Battery for Children at 5-year follow-up (FU5) were analysed using the Mann-Whitney U-tests. RESULTS: Twenty-seven (87.1%) and 18 (58.1%) EPTs attended the FU2 and FU5 examination, respectively. The rate of neurodevelopmental risk factors at birth of the two groups was quite similar. While there was no difference in the FU2 outcomes between groups, there were higher values in the CMT group's Fluid-Crystallised Index of the KABC-II. CONCLUSION: Our results indicate neither a beneficial nor a detrimental effect of CMT on neurodevelopment at 2 years but a trend of improved cognitive outcomes at 5 years more similar to cognitive scores of term-born infants than of standard treatment EPTs. The findings favour an RCT but must be interpreted cautiously due to the reduced sample size and non-randomised design.

Post-mortem magnetic resonance imaging with computed tomography-guided biopsy for foetuses and infants: a prospective, multicentre, cross-sectional study.

BACKGROUND: Post-mortem imaging has been suggested as an alternative to conventional autopsy in the prenatal and postnatal periods. Noninvasive autopsies do not provide tissue for histological examination, which may limit their clinical value, especially when infection-related morbidity and mortality are suspected. METHODS: We performed a prospective, multicentre, cross-sectional study to compare the diagnostic performance of post-mortem magnetic resonance imaging with computed tomography-guided biopsy (Virtopsy®) with that of conventional autopsy in foetuses and infants. Cases referred for conventional autopsy were eligible for enrolment. After post-mortem imaging using a computed tomography scanner and a magnetic resonance imaging unit, computed tomography-guided tissue sampling was performed. Virtopsy results were compared with conventional autopsy in determining the likely final cause of death and major pathologies. The primary outcome was the proportion of cases for which the same cause of death was determined by both methods. Secondary outcomes included the proportion of false positive and false negative major pathological lesions detected by virtopsy and the proportion of computed tomography-guided biopsies that were adequate for histological examination. RESULTS: Overall, 101 cases (84 fetuses, 17 infants) were included. Virtopsy and autopsy identified the same cause of death in 91 cases (90.1%, 95% CI 82.7 to 94.5). The sensitivity and specificity of virtopsy for determining the cause of death were 96.6% (95% CI 90.6 to 98.8) and 41.7% (95% CI 19.3 to 68.0), respectively. In 32 cases (31.7%, 95% CI 23.4 to 41.3), major pathological findings remained undetected by virtopsy, and in 45 cases (44.6%, 95% CI 35.2 to 54.3), abnormalities were diagnosed by virtopsy but not confirmed by autopsy. Computed tomography-guided tissue sampling was adequate for pathological comments in 506 of 956 biopsies (52.7%) and added important diagnostic value in five of 30 cases (16.1%) with an unclear cause of death before autopsy compared with postmortem imaging alone. In 19 of 20 infective deaths (95%), biopsies revealed infection-related tissue changes. Infection was confirmed by placental examination in all fetal cases. CONCLUSIONS: Virtopsy demonstrated a high concordance with conventional autopsy for the detection of cause of death but was less accurate for the evaluation of major pathologies. Computed tomography-guided biopsy had limited additional diagnostic value. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01888380).

Swiss neonatal caregivers express diverging views on parental involvement in shared decision-making for extremely premature infants.

AIM: Due to scarce available national data, this study assessed current attitudes of neonatal caregivers regarding decisions on life-sustaining interventions, and their views on parents' aptitude to express their infant's best interest in shared decision-making. METHODS: Self-administered web-based quantitative empirical survey. All 552 experienced neonatal physicians and nurses from all Swiss NICUs were eligible. RESULTS: There was a high degree of agreement between physicians and nurses (response rates 79% and 70%, respectively) that the ability for social interactions was a minimal criterion for an acceptable quality of life. A majority stated that the parents' interests are as important as the child's best interest in shared decision-making. Only a minority considered the parents as the best judges of what is their child's best interest. Significant differences in attitudes and values emerged between neonatal physicians and nurses. The language area was very strongly associated with the attitudes of neonatal caregivers. CONCLUSION: Despite clear legal requirements and societal expectations for shared decision-making, survey respondents demonstrated a gap between their expressed commitment to shared decision-making and their view on parental aptitude to formulate their infant's best interest. National guidelines need to address these barriers to shared decision-making to promote a more uniform nationwide practice.

Treatment of opioid withdrawal in neonates with morphine, phenobarbital, or chlorpromazine: a randomized double-blind trial.

Three suitable compounds (morphine, chlorpromazine, and phenobarbital) to treat neonatal abstinence syndrome were compared in a prospective multicenter, double-blind trial. Neonates exposed to opioids in utero were randomly allocated to one of three treatment groups. When a predefined threshold of a modified Finnegan score was reached, treatment started and increased stepwise until symptoms were controlled. If symptoms could not be controlled with the predefined maximal dose of a single drug, a second drug was added. Among 143 infants recruited, 120 needed pharmacological treatment. Median length of treatment for morphine was 22 days (95% CI 18 to 33), for chlorpromazine 25 days (95% CI 21 to 34), and for phenobarbital 32 days (95% CI 27 to 38) (p = ns). In the morphine group, only 3% of infants (1/33) needed a second drug; in the chlorpromazine group, this proportion was 56% (24/43), and in the phenobarbital group 30% (13/44).Conclusion: None of the drugs tested for treating neonatal abstinence syndrome resulted in a significantly shorter treatment length than the others. As morphine alone was able to control symptoms in almost all infants, it may be preferred to the two other drugs but should still be tested against more potent opioids such as buprenorphine.Trial registration: At ClinicalTrials.gov NCT02810782 (registered retrospectively).What is Known:• Neonates exposed to opiates in utero and presenting with withdrawal symptoms should first be treated by non-pharmacological supportive measures.• In those who fail, drugs have to be given, but there is controversy which drug is best.What is New:• Among three candidates, morphine, chlorpromazine and phenobarbital, none resulted in significantly shorter treatment time.• As morphine alone was able to control symptoms in almost all infants, it may be preferred to the two other drugs.

Correction to: Decision-making at the limit of viability: differing perceptions and opinions between neonatal physicians and nurses.

After publication of our article [1] it was brought to our attention that we did not have permission to reproduce the questionnaire in Additional File 1.

Correction to: decision-making at the limit of viability: differing perceptions and opinions between neonatal physicians and nurses.

After publication of the original article [1], the corresponding author noticed the given names and family names of the members included in the Swiss Neonatal End-of-Life Study Group were incorrectly reverted.

Decision-making at the limit of viability: differing perceptions and opinions between neonatal physicians and nurses.

BACKGROUND: In the last 20 years, the chances for intact survival for extremely preterm infants have increased in high income countries. Decisions about withholding or withdrawing intensive care remain a major challenge in infants born at the limits of viability. Shared decision-making regarding these fragile infants between health care professionals and parents has become the preferred model today. However, there is an ongoing ethical debate on how decisions regarding life-sustaining treatment should be reached and who should have the final word when health care professionals and parents do not agree. We designed a survey among neonatologists and neonatal nurses to analyze practices, difficulties and parental involvement in end-of-life decisions for extremely preterm infants. METHODS: All 552 physicians and nurses with at least 12 months work experience in level III neonatal intensive care units (NICU) in Switzerland were invited to participate in an online survey with 50 questions. Differences between neonatologists and NICU nurses and between language regions were explored. RESULTS: Ninety six of 121 (79%) physicians and 302 of 431(70%) nurses completed the online questionnaire. The following difficulties with end-of-life decision-making were reported more frequently by nurses than physicians: insufficient time for decision-making, legal constraints and lack of consistent unit policies. Nurses also mentioned a lack of solidarity in our society and shortage of services for disabled more often than physicians. In the context of limiting intensive care in selected circumstances, nurses considered withholding tube feedings and respiratory support less acceptable than physicians. Nurses were more reluctant to give parents full authority to decide on the course of action for their infant. In contrast to professional category (nurse or physician), language region, professional experience and religion had little influence if any on the answers given. CONCLUSIONS: Physicians and nurses differ in many aspects of how and by whom end-of-life decisions should be made in extremely preterm infants. The divergencies between nurses and physicians may be due to differences in ethics education, varying focus in patient care and direct exposure to the patients. Acknowledging these differences is important to avoid potential conflicts within the neonatal team but also with parents in the process of end-of-life decision-making in preterm infants born at the limits of viability.

Patterns of paediatric end-of-life care: a chart review across different care settings in Switzerland.

BACKGROUND: Paediatric end-of-life care is challenging and requires a high level of professional expertise. It is important that healthcare teams have a thorough understanding of paediatric subspecialties and related knowledge of disease-specific aspects of paediatric end-of-life care. The aim of this study was to comprehensively describe, explore and compare current practices in paediatric end-of-life care in four distinct diagnostic groups across healthcare settings including all relevant levels of healthcare providers in Switzerland. METHODS: In this nationwide retrospective chart review study, data from paediatric patients who died in the years 2011 or 2012 due to a cardiac, neurological or oncological condition, or during the neonatal period were collected in 13 hospitals, two long-term institutions and 10 community-based healthcare service providers throughout Switzerland. RESULTS: Ninety-three (62%) of the 149 reviewed patients died in intensive care units, 78 (84%) of them following withdrawal of life-sustaining treatment. Reliance on invasive medical interventions was prevalent, and the use of medication was high, with a median count of 12 different drugs during the last week of life. Patients experienced an average number of 6.42 symptoms. The prevalence of various types of symptoms differed significantly among the four diagnostic groups. Overall, our study patients stayed in the hospital for a median of six days during their last four weeks of life. Seventy-two patients (48%) stayed at home for at least one day and only half of those received community-based healthcare. CONCLUSIONS: The study provides a wide-ranging overview of current end-of-life care practices in a real-life setting of different healthcare providers. The inclusion of patients with all major diagnoses leading to disease- and prematurity-related childhood deaths, as well as comparisons across the diagnostic groups, provides additional insight and understanding for healthcare professionals. The provision of specialised palliative and end-of-life care services in Switzerland, including the capacity of community healthcare services, need to be expanded to meet the specific needs of seriously ill children and their families.

Fidgety movements in infants born very preterm: predictive value for cerebral palsy in a clinical multicentre setting.

AIM: This study assessed predictive values of fidgety movement assessment (FMA) in a large sample of infants born very preterm for developmental abnormalities, in particular for cerebral palsy (CP) at 2 years in an everyday clinical setting. METHOD: This is a multicentre study of infants born preterm with gestational age lower than 32.0 weeks. FMA was performed at 3 months corrected age; neurodevelopment (Bayley Scales of Infant Development, 2nd edition) and neurological abnormalities were assessed at 2 years. Predictive values of FMA for the development of CP were calculated and combined with abnormalities at cerebral ultrasound. RESULTS: Five hundred and thirty-five infants (gestational age 28.2wks [standard deviation 1.3wks]) were included. Eighty-one percent showed normal fidgety movements and 19% atypical (82 absent, 21 abnormal) fidgety movements. Absent fidgety movements predicted CP at 2 years with an odds ratio (OR) of 8.9 (95% confidence interval [CI] 4.1-17.0), a combination of atypical fidgety movements and major brain lesion on cerebral ultrasound predicted it with an OR of 17.8 (95% CI 5.2-61.6). Mean mental developmental index of infants with absent fidgety movements was significantly lower (p=0.012) than with normal fidgety movements. INTERPRETATION: Detection of infants at risk for later CP through FMA was good, but less robust when performed in a routine clinical setting; prediction improved when combined with neonatal cerebral ultrasound.

Comparison of three different methods for risk adjustment in neonatal medicine.

BACKGROUND: Quality improvement in health care requires identification of areas in need of improvement by comparing processes and patient outcomes within and between health care providers. It is critical to adjust for different case-mix and outcome risks of patient populations but it is currently unclear which approach has higher validity and how limitations need to be dealt with. Our aim was to compare 3 approaches towards risk adjustment for 7 different major quality indicators in neonatal intensive care (21 models). METHODS: We compared an indirect standardization, logistic regression and multilevel approach. Parameters for risk adjustment were chosen according to literature and the condition that they may not depend on processes performed by treating clinics. Predictive validity was tested using the mean Brier Score and by comparing area under curve (AUC) using high quality population based data separated into training and validation sets. Changes in attributional validity were analysed by comparing the effect of the models on the observed-to-expected ratios of the clinics in standardized mortality/morbidity ratio charts. RESULTS: Risk adjustment based on indirect standardization revealed inferior c-statistics but superior Brier scores for 3 of 7 outcomes. Logistic regression and multilevel modelling were equivalent to one another. C-statistics revealed that predictive validity was high for 8 and acceptable for 11 of the 21 models. Yet, the effect of all forms of risk adjustment on any clinic's comparison with the standard was small, even though there was clear risk heterogeneity between clinics. CONCLUSIONS: All three approaches to risk adjustment revealed comparable results. The limited effect of risk adjustment on clinic comparisons indicates a small case-mix influence on observed outcomes, but also a limited ability to isolate quality improvement potential based on risk-adjustment models. Rather than relying on methodological approaches, we instead recommend that clinics build small collaboratives and compare their indicators both in risk-adjusted and unadjusted form together. This allows qualitatively investigating and discussing the residual risk-differences within networks. The predictive validity should be quantified and reported and stratification into risk groups should be more widely used to correct for confounding.

Attitudes towards decisions about extremely premature infants differed between Swiss linguistic regions in population-based study.

AIM: Studies have provided insights into the different attitudes and values of healthcare professionals and parents towards extreme prematurity. This study explored societal attitudes and values in Switzerland with regard to this patient group. METHODS: A nationwide trilingual telephone survey was conducted in the French-, German- and Italian-speaking regions of Switzerland to explore the general population's attitudes and values with regard to extreme prematurity. Swiss residents of 18 years or older were recruited from the official telephone registry using quota sampling and a logistic regression model assessed the influence of socio-demographic factors on end-of-life decision-making. RESULTS: Of the 5112 people contacted, 1210 (23.7%) participated. Of these 5% were the parents of a premature infant and 26% knew parents with a premature infant. Most participants (77.8%) highlighted their strong preference for shared decision-making, and 64.6% said that if there was dissent then the parents should have the final word. Overall, our logistic regression model showed that regional differences were the most significant factors influencing decision-making. CONCLUSION: The majority of the Swiss population clearly favoured shared decision-making. The context of sociocultural demographics, especially the linguistic region in which the decision-making took place, strongly influenced attitudes towards extreme prematurity and decision-making.

Short courses of dual-strain probiotics appear to be effective in reducing necrotising enterocolitis.

AIM: Prophylactic probiotics to reduce necrotising enterocolitis (NEC) are mostly given for at least 28 days or until discharge. We describe the effects of a shorter duration dosing strategy. METHODS: Retrospective cohort study of neonates (birthweight 400-1500 g) in three neonatal intensive care units in Switzerland and Germany that embarked on probiotic prophylaxis given for 10 or 14 days, employing a fixed combination (Lactobacillus acidophilus plus Bifidobacterium infantis, each 10(9) CFU/day) licensed as a drug in Switzerland. Probiotics were initiated upon discontinuation of antibiotics, or on day 1-3 in infants without antibiotics. Repeat probiotic courses were given whenever antibiotics had been instituted and were discontinued. RESULTS: Birthweight and gestational age were similar in the two 24-month pre- and postimplementation cohorts. NEC rates fell from 33 of 633 (5.2%) to 8 of 591 infants alive at three days (1.4%; risk ratio (RR) 0.26, 95% confidence interval (CI) 0.12-0.55). The drop in NEC was significant both for infants of 400-999 g (6.4% to 2.5%) and 1000-1500 g birthweight (4.4% to 0.6%). Mortality was 5.1% (32/633) without, as opposed to 3.5% (21/591) with probiotics, respectively (RR 0.69, 95% CI 0.41-1.19). CONCLUSION: Short courses of a dual-strain probiotics appear to be effective in reducing NEC.

Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial.

IMPORTANCE: Very preterm infants are at risk of developing encephalopathy of prematurity and long-term neurodevelopmental delay. Erythropoietin treatment is neuroprotective in animal experimental and human clinical studies. OBJECTIVE: To determine whether prophylactic early high-dose recombinant human erythropoietin (rhEPO) in preterm infants improves neurodevelopmental outcome at 2 years' corrected age. DESIGN, SETTING, AND PARTICIPANTS: Preterm infants born between 26 weeks 0 days' and 31 weeks 6 days' gestation were enrolled in a randomized, double-blind, placebo-controlled, multicenter trial in Switzerland between 2005 and 2012. Neurodevelopmental assessments at age 2 years were completed in 2014. INTERVENTIONS: Participants were randomly assigned to receive either rhEPO (3000 IU/kg) or placebo (isotonic saline, 0.9%) intravenously within 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. MAIN OUTCOMES AND MEASURES: Primary outcome was cognitive development assessed with the Mental Development Index (MDI; norm, 100 [SD, 15]; higher values indicate better function) of the Bayley Scales of Infant Development, second edition (BSID-II) at 2 years corrected age. The minimal clinically important difference between groups was 5 points (0.3 SD). Secondary outcomes were motor development (assessed with the Psychomotor Development Index), cerebral palsy, hearing or visual impairment, and anthropometric growth parameters. RESULTS: Among 448 preterm infants randomized (mean gestational age, 29.0 [range, 26.0-30.9] weeks; 264 [59%] female; mean birth weight, 1210 [range, 490-2290] g), 228 were randomized to rhEPO and 220 to placebo. Neurodevelopmental outcome data were available for 365 (81%) at a mean age of 23.6 months. In an intention-to-treat analysis, mean MDI was not statistically significantly different between the rhEPO group (93.5 [SD, 16.0] [95% CI, 91.2 to 95.8]) and the placebo group (94.5 [SD, 17.8] [95% CI, 90.8 to 98.5]) (difference, -1.0 [95% CI, -4.5 to 2.5]; P = .56). No differences were found between groups in the secondary outcomes. CONCLUSIONS AND RELEVANCE: Among very preterm infants who received prophylactic early high-dose rhEPO for neuroprotection, compared with infants who received placebo, there were no statistically significant differences in neurodevelopmental outcomes at 2 years. Follow-up for cognitive and physical problems that may not become evident until later in life is required. 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.

Impact of perinatal factors on continuous early monitoring of brain electrocortical activity in very preterm newborns by amplitude-integrated EEG.

BACKGROUND: Amplitude-integrated electroencephalogram (aEEG) is increasingly used for neuromonitoring in preterms. We aimed to quantify the effects of gestational age (GA), postnatal age (PNA), and other perinatal factors on the development of aEEG early after birth in very preterm newborns with normal cerebral ultrasounds. METHODS: Continuous aEEG was prospectively performed in 96 newborns (mean GA: 29.5 (range: 24.4-31.9) wk, birth weight 1,260 (580-2,120) g) during the first 96 h of life. aEEG tracings were qualitatively (maturity scores) and quantitatively (amplitudes) evaluated using preestablished criteria. RESULTS: A significant increase in all aEEG measures was observed between day 1 and day 4 and for increasing GA (P < 0.001). The effect of PNA on aEEG development was 6.4- to 11.3-fold higher than that of GA. In multivariate regression, GA and PNA were associated with increased qualitative and quantitative aEEG measures, whereas small-for-GA status was independently associated with increased maximum aEEG amplitude (P = 0.003). Morphine administration negatively affected all aEEG measures (P < .05), and caffeine administration negatively affected qualitative aEEG measures (P = 0.02). CONCLUSION: During the first few days after birth, aEEG activity in very preterm infants significantly develops and is strongly subjected to the effect of PNA. Perinatal factors may alter the early aEEG tracing and interfere with its interpretation.

Changes in cerebral oxygenation during early postnatal adaptation in newborns delivered by vacuum extraction measured by near-infrared spectroscopy.

BACKGROUND: Newborns delivered by vacuum extraction quite often show clinical signs of a hemodynamic compromise, which is difficult to assess in terms of severity. The conventional means to measure the hemodynamic status are not sensitive enough to appreciate the severity of general, and more specifically of cerebral circulatory imbalance. The aim was to study cerebral tissue oxygenation during postnatal adaptation in these infants using near-infrared spectroscopy. METHODS: The tissue hemoglobin index (THI), tissue oxygenation index (TOI), arterial oxygen saturation (pre-ductal SaO2) and heart rate (HR) were recorded immediately after birth, and again after 12-24 hours of life in 15 newborns delivered by vacuum extraction due to fetal distress. A comparison with 19 healthy newborns delivered by elective cesarean section was performed. RESULTS: Newborns delivered by vacuum extraction had significantly higher THI 10 to 15 minutes after birth. TOI and HR were significantly higher in the first 5 min and SaO2 in the first 10 minutes but then did not differ from those after cesarean section. CONCLUSION: Infants delivered by vacuum extraction following fetal distress show transient deviations in cerebral oxygenation and perfusion after birth which were not detectable after 24 hours.

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

BACKGROUND: In 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/DESIGN: Foetuses, 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. DISCUSSION: There 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 REGISTRATION: ClinicalTrials.gov: NCT01888380.

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.

Early High-Dose Erythropoietin and Cognitive Functions of School-Aged Children Born Very Preterm.

Importance: Children born very preterm are at risk for long-term neurodevelopmental sequelae. Prophylactic high-dose recombinant human erythropoietin (rhEpo) shortly after birth has not been shown to improve cognitive, motor, and behavioral development at 2 and 5 years. Objective: To investigate whether early high-dose rhEpo is associated with better executive functions and processing speed-late-maturing cognitive functions-in school-aged children born very preterm. Design, Setting, and Participants: This single-center cohort study was a prospective, observational follow-up study of a multicenter neonatal clinical trial; 365 children born very preterm (mean gestational age, 29.3 weeks [range, 26.0-31.9 weeks]) who had been enrolled in the Swiss EPO Neuroprotection Trial at birth between 2005 and 2012, and who were included in the primary outcome analyses at 2 years, were eligible to be recruited for the EpoKids study between 2017 and 2021 when they were at school age. Term-born children were additionally recruited and included in a control group. Data were analyzed between May and September 2022. Exposure: Administration of rhEpo (3000 IU/kg) or placebo (saline, 0.9%) intravenously 3 times within the first 2 days of life as part of the Swiss EPO Neuroprotection Trial. Main Outcome and Measures: A comprehensive neuropsychological test battery assessed executive functions and processing speed, and parents reported on their child's executive functions in everyday life to test the hypothesis that early high-dose rhEpo administration is associated with better cognitive outcomes at school age. Results: In the EpoKids study, 214 children born very preterm (58.6% of 365 children in eligible cohort) were assessed at a mean age of 10.4 years (range, 6.9-13.4 years); 117 (54.7%) were boys. There was no evidence that the 117 children who had received rhEpo differed from the 97 children who had received placebo in any of the 15 executive function and processing speed tests, nor in parent-rated executive functions (estimates ranged from -0.138 to 0.084, all 95% CIs included 0). Irrespective of rhEpo or placebo allocation, children born very preterm scored lower on 11 of 15 executive function and processing speed tests than term-born peers (estimates ranged from 0.112 to 0.255, 95% CIs did not include 0). Conclusion and Relevance: This study found no evidence for a positive association between prophylactic early high-dose rhEpo administration and long-term neurodevelopmental outcomes after very preterm birth. These results suggest that a comprehensive approach, including pharmacological and nonpharmacological prevention and intervention strategies, is needed to support these children's neurodevelopmental outcome.