Publications by authors named "Rolf F Maier"

59 Publications

Antwort: Erwiderung auf den Leserbrief von Prof. Dr. Pohlandt.

Z Geburtshilfe Neonatol 2021 02 18;225(1):84-85. Epub 2021 Feb 18.

Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Marburg, Philipps-Universität, Marburg.

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http://dx.doi.org/10.1055/a-1345-2165DOI Listing
February 2021

Follow-up after very preterm birth in Europe.

Arch Dis Child Fetal Neonatal Ed 2021 Feb 10. Epub 2021 Feb 10.

Université de Paris, CRESS, Obstetrical Perinatal and Pediatric Epidemiology Research Team, EPOPé, INSERM, INRA, F-75004 Paris, France.

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http://dx.doi.org/10.1136/archdischild-2020-320823DOI Listing
February 2021

Augenärztliche Screening-Untersuchung bei Frühgeborenen (S2k-Level, AWMF-Leitlinien-Register-Nr. 024/010, März 2020).

Z Geburtshilfe Neonatol 2021 02 15;225(1):19-33. Epub 2021 Jan 15.

Klinik und Poliklinik für Augenheilkunde, Universitätsmedizin Greifswald.

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http://dx.doi.org/10.1055/a-1248-0649DOI Listing
February 2021

[What is the Optimal Minimum Provider Volume in the Provision of Care for Preterm Infants with a Birth Weight below 1250 g in Germany?]

Z Geburtshilfe Neonatol 2020 Oct 19;224(5):289-296. Epub 2020 Oct 19.

Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Marburg, Philipps-Universität, Marburg.

Introduction: Numerous studies have investigated volume-outcome relationships in the treatment of very low birth weight infants. However, studies addressing the identification of optimal thresholds when introducing minimum provider volumes for treatment of these infants do not exist.

Methods: Publicly available data (www.perinatalzentren.org) of more than 56,000 infants weighing less than 1250 g at birth (NB<1250) and treated in level-1 perinatal centers (highest level in Germany) between 2010 and 2018 was used for statistical analysis. Potentially avoidable deaths after the introduction of minimum provider volumes were calculated by deducting observed deaths from estimated deaths based on logistic regression models for every existing empirical provider volume. Various smoothing functions were used to ascertain optimal thresholds for minimum provider volumes.

Results: Independent of the observation period or smoothing technique, the highest number of potentially avoidable deaths was observed for minimum provider volumes of 50-60 NB<1250 per year. Introducing a minimum provider volume of 50 without a transition period would reduce the number of level-1 perinatal centers to a quarter of the current number in Germany. Approximately 60% of NB<1250 would have to be reallocated.

Conclusion: Analyses of resulting geographical distances are needed in the preparation of minimum provider volumes for treatment of NB<1250 in Germany. Such analyses should include perinatal centers expected to reach minimum provider volumes after subsequent reallocation in the future.
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http://dx.doi.org/10.1055/a-1259-2689DOI Listing
October 2020

Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial.

JAMA 2020 08;324(6):560-570

Neonatology, University Children's Hospital Tübingen, Tübingen, Germany.

Importance: Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds.

Objective: To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability.

Design, Setting, And Participants: Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018.

Interventions: Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state.

Main Outcome And Measures: The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth.

Results: Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups.

Conclusions And Relevance: Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age.

Trial Registration: ClinicalTrials.gov Identifier: NCT01393496.
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http://dx.doi.org/10.1001/jama.2020.10690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7420159PMC
August 2020

Managing mother's own milk for very preterm infants in neonatal units in 11 European countries.

Acta Paediatr 2021 01 8;110(1):123-126. Epub 2020 Oct 8.

EPIUnit-Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.

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http://dx.doi.org/10.1111/apa.15518DOI Listing
January 2021

Survey on clinical use and non-use of recombinant human erythropoietin in European neonatal units.

J Perinat Med 2020 Sep;48(7):744-750

Zentrum fuer Kinder- und Jugendmedizin, Philipps-Universitaet Marburg, Marburg, Germany.

Objectives Recombinant human erythropoietin (rhEPO) has been shown to effectively and safely prevent the anemia of prematurity and to reduce the transfusion need in very low birth weight (VLBW) infants and has been licensed for this indication in Europe in 1997. The objective of the study was to obtain information on the use or non-use of rhEPO in neonatal units in Germany and other European countries. Methods Anonymized 14-questions web-based questionnaire. Results Seventy-nine questionnaires from Germany and 63 questionnaires from other 15 European countries were completed. Of the responders, 39% indicated to use rhEPO routinely or occasionally in VLBW infants, whereas 61% responded to never use rhEPO in this population. The major reasons given for non-use were lack of recommendation in national guidelines (69%) and/or doubt about efficacy of rhEPO to reduce transfusion need (53%). Twenty-seven percent of the responders indicated to use rhEPO for neonates with birth weights above 1,500 g. Neuroprotection in VLBW infants (26%) and hypoxic ischemic encephalopathy in term neonates (27%) were given as indications for off label use of rhEPO. Conclusions This survey indicates that rhEPO is used for the anemia of prematurity as licensed in less than half of neonatal units in Germany and other European countries. On the other hand it seems to be used off label in neonates for neuroprotection in a considerable number of units although there is no final evidence on its neuroprotective effects.
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http://dx.doi.org/10.1515/jpm-2020-0070DOI Listing
September 2020

Defining Very Preterm Populations for Systematic Reviews With Meta-analyses.

JAMA Pediatr 2020 Oct;174(10):997-999

Obstetrical, Perinatal and Pediatric Epidemiology Research Team (EPOPé), Université de Paris, Epidemiology and Statistics Research Center (CRESS), Institut national de la santé et de la recherche médicale (INSERM), Institut national de la recherche agronomique (INRA), Paris, France.

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http://dx.doi.org/10.1001/jamapediatrics.2020.0956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296455PMC
October 2020

Unit policies regarding tocolysis after preterm premature rupture of membranes: association with latency, neonatal and 2-year outcomes (EPICE cohort).

Sci Rep 2020 06 12;10(1):9535. Epub 2020 Jun 12.

EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal.

After preterm premature rupture of membranes (PPROM), antibiotics and antenatal steroids are effective evidence-based interventions, but the use of tocolysis is controversial. We investigated whether a unit policy of tocolysis use after PPROM is associated with prolonged gestation and improved outcomes for very preterm infants in units that systematically use these other evidence-based treatments. From the prospective, observational, population-based EPICE cohort study (all very preterm births in 19 regions from 11 European countries, 2011-2012), we included 607 women with a singleton pregnancy and PPROM at 24-29 weeks' gestation, of whom 101, 195 and 311 were respectively managed in 17, 32 and 45 units with no-use, restricted and liberal tocolysis policies for PPROM. The association between unit policies and outcomes (early-onset sepsis, survival at discharge, survival at discharge without severe morbidity and survival at two years without gross motor impairment) was investigated using three-level random-intercept logistic regression models, showing no differences in neonatal or two-year outcomes by unit policy. Moreover, there was no association between unit policies and prolongation of gestation in a multilevel survival analysis. Compared to a unit policy of no-use of tocolysis after PPROM, a liberal or restricted policy is not associated with improved obstetric, neonatal or two-year outcomes.
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http://dx.doi.org/10.1038/s41598-020-65201-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293322PMC
June 2020

Postnatal Corticosteroids Policy for Very Preterm Infants and Bronchopulmonary Dysplasia.

Neonatology 2020 26;117(3):308-315. Epub 2020 May 26.

Department of Neonatology, Jeanne de Flandre Hospital, Lille CHRU, Lille, France.

Introduction: Postnatal corticosteroids (PNC) are effective for reducing bronchopulmonary dysplasia (BPD) in very preterm neonates but are associated with adverse effects including an increased risk of cerebral palsy. PNC use in Europe is heterogeneous across regions. This study aimed to assess whether European neonatal intensive care units (NICUs) with a low use of PNC or an explicit policy to reduce PNC use had higher risks of mortality or BPD.

Methods: We included 3,126 infants in 105 NICUs born between 24 + 0 and 29 + 6 weeks' gestational age in 19 regions in 11 countries in the EPICE cohort. First, we identified clusters of NICUs using hierarchical clustering based on PNC use and BPD prevalence and compared case mix and mortality between the clusters. Second, a multilevel analysis was performed to evaluate the association between a restrictive PNC policy and BPD occurrence.

Results: There were 3 clusters of NICUs: 52 with low PNC use and a low BPD rate, 37 with low PNC use and a high BPD rate, and 16 with high PNC use and a medium BPD rate. Neonatal mortality did not differ between clusters (p = 0.88). A unit policy of restricted PNC use was not associated with a higher risk of BPD (odds ratio 0.68; 95% confidence interval: 0.45-1.03) after adjustment.

Conclusion: Up to 49% of NICUs had low PNC use and low BPD rates, without a difference in mortality. Infants hospitalized in NICUs with a stated policy of low PNC use did not have an increased risk of BPD.
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http://dx.doi.org/10.1159/000507195DOI Listing
May 2020

Priorities for collaborative research using very preterm birth cohorts.

Arch Dis Child Fetal Neonatal Ed 2020 Sep 6;105(5):538-544. Epub 2020 Feb 6.

University of Tartu, Tartu University Hospital, Tartu, Estonia.

Objectives: To develop research priorities on the consequences of very preterm (VPT) birth for the RECAP Preterm platform which brings together data from 23 European VPT birth cohorts.

Design And Setting: This study used a two-round modified Delphi consensus process. Round 1 was based on 28 research themes related to childhood outcomes (<12 years) derived from consultations with cohort researchers. An external panel of multidisciplinary stakeholders then ranked their top 10 themes and provided comments. In round 2, panel members provided feedback on rankings and on new themes suggested in round 1.

Results: Of 71 individuals contacted, 64 (90%) participated as panel members comprising obstetricians, neonatologists, nurses, general and specialist paediatricians, psychologists, physiotherapists, parents, adults born preterm, policy makers and epidemiologists from 17 countries. All 28 initial themes were ranked in the top 10 by at least six panel members. Highest ranking themes were: education (73% of panel members' top 10 choices); care and outcomes of extremely preterm births, including ethical decisions (63%); growth and nutrition (60%); emotional well-being and social inclusion (55%); parental stress (55%) and impact of social circumstances on outcomes (52%). Highest ranking themes were robust across panel members classified by background. 15 new themes had at least 6 top 10 endorsements in round 2.

Conclusions: This study elicited a broad range of research priorities on the consequences of VPT birth, with good consensus on highest ranks between stakeholder groups. Several highly ranked themes focused on the socioemotional needs of children and parents, which have been less studied.
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http://dx.doi.org/10.1136/archdischild-2019-317991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547907PMC
September 2020

What drives change in neonatal intensive care units? A qualitative study with physicians and nurses in six European countries.

Pediatr Res 2020 08 2;88(2):257-264. Epub 2020 Jan 2.

Obstetrics, Perinatal and Paediatric Epidemiology Research Team, Centre for Epidemiology and Biostatistics (U1153), INSERM and DHU Risks in Pregnancy, Paris-Descartes University, Paris, France.

Background: Innovation is important to improve patient care, but few studies have explored the factors that initiate change in healthcare organizations.

Methods: As part of the European project EPICE on evidence-based perinatal care, we carried out semi-structured interviews (N = 44) with medical and nursing staff from 11 randomly selected neonatal intensive care units in 6 countries. The interviews focused on the most recent clinical or organizational change in the unit relevant to the care of very preterm infants. Thematic analysis was performed using verbatim transcripts of recorded interviews.

Results: Reported changes concerned ventilation, feeding and nutrition, neonatal sepsis, infant care, pain management and care of parents. Six categories of drivers to change were identified: availability of new knowledge or technology; guidelines or regulations from outside the unit; need to standardize practices; participation in research; occurrence of adverse events; and wish to improve care. Innovations originating within the unit, linked to the availability of new technology and seen to provide clear benefit for patients were more likely to achieve consensus and rapid implementation.

Conclusions: Innovation can be initiated by several drivers that can impact on the success and sustainability of change.
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http://dx.doi.org/10.1038/s41390-019-0733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223325PMC
August 2020

Management of an Extremely Low Birth Weight Infant with Bilateral Renal Obstruction Caused by Fungus Balls.

Case Rep Urol 2019 5;2019:3684734. Epub 2019 Nov 5.

Department of Urology and Pediatric Urology, University Hospital, Philipps-University Marburg, Baldingerstr. 1, 35043 Marburg, Germany.

We report an extremely low birth weight infant with anuria caused by bilateral fungus balls it was treated with a combination of antifungal therapy, irrigation and pyelotomy. This lead to a recovery of renal function, after a follow-up of 77 month no more Candida was cultured from urine.
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http://dx.doi.org/10.1155/2019/3684734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875406PMC
November 2019

Zum Beitrag: Frühgeburtenrate in 6 Perinatalzentren in Baden-Württemberg – Potenzial zur Reduktion der Frühgeborenenzahl.

Z Geburtshilfe Neonatol 2019 Aug 20;223(4):245-246. Epub 2019 Aug 20.

Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Marburg.

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http://dx.doi.org/10.1055/a-0950-6770DOI Listing
August 2019

Characteristics, management and outcomes of very preterm triplets in 19 European regions.

Int J Gynaecol Obstet 2019 Dec 15;147(3):397-403. Epub 2019 Sep 15.

Department of Obstetrics, University Hospital, Philipps University, Marburg, Germany.

Objective: To describe obstetrical care and in-hospital outcomes in very preterm triplet pregnancies in a European multiregional cohort.

Methods: Data from a prospective population-based study of very preterm births between 22 + 0 and 31 + 6 weeks of gestation in 19 regions from 11 European countries participating in the EPICE project in 2011/2012 were used to describe triplet pregnancies and compare them with twins and singletons.

Results: Triplets constituted 1.1% of very preterm pregnancies (97/8851) and 3.3% of very preterm live births (258/7900); these percentages varied from 0% to 2.6% and 0% to 6% respectively across the regions. In-hospital mortality after live birth was 12.4% and did not differ significantly from singletons or twins or by birth order. However, 28.9% of mothers with a triplet pregnancy experienced at least one neonatal death. Ninety percent of live-born triplets were delivered by cesarean. Vaginal delivery was associated with an Apgar score of less than 7, but not with in-hospital mortality.

Conclusions: The prevalence of very preterm triplets varies across European regions. Most triplets were born by cesarean and those born vaginally had lower Apgar scores. Overall, in-hospital mortality after live birth was similar to singletons and twins.
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http://dx.doi.org/10.1002/ijgo.12939DOI Listing
December 2019

Specialist health care services use in a European cohort of infants born very preterm.

Dev Med Child Neurol 2019 07 3;61(7):832-839. Epub 2018 Dec 3.

Obstetrical, Perinatal and Pediatric Epidemiology Research Team, Center for Epidemiology and Statistics, Sorbonne Paris Cité, Paris, France.

Aim: Children born very preterm require additional specialist care because of the health and developmental risks associated with preterm birth, but information on their health service use is sparse. We sought to describe the use of specialist services by children born very preterm in Europe.

Method: We analysed data from the multi-regional, population-based Effective Perinatal Intensive Care in Europe (EPICE) cohort of births before 32 weeks' gestation in 11 European countries. Perinatal data were abstracted from medical records and parents completed a questionnaire at 2 years corrected age (4322 children; 2026 females, 2296 males; median gestational age 29wks, interquartile range [IQR] 27-31wks; median birthweight 1230g, IQR 970-1511g). We compared parent-reported use of specialist services by country, perinatal risk (based on gestational age, small for gestational age, and neonatal morbidities), maternal education, and birthplace.

Results: Seventy-six per cent of the children had consulted at least one specialist, ranging across countries from 53.7% to 100%. Ophthalmologists (53.4%) and physiotherapists (48.0%) were most frequently consulted, but individual specialists varied greatly by country. Perinatal risk was associated with specialist use, but the gradient differed across countries. Children with more educated mothers had higher proportions of specialist use in three countries.

Interpretation: Large variations in the use of specialist services across Europe were not explained by perinatal risk and raise questions about the strengths and limits of existing models of care.

What This Paper Adds: Use of specialist services by children born very preterm varied across Europe. This variation was observed for types and number of specialists consulted. Perinatal risk was associated with specialist care, but did not explain country-level differences. In some countries, mothers' educational level affected use of specialist services.
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http://dx.doi.org/10.1111/dmcn.14112DOI Listing
July 2019

Culture-Negative Early-Onset Neonatal Sepsis - At the Crossroad Between Efficient Sepsis Care and Antimicrobial Stewardship.

Front Pediatr 2018 9;6:285. Epub 2018 Oct 9.

Neonatal and Pediatric Intensive Care Unit, Children's Hospital, Lucerne, Switzerland.

Sepsis is a leading cause of mortality and morbidity in neonates. Presenting clinical symptoms are unspecific. Sensitivity and positive predictive value of biomarkers at onset of symptoms are suboptimal. Clinical suspicion therefore frequently leads to empirical antibiotic therapy in uninfected infants. The incidence of culture confirmed early-onset sepsis is rather low, around 0.4-0.8/1000 term infants in high-income countries. Six to 16 times more infants receive therapy for culture-negative sepsis in the absence of a positive blood culture. Thus, culture-negative sepsis contributes to high antibiotic consumption in neonatal units. Antibiotics may be life-saving for the few infants who are truly infected. However, overuse of broad-spectrum antibiotics increases colonization with antibiotic resistant bacteria. Antibiotic therapy also induces perturbations of the non-resilient early life microbiota with potentially long lasting negative impact on the individual's own health. Currently there is no uniform consensus definition for neonatal sepsis. This leads to variations in management. Two factors may reduce the number of culture-negative sepsis cases. First, obtaining adequate blood cultures (0.5-1 mL) at symptom onset is mandatory. Unless there is a strong clinical or biochemical indication to prolong antibiotics physician need to trust the culture results and to stop antibiotics for suspected sepsis within 36-48 h. Secondly, an international robust and pragmatic neonatal sepsis definition is urgently needed. Neonatal sepsis is a dynamic condition. Rigorous evaluation of clinical symptoms ("organ dysfunction") over 36-48 h in combination with appropriately selected biomarkers ("dysregulated host response") may be used to support or refute a sepsis diagnosis.
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http://dx.doi.org/10.3389/fped.2018.00285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189301PMC
October 2018

Duration and Time Trends in Hospital Stay for Very Preterm Infants Differ Across European Regions.

Pediatr Crit Care Med 2018 Dec;19(12):1153-1161

Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in pregnancy, Paris Descartes University, Paris, France.

Objectives: To compare duration and changes over time in length of hospital stay for very preterm and extremely preterm infants in 10 European regions.

Design: Two area-based cohort studies from the same regions in 2003 and 2011/2012.

Setting: Ten regions from nine European countries.

Patients: Infants born between 22 + 0 and 31 + 6 weeks of gestational age and surviving to discharge (Models of Organising Access to Intensive Care for Very Preterm Births cohort in 2003, n = 4,011 and Effective Perinatal Intensive Care in Europe cohort in 2011/2012, n = 4,336).

Interventions: Observational study, no intervention.

Measurements And Main Results: Maternal and infant characteristics were abstracted from medical records using a common protocol and length of stay until discharge was adjusted for case-mix using negative binomial regression. Mean length of stay was 63.6 days in 2003 and varied from 52.4 to 76.5 days across regions. In 2011/2012, mean length of stay was 63.1 days, with a narrower regional range (54.0-70.1). Low gestational age, small for gestational age, low 5-minute Apgar score, surfactant administration, any surgery, and severe neonatal morbidities increased length of stay. Infant characteristics explained some of the differences between regions and over time, but large variations remained after adjustment. In 2011/2012, mean adjusted length of stay ranged from less than 54 days in the Northern region of the United Kingdom and Wielkopolska, Poland to over 67 days in the Ile-de-France region of France and the Eastern region of the Netherlands. No systematic decrease in very preterm length of stay was observed over time after adjustment for patient case-mix.

Conclusions: A better understanding of the discharge criteria and care practices that contribute to the wide differences in very preterm length of stay across European regions could inform policies to optimize discharge decisions in terms of infant outcomes and health system costs.
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http://dx.doi.org/10.1097/PCC.0000000000001756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282674PMC
December 2018

Cohort study from 11 European countries highlighted differences in the use and efficacy of hypothermia prevention strategies after very preterm birth.

Acta Paediatr 2018 06 19;107(6):958-966. Epub 2018 Feb 19.

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Aim: This study investigated the different strategies used in 11 European countries to prevent hypothermia, which continues to affect a large proportion of preterm births in the region.

Methods: We examined the association between the reported use of hypothermia prevention strategies in delivery rooms and body temperatures on admission to neonatal intensive care units (NICUs) in 5861 infants born at 22 + 0 to 31 +6 weeks of gestation. The use of plastic bags, wraps, caps, exothermic heat and mattresses was investigated.

Results: The proportion of infants born in units that systematically used one or more hypothermia prevention strategies was 88.2% and 50.9% of those infants were hypothermic on admission to NICUs. Of the 9.6% born in units without systematic hypothermia prevention, 73.2% were hypothermic. Only 2.2% of infants were born in units with no reported prevention strategies. Lower gestational age increased the probability of hypothermia. No significant differences were found between the various hypothermia prevention strategies. Hyperthermia was seen in 4.8% of all admitted infants.

Conclusion: Very preterm infants had lower risks of hypothermia on NICU admission if the unit used systematic prevention strategies. All the strategies had similar effects, possibly due to implementation rather than a strategy's specific efficacy.
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http://dx.doi.org/10.1111/apa.14230DOI Listing
June 2018

Wide variation in severe neonatal morbidity among very preterm infants in European regions.

Arch Dis Child Fetal Neonatal Ed 2019 Jan 20;104(1):F36-F45. Epub 2018 Jan 20.

Department of Health Sciences, University of Leicester, Leicester, UK.

Objective: To investigate the variation in severe neonatal morbidity among very preterm (VPT) infants across European regions and whether morbidity rates are higher in regions with low compared with high mortality rates.

Design: Area-based cohort study of all births before 32 weeks of gestational age.

Setting: 16 regions in 11 European countries in 2011/2012.

Patients: Survivors to discharge from neonatal care (n=6422).

Main Outcome Measures: Severe neonatal morbidity was defined as intraventricular haemorrhage grades III and IV, cystic periventricular leukomalacia, surgical necrotizing enterocolitis and retinopathy of prematurity grades ≥3. A secondary outcome included severe bronchopulmonary dysplasia (BPD), data available in 14 regions. Common definitions for neonatal morbidities were established before data abstraction from medical records. Regional severe neonatal morbidity rates were correlated with regional in-hospital mortality rates for live births after adjustment on maternal and neonatal characteristics.

Results: 10.6% of survivors had a severe neonatal morbidity without severe BPD (regional range 6.4%-23.5%) and 13.8% including severe BPD (regional range 10.0%-23.5%). Adjusted inhospital mortality was 13.7% (regional range 8.4%-18.8%). Differences between regions remained significant after consideration of maternal and neonatal characteristics (P<0.001) and severe neonatal morbidity rates were not correlated with mortality rates (P=0.50).

Conclusion: Severe neonatal morbidity rates for VPT survivors varied widely across European regions and were independent of mortality rates.
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http://dx.doi.org/10.1136/archdischild-2017-313697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762001PMC
January 2019

Serum titers of autoantibodies against α-synuclein and tau in child- and adulthood.

J Neuroimmunol 2018 02 11;315:33-39. Epub 2017 Dec 11.

Department of Neurology, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany; Chair of Geriatrics, University Hospital Essen, University Duisburg-Essen, Germaniastrasse 1-3, 45356 Essen, Germany.

Autoreactive antibodies against the proteins alpha-synuclein (α-syn) and tau are detectable in body fluids of both healthy and diseased elderly people. However, nothing is known about their presence or titers in children. To close this gap and to characterize their temporary expression levels, we used ELISA techniques to investigate the serum titers of α-syn and tau reactive autoantibodies in 37 and 32 adults and 37 and 31 children, respectively. Most serum samples from the children exhibited both antibody types and interestingly, the levels were similar to those observed in the adult serum samples. Furthermore, sex-specific analysis revealed significantly increased α-syn reactive autoantibody titers in female children. The presence of α-syn and tau reactive autoantibodies in early childhood indicates that both immunoglobulins belong to the pool of naturally occurring autoantibodies (nAbs), as their antigen-independent synthesis from birth is a crucial characteristic. Due to their general participation in the maintenance of the physiological homeostasis, we hypothesize that both investigated nAbs are involved in the metabolic regulation of their specific antigen. Therefore, they may be a part of a mechanism that already exists in the innate immunological repertoire to provide protection from pathologies caused by dysregulated α-syn and tau metabolisms.
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http://dx.doi.org/10.1016/j.jneuroim.2017.12.003DOI Listing
February 2018

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort.

JAMA Pediatr 2017 07;171(7):678-686

INSERM Joint Research Unit 1153, Obstetrical, Perinatal, and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, University Hospital Department Risks in Pregnancy, Paris Descartes University, Paris, France.

Importance: Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown.

Objective: To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants.

Design, Setting, And Participants: The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016.

Exposure: Time from first injection of ANS to delivery in hours and days.

Main Outcomes And Measures: Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia.

Results: Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%.

Conclusions And Relevance: Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.
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http://dx.doi.org/10.1001/jamapediatrics.2017.0602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710338PMC
July 2017

Variation in term birthweight across European countries affects the prevalence of small for gestational age among very preterm infants.

Acta Paediatr 2017 Sep 8;106(9):1447-1455. Epub 2017 Jun 8.

Children's Hospital, University Hospital, Philipps University, Marburg, Germany.

Aim: This study assessed the prevalence of small for gestational age (SGA) among very preterm (VPT) infants using national and European intrauterine references.

Methods: We generated country-specific and common European intrauterine growth references for 11 European countries, according to Gardosi's approach and Hadlock's foetal growth model, using national data on birthweights by sex. These references were applied to the Effective Perinatal Intensive Care in Europe (EPICE) cohort, which comprised 7766 live VPT births without severe congenital anomalies under 32 weeks of gestation in 2011-2012, to estimate the prevalence of infants with SGA birthweights, namely those below the 10th percentile.

Results: The SGA prevalence was 31.8% with country-specific references and 34.0% with common European references. The European references yielded a 10-point difference in the SGA prevalence between countries with lower term birthweights (39.9%) - Portugal, Italy and France - and higher term birthweights, namely Denmark, the Netherlands, Sweden (28.9%; p < 0.001). This was not observed with country-specific references, where the respective figures were 32.4% and 33.9% (p = 0.34), respectively.

Conclusion: One-third of VPT infants were SGA according to intrauterine references. Common European references showed significant differences in SGA prevalence between countries with high and low-term birthweights.
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http://dx.doi.org/10.1111/apa.13899DOI Listing
September 2017

Variability in Very Preterm Stillbirth and In-Hospital Mortality Across Europe.

Pediatrics 2017 Apr;139(4)

INSERM, Obstetrical, Perinatal and Paediatric Epidemiology Research Team, Centre for Epidemiology and Biostatistics (U1153), Paris-Descartes University, Paris, France.

Background And Objective: Stillbirth and in-hospital mortality rates associated with very preterm births (VPT) vary widely across Europe. International comparisons are complicated by a lack of standardized data collection and differences in definitions, registration, and reporting. This study aims to determine what proportion of the variation in stillbirth and in-hospital VPT mortality rates persists after adjusting for population demographics, case-mix, and timing of death.

Methods: Standardized data collection for a geographically defined prospective cohort of VPTs (22-31 weeks gestation) across 16 regions in Europe. Crude and adjusted stillbirth and in-hospital mortality rates for VPT infants were calculated by time of death by using multinomial logistic regression models.

Results: The stillbirth and in-hospital mortality rate for VPTs was 27.7% (range, 19.9%-35.9% by region). Adjusting for maternal and pregnancy characteristics had little impact on the variation. The addition of infant characteristics reduced the variation of mortality rates by approximately one-fifth (4.8% to 3.9%). The SD for deaths <12 hours after birth was reduced by one-quarter, but did not change after risk adjustment for deaths ≥12 hours after birth.

Conclusions: In terms of the regional variation in overall VPT mortality, over four-fifths of the variation could not be accounted for by maternal, pregnancy, and infant characteristics. Investigation of the timing of death showed that these characteristics only accounted for a small proportion of the variation in VPT deaths. These findings suggest that there may be an inequity in the quality of care provision and treatment of VPT infants across Europe.
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http://dx.doi.org/10.1542/peds.2016-1990DOI Listing
April 2017

Patent Ductus Arteriosus Treatment in Very Preterm Infants: A European Population-Based Cohort Study (EPICE) on Variation and Outcomes.

Neonatology 2017 26;111(4):367-375. Epub 2017 Jan 26.

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Background: Spontaneous closure of patent ductus arteriosus (PDA) occurs frequently in very preterm infants and despite the lack of evidence for treatment benefits, treatment for PDA is common in neonatal medicine.

Objectives: The aim of this work was to study regional variations in PDA treatment in very preterm infants (≤31 weeks of gestation), its relation to differences in perinatal characteristics, and associations with bronchopulmonary dysplasia (BPD) and survival without major neonatal morbidity.

Methods: This was a population-based cohort study in 19 regions in 11 European countries conducted during 2011 and 2012. A total of 6,896 infants with data on PDA treatment were included. The differences in infant characteristics were studied across regions using a propensity score derived from perinatal risk factors for PDA treatment. The primary outcomes were a composite of BPD or death before 36 weeks postmenstrual age, or survival without major neonatal morbidity.

Results: The proportion of PDA treatment varied from 10 to 39% between regions (p < 0.001), and this difference could not be explained by differences in perinatal characteristics. The regions were categorized according to a low (<15%, n = 6), medium (15-25%, n = 9), or high (>25%, n = 4) proportion of PDA treatment. Infants treated for PDA, compared to those not treated, were at higher risk of BPD or death in all regions, with an overall propensity score adjusted risk ratio of 1.33 (95% confidence interval 1.18-1.51). Survival without major neonatal morbidity was not related to PDA treatment.

Conclusions: PDA treatment varies largely across Europe without associated variations in perinatal characteristics or neonatal outcomes. This finding calls for more uniform guidance for PDA diagnosis and treatment in very preterm infants.
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http://dx.doi.org/10.1159/000454798DOI Listing
March 2018

Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide.

PLoS One 2017 3;12(1):e0169352. Epub 2017 Jan 3.

Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, Division of Neonatology, University of Leipzig, Leipzig, Germany.

Background: Ventilated preterm infants frequently develop bronchopulmonary dysplasia (BPD) which is associated with elevated inflammatory mediators in their tracheal aspirates (TA). In animal models of BPD, inhaled nitric oxide (iNO) has been shown to reduce lung inflammation, but data for human preterm infants is missing.

Methods: Within a European multicenter trial of NO inhalation for preterm infants to prevent BPD (EUNO), TA was collected to determine the effects of iNO on pulmonary inflammation. TA was collected from 43 premature infants randomly assigned to receive either iNO or placebo gas (birth weight 530-1230 g, median 800 g, gestational age 24 to 28 2/7 weeks, median 26 weeks). Interleukin (IL)-1β, IL-6, IL-8, transforming growth factor (TGF)-β1, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, acid sphingomyelinase (ASM), neuropeptide Y and leukotriene B4 were measured in serial TA samples from postnatal day 2 to 14. Furthermore, TA levels of nitrotyrosine and nitrite were determined under iNO therapy.

Results: The TA levels of IP-10, IL-6, IL-8, MIP-1α, IL-1β, ASM and albumin increased with advancing postnatal age in critically ill preterm infants, whereas nitrotyrosine TA levels declined in both, iNO-treated and placebo-treated infants. The iNO treatment generally increased nitrite TA levels, whereas nitrotyrosine TA levels were not affected by iNO treatment. Furthermore, iNO treatment transiently reduced early inflammatory and fibrotic markers associated with BPD development including TGF-β1, IP-10 and IL-8, but induced a delayed increase of ASM TA levels.

Conclusion: Treatment with iNO may have played a role in reducing several inflammatory and fibrotic mediators in TA of preterm infants compared to placebo-treated infants. However, survival without BPD was not affected in the main EUNO trial.

Trial Registration: NCT00551642.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207654PMC
August 2017