Publications by authors named "Jean-Claude Fauchère"

45 Publications

Effect of Early Recombinant Human Erythropoietin on Neurodevelopmental Outcomes at Age 5 Years-Reply.

JAMA 2021 04;325(14):1471-1472

Department of Neonatology, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1001/jama.2021.0836DOI Listing
April 2021

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

Acta Paediatr 2021 Mar 3. Epub 2021 Mar 3.

Department of Neonatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1111/apa.15828DOI Listing
March 2021

Overlapping borders: limit of viability and late terminations of pregnancy - a retrospective multicentre observational study.

Swiss Med Wkly 2020 Jan 7;150:w20186. Epub 2020 Feb 7.

NEO FOR NAMIBIA, Lucerne, Switzerland.

Aims Of The Study: Based on an incidental observation made in the context of the Swiss National Science Foundation (SNSF) Project 67 “End-of-life decision-making in extremely low birth weight infants in Switzerland”, this retrospective multicentre observational study aimed to analyse circumstances of delivery room deaths after late termination of pregnancy (LTOP) in Switzerland over a 3-year period.

Methods: All delivery room deaths (including live and stillbirths) following LTOP among infants with a gestational age between 22 0/7 and 27 6/7 weeks at the nine Swiss level III perinatal centres between 1 July 2012 and 30 June 2015 were analysed. Indications for LTOP were classified as either (a) maternal emergencies or (b) fetal anomalies severe enough to cause significant maternal psychological distress. Whenever possible, specific diagnoses were recorded. Spontaneous intrapartum death and fetal death caused by injection of a cardioplegic drug were distinguished for stillborn infants.

Results: A total of 465 delivery room deaths among extremely low gestational age newborns (ELGANs) were identified over the 3-year study period of the SNSF project. Of these, 195 (42%) occurred in the context of LTOP. Central nervous system malformations, chromosomal anomalies, severe congenital heart disease, multiple malformations and maternal emergencies accounted for 70% of all LTOPs. LTOPs resulted in live births in 76 (39%) cases. No correlation between gestational age and rate of live births was observed. Fetal death caused by injection of a cardioplegic drug was documented in only three cases. All infants born alive after LTOP died in the delivery room without resuscitation attempts. The use of drugs for palliative care in these patients was either rare or, alternatively, incompletely documented.

Conclusion: LTOPs contribute significantly to mortality rates among ELGANs and should therefore be included in perinatal registries. Uniform reporting of LTOPs should be established. Infants born alive after LTOP are entitled to comprehensive palliative care like any other infant born under different circumstances. Development of national guidelines for LTOPs (including the role of fetal death caused by injection of a cardioplegic drug and palliative birth as an alternative to induced abortion) would be highly desirable to guarantee acceptable standards of care.
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http://dx.doi.org/10.4414/smw.2020.20186DOI Listing
January 2020

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

BMC Pediatr 2020 Jan 31;20(1):47. Epub 2020 Jan 31.

Department of Neonatology, University Hospital Zurich, Frauenklinikstrasse 10, 8091, Zürich, Switzerland.

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.
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http://dx.doi.org/10.1186/s12887-019-1890-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993516PMC
January 2020

Performance Assessment of a Dedicated Reflectance Pulse Oximeter in a Neonatal Intensive Care Unit.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:1502-1505

The measurement of peripheral oxygen saturation (SpO2) in neonatal intensive care units (NICUs) poses a significant challenge. Motion artifacts due to the patient's limb motion induce many false alarms, which in turn cause an additional workload for the medical staff and anxiety for the parents. We developed a reflectance pulse oximeter dedicated to be placed at the patient's forehead, which is less prone to such artifacts. We trained our algorithms for SpO2 estimation on 8 adult healthy volunteers participating in a controlled desaturation study. We then validated our SpO2 monitoring system on 25 newborn patients monitored in an NICU. We further evaluated the versatility and resilience to low signal-tonoise ratios (SNR) of our solution by testing it on signals acquired in a low-perfusion region (upper right part of the chest) of our adult volunteers. We obtained an SpO2 estimation accuracy ($A _{\mathbf {rms}}$) of 1.9 % and 3.1 % at the forehead and the chest in our adult volunteers, respectively. These performances were obtained after automatic rejection of 0.1 % and 30.0 %, respectively, of low-SNR signals by our dedicated quality index. In the dataset recorded on newborn patients in the NICU, we obtained an accuracy of 3.9 % after automatic rejection of 11.7 % of low-SNR signals by our quality index. These analyses were carried out following the procedures suggested by the ISO 80601-2-61:2011 standard, which specifies a target $A _{\mathbf {rms}} \le $ 4 % for SpO2 monitoring applications. These promising results suggest that reflectance pulse oximeters can achieve clinically acceptable accuracy, while being placed at locations less sensitive to limb motion artifacts - such as the forehead - thereby reducing the amount of SpO2-related false alarms in NICUs.
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http://dx.doi.org/10.1109/EMBC.2018.8512504DOI Listing
July 2018

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

BMC Pediatr 2018 07 9;18(1):226. Epub 2018 Jul 9.

Department of Neonatology, University Hospital Zurich, Frauenklinikstrasse 10, 8091, Zürich, Switzerland.

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.
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http://dx.doi.org/10.1186/s12887-018-1204-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038305PMC
July 2018

Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study.

BMJ Open 2018 04 24;8(4):e022157. Epub 2018 Apr 24.

Department of Neonatology and Pediatric Intensive Care, University Children's Hospital Zurich, Zurich, Switzerland.

Introduction: Premature infants are particularly vulnerable to brain injuries with associated cognitive and behavioural deficits. The worldwide first randomised interventional multicentre trial investigating the neuroprotective effects of erythropoietin (entitled 'Does erythropoietin improve outcome in very preterm infants?' (NCT00413946)) included 450 very preterm infants in Switzerland. MRI at term equivalent age showed less white matter (WM) injury in the erythropoietin group compared with the placebo group. Despite these promising imaging findings, neurodevelopmental outcome at 2 years showed no beneficial effect of early erythropoietin. One explanation could be that the assessment of more complex cognitive functions such as executive functions (EFs) is only possible at a later age. We hypothesise that due to improved WM development and fewer WM injuries, children born preterm treated with early erythropoietin will have better EF abilities at 7-12 years than those treated with placebo.

Methods And Analysis: 365 children who were included into the primary analysis of the original trial (NCT00413946) will be eligible in this prospective follow-up study at the age of 7-12 years. 185 children born at term will be control children. Primary outcome measures are EF abilities and processing speed, while secondary outcomes are academic performance, IQ, fine motor abilities and global brain connectivity. A comprehensive test battery will be applied to assess EFs. MRI will be performed to assess global brain connectivity. Cognitive scores and MRI measures will be compared between both groups using the Wilcoxon test. Propensity score matching will be used to balance gender, age, socioeconomic status and other potentially unbalanced variables between the children born preterm and the healthy control children.

Ethics And Dissemination: The cantonal ethical committee granted ethical approval for this study (KEK 2017-00521). Written consent will be obtained from the parents. Findings from this study will be disseminated via international and national conference presentations and publications in peer-reviewed journals.
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http://dx.doi.org/10.1136/bmjopen-2018-022157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922511PMC
April 2018

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

BMC Pediatr 2018 02 22;18(1):81. Epub 2018 Feb 22.

Department of Neonatology, University Hospital Zurich, Frauenklinikstrasse 10, 8091, Zürich, Switzerland.

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.
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http://dx.doi.org/10.1186/s12887-018-1040-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822553PMC
February 2018

Sources of distress for physicians and nurses working in Swiss neonatal intensive care units.

Swiss Med Wkly 2017 3;147:w14477. Epub 2017 Aug 3.

Department of Neonatology, Perinatal Centre, University Hospital Zurich, University of Zurich, Switzerland.

Background: Medical personnel working in intensive care often face difficult ethical dilemmas. These may represent important sources of distress and may lead to a diminished self-perceived quality of care and eventually to burnout.

Aims Of The Study: The aim of this study was to identify work-related sources of distress and to assess symptoms of burnout among physicians and nurses working in Swiss neonatal intensive care units (NICUs).

Methods: In summer 2015, we conducted an anonymous online survey comprising 140 questions about difficult ethical decisions concerning extremely preterm infants. Of these 140 questions, 12 questions related to sources of distress and 10 to burnout. All physicians and nurses (n = 552) working in the nine NICUs in Switzerland were invited to participate.

Results: The response rate was 72% (398). The aspects of work most commonly identified as sources of distress were: lack of regular staff meetings, lack of time for routine discussion of difficult cases, lack of psychological support for the NICU staff and families, and missing transmission of important information within the caregiver team. Differences between physicians' and nurses' perceptions became apparent: for example, nurses were more dissatisfied with the quality of the decision-making process. Different perceptions were also noted between staff in the German- and French- speaking parts of Switzerland: for example, respondents from the French part rated lack of regular staff meetings as being more problematic. On the other hand, personnel in the French part were more satisfied with their accomplishments in the job. On average, low levels of burnout symptoms were revealed, and only 6% of respondents answered that the work-related burden often affected their private life.

Conclusions: Perceived sources of distress in Swiss NICUs were similar to those in ICU studies. Despite rare symptoms of burnout, communication measures such as regular staff meetings and psychological support to prevent distress were clearly requested.
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http://dx.doi.org/10.4414/smw.2017.14477DOI Listing
June 2018

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

Children (Basel) 2017 05 30;4(6). Epub 2017 May 30.

Department of Neonatology, University Hospital Zürich, 8091 Zürich, Switzerland.

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.
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http://dx.doi.org/10.3390/children4060043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483618PMC
May 2017

Exploring societal solidarity in the context of extreme prematurity.

Swiss Med Wkly 2017 7;147:w14418. Epub 2017 Mar 7.

Institute of Biomedical Ethics and History of Medicine, University of Zurich, Switzerland.

Question: Extreme prematurity can result in long-term disabilities. Its impact on society is often not taken into account and deemed controversial. Our study examined attitudes of the Swiss population regarding extreme prematurity and people's perspectives regarding the question of solidarity with disabled people.

Methods: We conducted a nationwide representative anonymous telephone survey with 1210 Swiss residents aged 18 years or older. We asked how people estimate their own personal solidarity, the solidarity of their social environment and the solidarity across the country with disabled persons. Spearman's correlation calculations were used to assess if a correlation exists between solidarity and setting financial limits to intensive care and between solidarity and withholding neonatal intensive care.

Results: According to 36.0% of the respondents intensive medical care should not be withheld from extremely preterm infants, even if their chances for an acceptable quality of life were poor. For 28.8%, intensive care should be withheld from these infants, and 26.9% held an intermediate position depending on the situation. A total of 31.5% were against setting a financial limit to treatment of extremely preterm newborns with an uncertain future quality of life, 34.2% were in favour and 26.9% were deliberating. A majority (88.8%) considered their solidarity toward disabled people as substantial; the solidarity of their personal environment and of the society at large was estimated as high by 79.1% and 48.6%, respectively.

Conclusions: The Swiss population expressed a high level of solidarity which may alleviate some pressure on parents and health care providers in the decision-making process in neonatal intensive care units. In addition, there was no relationship between solidarity and people's willingness to pay for the care or withholding treatment of extremely preterm babies.
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http://dx.doi.org/10.4414/smw.2017.14418DOI Listing
October 2017

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

Acta Paediatr 2017 Mar 22;106(3):423-429. Epub 2016 Dec 22.

Department of Neonatology, Perinatal Centre, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1111/apa.13680DOI Listing
March 2017

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

JAMA 2016 May;315(19):2079-85

Department of Neonatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1001/jama.2016.5504DOI Listing
May 2016

Noninvasive prenatal testing: more caution in counseling is needed in high risk pregnancies with ultrasound abnormalities.

Eur J Obstet Gynecol Reprod Biol 2016 May 8;200:72-5. Epub 2016 Mar 8.

Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.

Objective: Non-invasive prenatal testing (NIPT) is increasingly being used in prenatal aneuploidy screening. The objective of this study was to assess the positive predictive value in our cohort of 68 cases with positive NIPT result. In addition, we wondered if the use of NIPT in cases with ultrasound abnormalities is appropriate, given the limited number of chromosomes investigated.

Design: We performed confirmative invasive testing using karyotyping, fluorescence in situ hybridization (FISH) and/or high-resolution chromosomal microarray analysis.

Results: In line with the published data, the positive NIPT result was confirmed in 64.7% of cases. Inconclusive and negative NIPT results followed by cytogenetically pathologic findings were encountered in three and in five cases, respectively. Four of the five fetuses with negative NIPT but pathologic cytogenetic findings were born with several malformations and diagnosed right after birth with severe genetic conditions. Of note, in all of those four cases, NIPT was offered despite the finding of major fetal ultrasound abnormalities and despite the fact that the family would not have opposed invasive testing or pregnancy termination.

Conclusion: More education of health care providers and caution in counseling and interpretation of test results are needed in order to meet the challenges that this new test, which enriches our diagnostic options in prenatal testing, poses.
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http://dx.doi.org/10.1016/j.ejogrb.2016.02.042DOI Listing
May 2016

Characterizing Fluctuations of Arterial and Cerebral Tissue Oxygenation in Preterm Neonates by Means of Data Analysis Techniques for Nonlinear Dynamical Systems.

Adv Exp Med Biol 2016 ;876:511-519

Biomedical Optics Research Laboratory, Department of Neonatology, University Hospital Zurich, University of Zurich, 8091, Zurich, Switzerland.

The cerebral autoregulatory state as well as fluctuations in arterial (SpO2) and cerebral tissue oxygen saturation (StO2) are potentially new relevant clinical parameters in preterm neonates. The aim of the present study was to test the investigative capabilities of data analysis techniques for nonlinear dynamical systems, looking at fluctuations and their interdependence. StO2, SpO2 and the heart rate (HR) were measured on four preterm neonates for several hours. The fractional tissue oxygenation extraction (FTOE) was calculated. To characterize the fluctuations in StO2, SpO2, FTOE and HR, two methods were employed: (1) phase-space modeling and application of the recurrence quantification analysis (RQA), and (2) maximum entropy spectral analysis (MESA). The correlation between StO2 and SpO2 as well as FTOE and HR was quantified by (1) nonparametric nonlinear regression based on the alternating conditional expectation (ACE) algorithm, and (2) the maximal information-based nonparametric exploration (MINE) technique. We found that (1) each neonate showed individual characteristics, (2) a ~60 min oscillation was observed in all of the signals, (3) the nonlinear correlation strength between StO2 and SpO2 as well as FTOE and HR was specific for each neonate and showed a high value for a neonate with a reduced health status, possibly indicating an impaired cerebral autoregulation. In conclusion, our data analysis framework enabled novel insights into the characteristics of hemodynamic and oxygenation changes in preterm infants. To the best of our knowledge, this is the first application of RQA, MESA, ACE and MINE to human StO2 data measured with near-infrared spectroscopy (NIRS).
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http://dx.doi.org/10.1007/978-1-4939-3023-4_64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125790PMC
May 2016

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

J Pediatr 2015 Jul 8;167(1):52-7.e1-3. Epub 2015 Apr 8.

Division of Neonatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1016/j.jpeds.2015.02.052DOI Listing
July 2015

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

Neonatology 2014 20;106(2):114-9. Epub 2014 Jun 20.

Division of Neonatology, University Hospital Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1159/000362784DOI Listing
May 2015

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

BMC Pediatr 2014 Jan 27;14:21. Epub 2014 Jan 27.

Division of Neonatology, Department Obstetrics & Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, Zurich CH-8091, Switzerland.

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.
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http://dx.doi.org/10.1186/1471-2431-14-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913969PMC
January 2014

The European database for subspecialist training in neonatology - transparency achieved.

Neonatology 2013 31;103(1):74-82. Epub 2012 Oct 31.

Department of Neonatology, The National University Hospital Rigshospitalet, Copenhagen, Denmark. Breindahl @ dadlnet.dk

Background: The European Society for Neonatology (ESN) developed a curriculum for subspecialist training in Europe recommending standards for national neonatal training programmes. We speculate whether these official recommendations are widely accepted or used in practice.

Objectives: To characterize the variation in national neonatal training programmes, to enhance transparency, and to compare them to the ESN Curriculum.

Methods: We constructed a database based on the backbone of the ESN Curriculum: (1) training - knowledge, (2) training - skills, (3) key competencies, (4) personal development, and (5) recording of progress. National neonatal representatives from all 30 member states of the Union of European Medical Specialties (UEMS) provided data on national training programmes.

Results: Although only one country (3%) based its neonatology training entirely on the ESN Curriculum, we found high levels of uniformity among the UEMS member countries regarding knowledge, skills, and key competencies needed to practice neonatology at a tertiary care level. Discrepancy was encountered on ethical and legal issues and on personal development of the trainees. Mentoring and professional evaluation was generally not implemented in the participating countries.

Conclusions: There is an awareness and readiness to focus on educational demands for neonatal trainees. Further discussions about the overall educational goals of neonatal training and the essence of practicing neonatology in each country are needed. The ESN will undertake this process to provide an updated and effective syllabus aimed to harmonize care and outcomes for babies and their families across Europe.
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http://dx.doi.org/10.1159/000342932DOI Listing
May 2013

Urinary erythropoietin concentrations after early short-term infusion of high-dose recombinant epo for neuroprotection in preterm neonates.

Neonatology 2012 4;102(3):172-7. Epub 2012 Jul 4.

Department of Neonatology, Charité - Universitätsmedizin Berlin, Germany.

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.
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http://dx.doi.org/10.1159/000339283DOI Listing
February 2013

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland. 2011 revision of the Swiss recommendations.

Swiss Med Wkly 2011 18;141:w13280. Epub 2011 Oct 18.

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

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.
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http://dx.doi.org/10.4414/smw.2011.13280DOI Listing
February 2012

Reproducibility of cerebral tissue oxygen saturation measurements by near-infrared spectroscopy in newborn infants.

J Biomed Opt 2011 Sep;16(9):097004

University Hospital Zurich, Biomedical Optics Research Laboratory, Division of Neonatology, Department of Obstetrics and Gynecology, 8091 Zurich, Switzerland.

Early detection of cerebral hypoxemia is an important aim in neonatology. A relevant parameter to assess brain oxygenation may be the cerebral tissue oxygen saturation (StO(2)) measured by near-infrared spectroscopy (NIRS). So far the reproducibility of StO(2) measurements was too low for clinical application, probably due to inhomogeneities. The aim of this study was to test a novel sensor geometry which reduces the influence of inhomogeneities. Thirty clinically stable newborn infants, with a gestational age of median 33.9 (range 26.9 to 41.9) weeks, birth weight of 2220 (820 to 4230) g, postnatal age of 5 (1 to 71) days were studied. At least four StO(2) measurements of 1 min duration were carried out using NIRS on the lateral head. The sensor was repositioned between measurements. Reproducibility was calculated by a linear mixed effects model. The mean StO(2) was 79.99 ± 4.47% with a reproducibility of 2.76% and a between-infant variability of 4.20%. Thus, the error of measurement only accounts for 30.1% of the variability. The novel sensor geometry leads to considerably more precise measurements compared to previous studies with, e.g., ∼5% reproducibility for the NIRO 300. The novel StO(2) values hence have a higher clinical relevance.
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http://dx.doi.org/10.1117/1.3622756DOI Listing
September 2011

MicroRNA-96 directly inhibits γ-globin expression in human erythropoiesis.

PLoS One 2011 28;6(7):e22838. Epub 2011 Jul 28.

Division of Haematology, University Children's Hospital, Zurich, Switzerland.

Fetal hemoglobin, HbF (α(2)γ(2)), is the main hemoglobin synthesized up to birth, but it subsequently declines and adult hemoglobin, HbA (α(2)β(2)), becomes predominant. Several studies have indicated that expression of the HbF subunit γ-globin might be regulated post-transcriptionally. This could be confered by ∼22-nucleotide long microRNAs that associate with argonaute proteins to specifically target γ-globin mRNAs and inhibit protein expression. Indeed, applying immunopurifications, we found that γ-globin mRNA was associated with argonaute 2 isolated from reticulocytes that contain low levels of HbF (<1%), whereas association was significantly lower in reticulocytes with high levels of HbF (90%). Comparing microRNA expression in reticulocytes from cord blood and adult blood, we identified several miRNAs that were preferentially expressed in adults, among them miRNA-96. The overexpression of microRNA-96 in human ex vivo erythropoiesis decreased γ-globin expression by 50%, whereas the knock-down of endogenous microRNA-96 increased γ-globin expression by 20%. Moreover, luciferase reporter assays showed that microRNA-96 negatively regulates expression of γ-globin in HEK293 cells, which depends on a seedless but highly complementary target site located within the coding sequence of γ-globin. Based on these results we conclude that microRNA-96 directly suppresses γ-globin expression and thus contributes to HbF regulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022838PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145767PMC
December 2011

Health-related quality of life of former very preterm infants in adulthood.

Acta Paediatr 2012 Feb 7;101(2):e59-63. Epub 2011 Sep 7.

Division of Neonatology, University Hospital Zurich, Switzerland.

Aim: To assess health-related quality of life of young adults born very preterm compared with a term control group.

Methods: A cohort of preterm infants <1250 g and a term control group, both born between 1983 and 1985, were surveyed as adults at the median age of 23 years. Questionnaires including the Short Form 36 Health Survey (SF 36) and a modified lifestyle questionnaire assessed quality of life, health attitudes, height and weight, chronic diseases, medication and drug consumption.

Results: Fifty-two preterms and 75 controls matched for age and sex participated in the study. There were no significant differences in the quality of life as assessed by SF 36. Former preterms were significantly smaller than their term controls but not so for body mass index. The overall consumption of illicit drugs was significantly lower in former preterms. Moreover, former preterms went significantly less often in for sports. There was a trend for higher prevalence of chronic diseases in male compared to female preterms, but their use of medication was significantly lower.

Conclusion: Adults born very preterm show no significant differences in their quality of life when compared to controls in early adulthood. However, based on their lifestyle and health disadvantages, male preterm subjects constitute a risk group when entering early adulthood with a clear need for continued attention.
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http://dx.doi.org/10.1111/j.1651-2227.2011.02422.xDOI Listing
February 2012

Near-infrared spectroscopy measurements of cerebral oxygenation in newborns during immediate postnatal adaptation.

J Pediatr 2010 Mar 14;156(3):372-6. Epub 2009 Nov 14.

Department Obstetrics & Gynecology, Clinic of Neonatology, University Hospital Zurich, Zurich, Switzerland.

Objective: In view of growing concerns regarding the optimal supplementation of oxygen at birth, we measured cerebral oxygenation during the first minutes of life.

Study Design: Using near-infrared spectroscopy, changes in cerebral oxygenated hemoglobin (O(2)Hb), dexoxygenated hemoglobin (HHb), and tissue oxygenation index (TOI) were measured during the first 15 minutes of life in 20 healthy newborn infants delivered at term by elective cesarean section.

Results: O(2)Hb and TOI increased rapidly within the first minutes of life (median slope for O(2)Hb, 3.4 micromol/L/min; range, 1.4 to 20.6 micromol/L/min; median slope for TOI, 4.2 %/min; range, -0.4 to 27.3%/min), and cerebral HHb decreased (median slope, -4.8 micromol/L/min; range, -0.2 to -20.6 micromol/L/min). O(2)Hb, TOI, and HHb all reached a plateau within 8 minutes.

Conclusions: A significant increase in cerebral O(2)Hb and TOI and a significant decrease in HHb occur during immediate adaptation in healthy term newborns, reaching a steady plateau at around 8 minutes after birth.
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http://dx.doi.org/10.1016/j.jpeds.2009.09.050DOI Listing
March 2010

Comparison of a new transcutaneous bilirubinometer (Bilimed) with serum bilirubin measurements in preterm and full-term infants.

BMC Pediatr 2009 Nov 12;9:70. Epub 2009 Nov 12.

Clinic of Neonatology, University Hospital Zurich, Switzerland.

Background: The gold standard to assess hyperbilirubinemia in neonates remains the serum bilirubin measurement. Unfortunately, this is invasive, painful, and costly. Bilimed, a new transcutaneous bilirubinometer, suggests more accuracy compared to the existing non-invasive bilirubinometers because of its new technology. It furthermore takes into account different skin colours. No contact with the skin is needed during measurement, no additional material costs occur. Our aim was to assess the agreement between the Bilimed and serum bilirubin in preterm and term infants of different skin colours.

Methods: The transcutaneous bilirubin measurements were performed on the infant's sternum and serum bilirubin was determined simultaneously. The agreement between both methods was assessed by Pearson's correlation and by Bland-Altman analysis.

Results: A total of 117 measurement cycles were performed in 99 term infants (group1), further 47 measurements in 38 preterm infants born between 34 - 36 6/7 gestational weeks (group 2), and finally 21 measurements in 13 preterm infants born between 28 - 33 6/7 gestational weeks (group 3). The mean deviation and variability (+/- 2SD) of the transcutaneous from serum bilirubin were: -14 (+/- 144) micromol/l; -0.82 (+/- 8.4) mg/dl in group 1, +16 (+/- 91) micromol/l;+0.93(+/- 5.3) mg/dl in group 2 and -8 (+/- 76) micromol/l; -0.47 (+/- 4.4) mg/dl in group 3. These limits of agreement are too wide to be acceptable in a clinical setting. Moreover, there was to be a trend towards less good agreement with increasing bilirubin values.

Conclusion: Despite its new technology the Bilimed has no advantages, and more specifically no better agreement not only in term and near-term Caucasian infants, but also in non-Caucasian and more premature infants.
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http://dx.doi.org/10.1186/1471-2431-9-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784449PMC
November 2009

Shared or discordant grief in couples 2-6 years after the death of their premature baby: effects on suffering and posttraumatic growth.

Psychosomatics 2009 Mar-Apr;50(2):123-30

Dept. of Psychiatry, University Hospital, Zurich, Switzerland.

Background: The loss of a baby causes severe short- and long-term distress to parents and their marital relationship, but little is known about how this distress is shared between spouses. The authors hypothesized that the grief-related concordance within a couple 2 to 6 years after the loss of a premature baby could be an indicator of shared emotional distress within a couple.

Objective: The authors investigated the long-term grief experience among couples.

Method: A group of 44 parents (22 couples) were assessed by questionnaire regarding grief, suffering, posttraumatic growth, and affective symptoms, and semistructured interviews with 6 couples added qualitative information about processes within couples.

Results: The extent of grief concordance was found to be related to different patterns of suffering and posttraumatic growth within couples.

Conclusion: The emotional exchange between partners after the loss of the child appears to be crucial for a process of concordant grief, which in turn is associated with a more synchronous process of individual posttraumatic growth.
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http://dx.doi.org/10.1176/appi.psy.50.2.123DOI Listing
September 2009

An approach to using recombinant erythropoietin for neuroprotection in very preterm infants.

Pediatrics 2008 Aug;122(2):375-82

Clinic of Neonatology, University Hospital Zurich, Zurich, Switzerland.

Objective: Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome.

Methods: This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth.

Results: The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count.

Conclusions: No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.
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http://dx.doi.org/10.1542/peds.2007-2591DOI Listing
August 2008

Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children.

Eur J Immunol 2007 Nov;37(11):3270-80

Division of Immunology/Hematology/BMT, University Children's Hospital, Zürich, Switzerland.

CD31(+)CD45RA(+)RO(-) lymphocytes contain high numbers of T cell receptor circle (TREC)-bearing T cells; however, the correlation between CD31(+)CD4(+) lymphocytes and TREC during aging and under lymphopenic conditions has not yet been sufficiently investigated. We analyzed TREC, telomere length and telomerase activity within sorted CD31(+) and CD31(-) CD4(+) lymphocytes in healthy individuals from birth to old age. Sorted CD31(+)CD45RA(+)RO(-) naive CD4(+) lymphocytes contained high TREC numbers, whereas CD31(+)CD45RA(-)RO(+) cells (comprising < or =5% of CD4(+) cells during aging) did not contain TREC. CD31(+) overall CD4(+) cells remained TREC rich despite an age-related tenfold reduction from neonatal (100 : 1000) to old age (10 : 1000). Besides a high TREC content, CD31(+)CD45RA(+)RO(-)CD4(+) cells exhibited significantly longer telomeres and higher telomerase activity than CD31(-)CD45RA(+)RO(-)CD4(+) cells, suggesting that CD31(+)CD45RA(+)RO(-)CD4(+) cells represent a distinct population of naive T cells with particularly low replicative history. To analyze the value of CD31 in lymphopenic conditions, we investigated six children after allogeneic hematopoietic stem cell transplantation (HSCT). Reemerging overall CD4(+) as well as naive CD45RA(+)RO(-)CD4(+) cells predominantly expressed CD31 and correlated well with the recurrence of TREC 5-12 months after HSCT. Irrespective of limitations in the elderly, CD31 is an appropriate marker to monitor TREC-rich lymphocytes essentially in lymphopenic children after HSCT.
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http://dx.doi.org/10.1002/eji.200636976DOI Listing
November 2007