Errors in the classification of pregnant women according to Robson ten-group classification system.

OBJECTIVES: The Robson Ten-Group Classification System (TGCS) is widely used as a classification system for perinatal analyses such as Caesarean section (CS) rates. In Germany, standardised data sets on deliveries are classified by quality assurance institutions using the TGCS. This observational study aims to evaluate potential errors in the TCGS classification of deliveries. STUDY DESIGN: Manual TGCS classification of all 1370 deliveries in an obstetric unit in 2018 and comparison with semi-automatic TGCS classifications of the quality assurance institution. RESULTS: In the manual classification, 259 out of 1370 births (18.9 %) were assigned to a different Robson group than in the semi-automatic classification. The proportions of births by Robson group were significantly different in TGCS group 1 (32.2 % vs. 37.6 %, p = 0.0034) and group 2 (18.4 % vs. 14.4 %, p = 0.0053). Concordance between manual and semi-automatic classifications ranged from 59.5 % in group 2 to 100.0 % in groups 6, 7, 8, and 9. The most frequent mismatches were for the parameters "onset of labour" in 184 cases (13.4 %), "parity" in 42 cases (3.1 %) and "previous uterine scars" in 23 cases (1.7 %). In the manual classification, there were significant differences in the CS rate in group 1 (7.9 % vs. 2.5 %, p < 0.0001), group 2 (30.2 % vs. 48.2 %, p < 0.0001), and group 4 (14.1 % vs. 37.4 %, p = 0.0004), compared to the semi-automatic classification. CONCLUSIONS: Due to incorrect data entry and unclear definitions of criteria, quality assurance data in obstetric databases may contain a relevant proportion of errors, which could influence statistics with TGCS in context of CS rates in international comparisons.

Trends in Apgar scores and umbilical artery pH: a population-based cohort study on 10,696,831 live births in Germany, 2008-2022.

Low Apgar scores and low umbilical arterial (UA) blood pH are considered indicators of adverse perinatal events. This study investigated trends of these perinatal health indicators in Germany. Perinatal data on 10,696,831 in-hospital live births from 2008 to 2022 were obtained from quality assurance institutes. Joinpoint regression analysis was used to quantify trends of low Apgar score and UA pH. Additional analyses stratified by mode of delivery were performed on term singletons with cephalic presentation. Robustness against unmeasured confounding was analyzed using the E-value sensitivity analysis. The overall rates of 5-min Apgar scores < 7 and UA pH < 7.10 in liveborn infants were 1.17% and 1.98%, respectively. For low Apgar scores, joinpoint analysis revealed an increase from 2008 to 2011 (annual percent change (APC) 5.19; 95% CI 3.66-9.00) followed by a slower increase from 2011 to 2019 (APC 2.56; 95% CI 2.00-3.03) and a stabilization from 2019 onwards (APC - 0.64; 95% CI - 3.60 to 0.62). The rate of UA blood pH < 7.10 increased significantly between 2011 and 2017 (APC 5.90; 95% CI 5.15-7.42). For term singletons in cephalic presentation, the risk amplification of low Apgar scores was highest after instrumental delivery (risk ratio 1.623, 95% CI 1.509-1.745), whereas those born spontaneous had the highest increase in pH < 7.10 (risk ratio 1.648, 95% CI 1.615-1.682).          Conclusion: Rates of low 5-min Apgar scores and UA pH in liveborn infants increased from 2008 to 2022 in Germany. What is Known: • Low Apgar scores at 5 min after birth and umbilical arterial blood pH are associated with adverse perinatal outcomes. • Prospective collection of Apgar scores and arterial blood pH data allows for nationwide quality assurance. What is New: • The rates of liveborn infants with 5-min Apgar scores < 7 rose from 0.97 to 1.30% and that of umbilical arterial blood pH < 7.10 from 1.55 to 2.30% between 2008-2010 and 2020-2022. • In spontaneously born term singletons in cephalic presentation, the rate of metabolic acidosis with pH < 7.10 and BE < -5 mmol/L in umbilical arterial blood roughly doubled between the periods 2008-2010 and 2020-2022.

Analgosedation for less-invasive surfactant administration: Variations in practice.

BACKGROUND: Less-invasive surfactant administration (LISA) is widely used for surfactant delivery to spontaneously breathing preterm infants on nasal CPAP. However, the use of analgesia and/or sedation for the LISA procedure remains controversial. METHODS: We conducted a cross-sectional survey of all tertiary neonatal intensive care units (NICUs) in Austria, Germany, and Switzerland to assess current practices of analgosedation for LISA in preterm infants. RESULTS: Eighty-eight of 172 (51.2%) NICUs responded to the survey, of which 83 (94.3%) perform LISA. Analgosedation for LISA is used in 60 (72.3%) NICUs. Twenty-eight of those (46.7%) have unit protocols to guide analgosedation while 32 (53.3%) administer medication at the discretion of the attending physician. Ketamine (45.0% of NICUs), propofol (41.7%), fentanyl (21.7%), morphine (20.0%), and midazolam (20.0%) were most frequently used for analgosedation for LISA. Nine (10.7%) NICUs reported the use of pain or distress scores during LISA. CONCLUSION: LISA is well established among tertiary NICUs in the German-speaking countries. However, there are considerable variations regarding the use of analgosedation. More evidence is required to guide clinicians seeking to safely and effectively deliver surfactant via a thin catheter to spontaneously breathing preterm infants.

Therapeutic hypothermia for encephalopathic newborns with congenital heart defect: A cross-sectional survey on current practices and opinions in Germany.

Background: Therapeutic hypothermia (TH) reduces neonatal mortality and long-term neurodevelopmental impairment in infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) caused by perinatal asphyxia. There is an increasing trend to apply TH in other indications and populations, such as infants with mild HIE or neonates with congenital heart defects (CHD), even though there is little evidence to support or refute this. Objective: The aim of this survey was to analyze practice variations with respect to TH use in neonates with CHD and to assess expert opinions on this topic across tertiary neonatal departments in Germany. Methods/Design: A web-based survey was sent to all tertiary neonatal departments in Germany. The questionnaire contained 32 multiple-choice questions. The survey inquired current practices on TH in newborns with CHD and expert opinions on various clinical scenarios. Main results: A total 80 (51.3%) neonatal departments partially completed the survey, and 69 (44.2%) respondents filled out the whole questionnaire. All 80 (100.0%) departments perform TH. TH is offered by 76 (95.0%) respondents to encephalopathic newborns with simple CHD. In infants with critical/complex CHD, TH is offered after perinatal asphyxial HIE and in newborns with encephalopathy after severe acidosis associated with cardiac complications by 25 (31.3%), or 17 (22.1%) respondents, respectively, whereas a clear majority of centers reject TH in these infants. Unclear effects of TH on any ongoing prostaglandin therapy (57.6 and 52.3%, respectively), an increased risk for adverse reactions during TH (51.6 and 52.3%, respectively) and lack of evidence (33.3 and 53.8%, respectively) are the most frequently cited reasons for not performing TH in these infants. The majority of experts from neonatal departments providing comprehensive care for neonates with severe CHD support the initiation of TH in encephalopathic neonates. Discussion: The considerable heterogeneity in the use of TH in neonates with CHD emphasizes the need for further research to optimize treatment strategies for these patients.

The Impact of Prematurity on Morbidity and Mortality in Newborns with Dextro-transposition of the Great Arteries.

Prematurity is a risk factor for adverse outcomes after arterial switch operation in newborns with D-TGA (D-TGA). In this study, we sought to investigate the impact of prematurity on postnatal and perioperative clinical management, morbidity, and mortality during hospitalization in neonates with simple and complex D-TGA who received arterial switch operation (ASO). Monocentric retrospective analysis of 100 newborns with D-TGA. Thirteen infants (13.0%) were born premature. Preterm infants required significantly more frequent mechanical ventilation in the delivery room (69.2% vs. 34.5%, p = 0.030) and during the preoperative course (76.9% vs. 37.9%, p = 0.014). Need for inotropic support (30.8% vs. 8.0%, p = 0.035) and red blood cell transfusions (46.2% vs. 10.3%, p = 0.004) was likewise increased. Preoperative mortality (23.1% vs 0.0%, p = 0.002) was significantly increased in preterm infants, with necrotizing enterocolitis as cause of death in two of three infants. In contrast, mortality during and after surgery did not differ significantly between the two groups. Cardiopulmonary bypass times were similar in both groups (median 275 vs. 263 min, p = 0.322). After ASO, arterial lactate (34.5 vs. 21.5 mg/dL, p = 0.007), duration of mechanical ventilation (median 175 vs. 106 h, p = 0.038), and venous thrombosis (40.0% vs. 4.7%, p = 0.004) were increased in preterm, as compared to term infants. Gestational age (adjusted unit odds ratio 0.383, 95% confidence interval 0.179-0.821, p = 0.014) was independently associated with mortality. Prematurity is associated with increased perioperative morbidity and increased preoperative mortality in D-TGA patients.

Outcomes in very low birthweight infants with severe congenital heart defect following cardiac surgery within the first year of life.

OBJECTIVES: Very low birthweight (<1500 g, VLBW) infants with severe congenital heart defect (CHD) are at increased risk for perinatal and operative mortality. This study aims to describe morbidity, long-term mortality and neuro-developmental outcome in early childhood in VLBW infants who received cardiac surgery for severe CHD within 1 year after birth. METHODS: Monocentric observational study on VLBW infants with severe CHD born between 2008 and 2017. Neurodevelopmental impairment at 2 years corrected age was defined as cognitive deficit, cerebral palsy or major neurosensory deficit. RESULTS: A total of 24 patients were included. Twenty-one (87.5%) infants underwent cardiac surgery with hypothermia during cardiopulmonary bypass (median temperature 30.3°C, interquartile range 27.0-32.0°C) at a median age of 96 (40-188) days. Seven (29.2%, 95% confidence interval 14.9-49.2%) patients died within the first year after cardiac surgery. Survival rates decreased with increasing STAT mortality category of the surgical procedure. Neurodevelopmental impairment at 2 years of corrected age was found in 9 out of 17 (52.9%) surviving infants, with 8 infants (47.1%) presenting with a cognitive deficit or delay and 4 infants (23.5%) being diagnosed with cerebral palsy. Survival without neuro-developmental impairment was 29.2% (n = 7, 95% confidence interval 14.9-49.2%) in the entire study cohort. Eighty percent of the newborns with dextro-transposition of the great arteries, but no patient with univentricular anatomy, survived without neuro-developmental impairment. CONCLUSIONS: Individual VLBW infants with severe CHD may develop well despite the high combined risk for adverse outcomes. The type of cardiac malformation may affect early- and long-term outcomes.

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia.

BACKGROUND: To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. METHODS: Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. RESULTS: RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. CONCLUSIONS: Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

Preoperative Anemia and Outcomes After Corrective Surgery in Neonates With Dextro-Transposition of the Great Arteries.

OBJECTIVES: The authors aimed to assess whether untreated preoperative anemia was associated with increased risk for adverse outcomes after the arterial switch operation in neonates with dextro-transposition of the great arteries (d-TGA). DESIGN: Retrospective cohort study. SETTING: Single cardiac surgery center. PARTICIPANTS: Eighty-two newborns with d-TGA. INTERVENTIONS: The authors categorized the cohort into the following two groups: the infants with preoperative anemia group (defined as a hematocrit <0.40 L/L) and the control group. MEASUREMENTS AND MAIN RESULTS: Preoperative anemia was diagnosed in 21 (25.6%) infants. Anemic infants received intraoperative red blood cell transfusions significantly more often than controls (81.0% v 34.4%, p < 0.001). No differences were observed in the incidence of adverse events, duration of hospitalization (median 27 days v 26 days, p = 0.881), and mortality (0% v 4.9%, p = 0.566). Postnatal hematocrit was the only variable independently associated with preoperative anemia in multivariate logistic regression analysis (unit odds ratio, 0.832; 95% confidence interval, 0.743-0.931; p = 0.001). CONCLUSIONS: Untreated preoperative anemia was not associated with adverse outcomes in neonates undergoing reparative surgery for d-TGA.

Hypothermia for cardiogenic encephalopathy in neonates with dextro-transposition of the great arteries.

OBJECTIVES: Neonates with dextro-transposition of the great arteries (d-TGA) may experience rapid haemodynamic deterioration and profound hypoxaemia after birth. We report on d-TGA patients with severe acidosis, encephalopathy and their treatment with systemic hypothermia. METHODS: This study is a single-centre retrospective cohort analysis of newborns with d-TGA. RESULTS: Ninety-five patients (gestational age ≥35 weeks) with d-TGA and intended arterial switch operation were included. Ten infants (10.5%) with umbilical arterial blood pH > 7.10 experienced profound acidosis (pH < 7.00) within the first 2 h of life. Six of these patients displayed signs of encephalopathy and received therapeutic hypothermia. Apgar scores at 5 min independently predicted the development of neonatal encephalopathy during postnatal transition (unit Odds Ratio 0.17, 95% confidence interval 0.06-0.49, P = 0.001). Infants treated with hypothermia had a more severe preoperative course and required more often mechanical ventilation (100% vs 35%, P = 0.003), treatment with inhaled nitric oxide (50% vs 2.4%, P = 0.002) and inotropic support (67% vs 3.5%, P < 0.001), as compared to non-acidotic controls. The median age at cardiac surgery was 12 (range 6-14) days in cooled infants and 8 (4-59) days in controls (P = 0.088). Postoperative morbidity and total duration of hospitalization were not increased in infants receiving preoperative hypothermia. Mortality in newborns with severe preoperative acidosis was zero. CONCLUSIONS: Newborn infants with d-TGA have a substantial risk for profound acidosis during the first hours of life. Systemic hypothermia for encephalopathic patients may delay corrective surgery without compromising perioperative outcomes.

Effect of a Dual-Strain Probiotic on Necrotizing Enterocolitis in Neonates with Ductal-Dependent Congenital Heart Disease: A Retrospective Cohort Study.

BACKGROUND: Newborns with ductal-dependent congenital heart disease (CHD) are at increased risk for developing necrotizing enterocolitis (NEC). OBJECTIVES: To investigate whether the use of dual-strain probiotics is beneficial for prevention of NEC in CHD patients, as demonstrated for premature infants. STUDY DESIGN: Single-center retrospective cohort study of newborns with ductal-dependent CHD before and after implementation of oral dual-strain probiotics containing Bifidobacterium infantis and Lactobacillus acidophilus, on each day of exposure to prostaglandin E1 (PGE1). RESULTS: Birth weight, gestational age, and distribution of heart defects were similar in both cohorts. NEC occurred in 6 of 247 (2.4%) patients without probiotics, and in 3 of 242 (1.2%) patients who received probiotics (p = 0.504). NEC-related mortality (0.4 vs. 0.4%, p = 1.000) and overall mortality (11.0 vs. 8.7%, p = 0.448) were likewise not different. PGE1 exposure was 1,788 and 2,455 days, respectively. In subgroup analysis of 152 infants with aortic arch malformations, such as coarctation of the aorta and interrupted aortic arch, we observed a significant reduction of NEC frequency (5.6 vs. 0.0%, p = 0.048). CONCLUSIONS: This is the first study to investigate the effect of a dual-strain probiotic on NEC in CHD patients. Infants with aortic arch malformations appear to benefit from dual-strain probiotics. Due to the scarcity of concurrence of ductal-dependent CHD and NEC, a clinical trial on probiotics to decrease risk of NEC in infants with ductal-dependent CHD would require several thousand infants.

Delivery room asphyxia in neonates with ductal-dependent congenital heart disease: a retrospective cohort study.

OBJECTIVE: We aimed to investigate the clinical course and outcome of newborns with ductal-dependent congenital heart disease (CHD) who suffered from perinatal asphyxia. STUDY DESIGN: Clinical data of 504 patients with ductal-dependent CHD and perinatal asphyxia were retrospectively analyzed over a 10-year period (2005-2014). RESULT: Perinatal asphyxia was diagnosed in 17 (3.4%) patients, comprising two nonoverlapping groups: Five infants with intrauterine acidosis (umbilical artery pH < 7.0), and 12 infants with persistent or deteriorating postnatal depression (Apgar score <6 at 10 min of life). Preoperative (41.7%, p < 0.001) and overall mortality (50.0%, p = 0.001) were increased in infants with asphyxia caused by persistent or deteriorating postnatal depression. Apgar scores at 10 min were independently associated with preoperative (OR 0.479, 95% CI 0.342-0.672, p < 0.001) and overall death (OR 0.655, 95% CI 0.537-0.799, p < 0.001). CONCLUSIONS: Asphyxia caused by postnatally deteriorating depression rather than fetal acidosis is associated with high mortality.

Therapeutic Hypothermia After Perinatal Asphyxia in Infants With Severe, Ductal-Dependent Congenital Heart Disease.

OBJECTIVES: Patients with severe congenital heart disease and cardiac anomalies such as restrictive foramen ovale, intact atrial septum, or narrowing of ductus arteriosus are at risk for perinatal asphyxia, leading to hypoxic-ischemic encephalopathy. We hypothesize that therapeutic hypothermia can be applied to these patients and seek to investigate feasibility and safety of this method. DESIGN: A retrospective observational study. SETTING: The Department of Neonatology of Charité, University Hospital, Berlin, Germany. PATIENTS: Newborns with severe congenital heart disease and perinatal asphyxia were retrospectively analyzed over a 6-year period. INTERVENTIONS: Application of therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Ten patients with perinatal asphyxia were enrolled in this study. All patients received low-dose prostaglandin E1 for ductal maintenance. Three patients without evidence for hypoxic-ischemic encephalopathy did not receive therapeutic hypothermia. One patient died at the age of 15 hours, and therapeutic hypothermia was discontinued after 19 hours in another patient with severe arterial hypotension. Adverse effects during hypothermia included respiratory insufficiency (100%), arterial hypotension (71%), the need for inotropic support (71%), and pulmonary hypertension (43%), the latter associated with prolonged postoperative inotropic support. No neurologic complications occurred before or after the surgery. Operative outcome of surviving patients was excellent. Early brain MRI scans were suggestive of good neurodevelopmental prognosis for most patients. CONCLUSIONS: Therapeutic hypothermia can be applied to patients with severe congenital heart disease and hypoxic-ischemic encephalopathy. Low-dose prostaglandin E1 infusions are safe for ductal maintenance during cooling, but cardiopulmonary adverse effects should be anticipated.

Perinatal outcomes after previable preterm premature rupture of membranes before 24 weeks of gestation.

OBJECTIVE: A current descriptive assessment of perinatal outcomes in pregnancies complicated by previable preterm premature rupture of membranes (pPPROM) at <24 weeks of gestation, after expectant treatment. STUDY DESIGN: Maternal and short-term neonatal data were collected for patients with pPPROM. RESULTS: Seventy-three patients with 93 fetuses were hospitalized with pPPROM at 15-24 weeks' gestation. Among these patients, 27.4% (n=20) chose pregnancy termination, 27.4% (n=20) miscarried and 45.2% (n=33) proceeded to live births. After a median latency period of 38 days, ranging from 1 to 126 days, 24 singletons and 20 multiples were live-born, of whom 79.5% (n=35) survived the perinatal period. The main neonatal sequelae were pulmonary hypoplasia (29.5%; n=13), connatal infection (56.8%; n=25), intraventricular hemorrhage (25%; n=11; resulting in five neonatal deaths) and Potter's syndrome (15.9%; n=7). Nine newborns died, within an average of 2.8 days (range, 1-10 days). The overall neonatal survival rate was 51.5% - including miscarriages but not elective terminations. The intact survival rate was 45.5% of all live-born neonates. CONCLUSIONS: Even with limited treatment options, overall neonatal survival is increasing. However, neonatal mortality and morbidity rates remain high. The gestational age at membrane rupture does not predict neonatal outcome.

Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury.

BACKGROUND: Hypoxia ischemia (HI) to the developing brain occurs in 1-6 in 1000 live births. Large numbers of survivors have neurological long-term sequelae. However, mechanisms of recovery after HI are not understood and preventive measures or clinical treatments are not effective. Poly(ADP-ribose) polymerase-1 is overactivated in response to ischemia. In neonatal mice HI activates PARP-1 but its role in perinatal brain injury remains uncertain. OBJECTIVE: Aim of this study was to explore the effect of TES448 (PARP-1-inhibitor) and hypothermia after an ischemic insult. DESIGN AND METHODS: 10-day-old Wistar rats underwent HI. TES448 was given 10 min, 3 hrs, and 6 hrs after hypoxia. Hypothermia was started 30 min after HI and brains were dissected at P12. Western blotting and histological staining were used to evaluate for degree of injury. RESULTS: Protein expression of PARP-1 levels was diminished after TES448 treatment. Cresyl violet and TUNEL staining revealed decreased injury in male rat pups following TES448 and combined treatment. Female rats showed increased numbers of TUNEL-positive cells after combined therapy. TES448 inhibited microglia activation after hypoxic-ischemic injury. A cellular response including NeuN, Olig2, and MBP was not affected by PARP-1-inhibition. CONCLUSIONS: Inhibition of PARP-1 and hypothermia lead to an alteration of injury but this effect is sexually dimorphic.

The rationale for third trimester testing of vertical HIV transmission in neonates with CMV infection.

We report on a late-preterm neonate with severe congenital cytomegalovirus (CMV) infection, refractory to antiviral therapy with ganciclovir. Subsequent immune diagnostics led to the finding of HIV infection at day 69, even though the mother tested negative for HIV in early pregnancy. Thus, in congenital CMV infection, HIV testing should be performed to elucidate maternal HIV seroconversion during late pregnancy. Our case strongly supports third trimester screening of HIV infection acquired during pregnancy, yet recommended only for women with traditional risk factors for HIV or living in an area of high HIV prevalence.

Effects of repetitive exposure to pain and morphine treatment on the neonatal rat brain.

BACKGROUND: Untreated exposure to pain in preterm neonates might damage the vulnerable premature brain and alter development. Pain treatment is limited because analgesic agents may also have adverse neurodevelopmental consequences in newborns. OBJECTIVE: To study the effects of neonatal pain and morphine treatment on the developing brain in a neonatal rat model. METHODS: Newborn rats were randomly assigned to: treatment with formalin injections (group 1), saline injections (group 2) and controls receiving no injections (group 3). Treatment was given on postnatal days 1-3 (model A), 1-5 (model B) and 10-12 (model C). Brains were studied histologically and protein expression was evaluated (protein kinase C epsilon and doublecortin). Effects of preemptive morphine treatment were studied in the same models (models A+M and B+M). RESULTS: Formalin injections resulted in increased apoptotic scores in models A and B. Saline injections increased the number of degenerative cells only in model B. Morphine showed protective effects in formalin-treated animals of model A+M and saline-treated animals of model B+M only. In model C, no neurodegenerative effects were detected. The protein expression of doublecortin showed a pain-related upregulation in the thalamus region, whereas protein kinase C epsilon expression was upregulated in the cortex. CONCLUSIONS: Severe inflammatory pain and pain caused by repetitive injections in neonatal rats may cause major changes in the developing brain during the first week of life. Morphine may only protect the newborn brain against these changes in specific situations.

A critical role for Fas/CD-95 dependent signaling pathways in the pathogenesis of hyperoxia-induced brain injury.

OBJECTIVE: Prematurely born infants are at risk for development of neurocognitive impairment in later life. Oxygen treatment has been recently identified as a trigger of neuronal and oligodendrocyte apoptosis in the developing rodent brain. We investigated the role of the Fas death receptor pathway in oxygen-triggered developmental brain injury. METHODS: Six-day-old Wistar rats were exposed to 80% oxygen for various periods (2, 6, 12, 24, 48, and 72 hours), and mice deficient in either Fas (B6.MRL-Tnfrsf6(lpr)) or Fas ligand (B6Smn.C3-Fasl(gld)) and control mice (C57BL/6J) were exposed to 80% oxygen for 24 hours. Polymerase chain reaction, Western blotting, and caspase activity assays of thalamus and cortex tissue were performed. RESULTS: Fas and Fas ligand messenger RNA and protein were upregulated. Furthermore, hyperoxia resulted in induction of downstream signaling events of Fas, such as Fas-associated death domain (FADD), the long and short form of FADD-like interleukin-1beta-converting enzyme (FLICE) inhibitory protein (FLIP-L, FLIP-S), and cleavage of caspase-8 and caspase-3. Injection of a selective caspase-8 inhibitor (TRP801, 1mg/kg) at the beginning of hyperoxia blocked subsequent caspase-3 cleavage in this model. B6.MRL-Tnfrsf6(lpr) mice were protected against oxygen-mediated injury, confirming Fas involvement in hyperoxia-induced cell death. Mice deficient in Fas ligand did not differ from control animals in the amount of cell death. INTERPRETATION: We conclude that neonatal hyperoxia triggers Fas receptor and its downstream signaling events in a Fas ligand-independent fashion. Lack of functional Fas receptors and selective pharmacological inhibition of caspase-8 prevents activation of caspase-3 and provides significant neuroprotection.