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We explored whether subnormal forced expiratory volume within 1 s (FEVThe multi-centre, randomised Nonintubated Surfactant Application trial enrolled 211 preterm infants born at 23-26 weeks of gestation from 13 level III neonatal intensive care units from April 2009 to March 2012. They received surfactant via LISA (n = 107) or after conventional endotracheal intubation (n = 104). The follow-up assessments were carried out by a single team blinded to the group assignments. The main outcome was FEVSpirometry was successful in 102/121 children. The other children died or were lost to follow-up. Median FEVThe proportion of children aged 5-9 years with subnormal FEV

AIM The aim of this study was to evaluate neurocognitive outcome at 24 months of corrected age after less invasive surfactant application (LISA) in preterm infants born at 23-26 weeks of gestational age. METHODS Surviving participants of a LISA trial conducted in 13 German level III neonatal intensive care units were reviewed for assessment of developmental outcome, hearing and vision problems, growth and rehospitalisation days. Maternal depression, breastfeeding rates and socio-economic factors were evaluated as potentially confounding factors. RESULTS In total, 156/182 infants took part in the study, 78 had received surfactant via LISA and 78 via endotracheal intubation. 22% of LISA infants compared to 42% of intubated infants had a psychomotor development index (PDI)

Less invasive surfactant administration (LISA) is a method to deliver surfactant to spontaneously breathing premature infants via a thin catheter. Here we report the two-year outcome from the AMV (avoid mechanical ventilation) study, the first randomized controlled trial on this mode of surfactant delivery. No statistically significant differences in weight, length or neurodevelopmental outcome (Bayley II scores) were found between the LISA intervention group (n = 95) and the control group (n = 84) that received standard treatment.Conclusion: No differences in outcome were observed at 2 years. LISA seems safe in that aspect. What is Known:• LISA is a method that is in increasing use for surfactant delivery to spontaneously breathing infants. LISA reduces the need for mechanical ventilation. What is New:• Outcome data at 2 years from the first randomized study with LISA raise no safety concerns in comparison to a group of infants that received standard treatment.

Background Less-invasive surfactant administration (LISA) is increasingly used. We investigated the feasibility of a new LISA-device (Neofact®) in neonates. Design Prospective observational pilot study with open-label LISA in two tertiary neonatal intensive care units. Patients 20 infants with a gestational age of ≥26+0/7 weeks and an indication for LISA (Respiratory Severity Score (RSS)≥5 or fraction of inspired oxygen (FiO2) ≥0.30). Infants with respiratory tract malformations or unavailability of an instructed neonatologist were excluded. Main outcome measures Success of LISA, defined as laryngoscopy-confirmed intratracheal catheter position or a decrease in FiO2 by ≥0.05 or to 0.21, accompanied by an RSS decrease of ≥2; number of attempts needed for tracheal catheterisation. Results 20/57 screened infants were enrolled. Successful application occurred in 19/20 (95%). One application failed after three attempts. No device-related adverse events occurred. The median number of attempts was 2, success rate per attempt 19/31 (61%). Conclusion LISA via Neofact® appears feasible., This paper reports on a new medical device to administer surfanctant (LISA technique), including a useful video on the tool.

Zusammenfassung Ziel Die Prävention der Hypothermie ist eine der wichtigsten Maßnahmen bei der Erstversorgung kleiner Frühgeborener. Es existiert eine umfassende Datenlage zu diversen Präventionsmaßnahmen (z. B. Anwärmen der Atemluft, sterile Folien, Wärmestrahler, Gelmatratzen etc.), jedoch gibt es bislang keine Empfehlungen bzw. Vergleichsstudien zu dem Teilaspekt der optimalen Raumtemperatur im Erstversorgungsraum. Methoden Vergleich der rektalen Aufnahmetemperaturen von Frühgeborenen unter 1500 g nach postnataler Versorgung in zwei unterschiedlich warmen Erstversorgungsräumen (28°C vs. 34°C) als retrospektive Kohortenstudie. Ergebnisse Es zeigte sich, dass eine höhere Temperatur im Erstversorgungsraum signifikant weniger hypotherme Frühgeborene (Aufnahmetemperatur 37,5°C zur Folge hatte. Fazit Die Auskühlung von Frühgeborenen könnte durch eine höhere Temperatur im Erstversorgungsraum mit verhindert werden. Weitere Studien sollten diesen Teilaspekt untermauern, wodurch eventuell eine Aussage zur optimalen Temperatur im Erstversorgungsraum gegeben werden könnte.

ObjectiveTo determine if survival rates of preterm infants receiving active perinatal care improve over time.DesignThe German Neonatal Network is a cohort study of preterm infants with birth weight Setting43 German level III neonatal intensive care units (NICUs).Patients8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care.InterventionsParticipating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25–P75) and low (Main outcome measuresDeath by any cause before discharge.ResultsTotal survival increased from 85.8% in 2011–2013 to 87.4% in 2014–2016. This increase was due to reduced mortality of NICUs with low survival rates in 2011–2013. Survival increased in these centres from 53% to 64% in the 22–24 weeks strata and from 73% to 84% in the 25–26 weeks strata.ConclusionsOur data support previous reports that active perinatal care of very immature infants improves outcomes at the border of viability and survival rates at higher gestational ages. The high total number of surviving infants below 24 weeks of gestation challenges national recommendations exclusively referring to gestational age as the single criterion for providing active care. However, more data are needed before recommendations for parental counselling should be reconsidered.Trial registrationApproval by the local institutional review board for research in human subjects of the University of Lübeck (file number 08–022) and by the local ethic committees of all participating centres has been given.

To determine the frequency of obstetrical adverse events and clinical outcome in infants following antenatal hyperimmune globulin (HIG) treatment for primary cytomegalovirus (CMV) infection in pregnancy. Data from 50 women including three twin pregnancies were retrospectively evaluated. Primary infection was defined by seroconversion or the presence of CMV-specific IgM and low IgG avidity. All women received two or more infusions of HIG (200 U/kg). Congenital CMV (cCMV) infection was diagnosed by detection of CMV in amniotic fluid and/or neonatal urine. We compared gestational age (GA) at birth, head circumference (HC) and birth weight (BW) of infants in our study cohort with those of live-born infants delivered in our clinic between 2015 and 2016. Median gestational age at time of maternal CMV diagnosis was 13 weeks. One-hundred-forty-one maternal HIG doses were given. No HIG-related severe adverse reactions occurred. Preterm birth rate was 4.2% (2/47) in singleton pregnancies. None of the neonates had birth weight or head circumference

retrospective cohort study.

In a large cohort study of the German Neonatal Network (GNN) we aimed to evaluate whether less invasive surfactant administration (LISA) strategy is associated with complications of preterm birth. Within the observational period n = 7533 very-low-birth-weight infants (VLBWI) with gestational age 22 0/7 to 28 6/7 weeks were enrolled in GNN; n = 1214 VLBWI never received surfactant, n = 2624 VLBWI were treated according to LISA procedure, n = 3695 VLBWI had surfactant via endotracheal tube (ETT). LISA was associated with a reduced risk for adverse outcome measures including mortality [odds ratio (OR) 0.66 (95% CI: 0.51–0.84), p

Background: Recent studies indicate an increasing use of less invasive surfactant administration. Different techniques have been shown with distinct risks and benefits. The aim of this study was to develop a new method that simplifies this procedure. Objectives: An applicator was developed and tested on a manikin to make tracheal surfactant application easier and faster. Methods: A device for oral administration of a catheter into the trachea was developed. After refining, it was tested by 9 neonatologists on a manikin. The primary aim was device feasibility, which was defined as successful intubation within 30 s. Results: The first device showed success in 30 of 33 measurements (90.9%). After refinement, the final device showed successful intubation in all 27 trials (100%). Conclusion: The new technique was feasible in this manikin test and should be confirmed in a clinical study.

Surfactant is usually given to mechanically ventilated preterm infants via an endotracheal tube to treat respiratory distress syndrome. We tested a new method of surfactant application to spontaneously breathing preterm infants to avoid mechanical ventilation.In a parallel-group, randomised controlled trial, 220 preterm infants with a gestational age between 26 and 28 weeks and a birthweight less than 1·5 kg were enrolled in 12 German neonatal intensive care units. Infants were independently randomised in a 1:1 ratio with variable block sizes, to standard treatment or intervention, and randomisation was stratified according to centre and multiple birth status. Masking was not possible. Infants were stabilised with continuous positive airway pressure and received rescue intubation if necessary. In the intervention group, infants received surfactant treatment during spontaneous breathing via a thin catheter inserted into the trachea by laryngoscopy if they needed a fraction of inspired oxygen more than 0·30. The primary endpoint was need for any mechanical ventilation, or being not ventilated but having a partial pressure of carbon dioxide more than 65 mm Hg (8·6 kPa) or a fraction of inspired oxygen more than 0·60, or both, for more than 2 h between 25 h and 72 h of age. Analysis was by intention to treat. This study is registered, number ISRCTN05025922.108 infants were assigned to the intervention group and 112 infants to the standard treatment group. All infants were analysed. On day 2 or 3 after birth, 30 (28%) infants in the intervention group were mechanically ventilated versus 51 (46%) in the standard treatment group (number needed to treat 6, 95% CI 3-20, absolute risk reduction 0·18, 95% CI 0·30-0·05, p=0·008). 36 (33%) infants in the intervention group were mechanically ventilated during their stay in the hospital compared with 82 (73%) in the standard treatment group (number needed to treat: 3, 95% CI 2-4, p0·0001). The intervention group had significantly fewer median days on mechanical ventilation, (0 days. IQR 0-3 vs 2 days, 0-5) and a lower need for oxygen therapy at 28 days (30 infants [30%] vs 49 infants [45%], p=0·032) compared with the standard treatment group. We recorded no differences between groups for mortality (seven deaths in the intervention group vs five in the standard treatment group) and serious adverse events (21 vs 28).The application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving continuous positive airway pressure reduces the need for mechanical ventilation.German Ministry of Research and Technology, University of Lübeck, and Chiesi Pharmaceuticals.

Objective To assess whether breastmilk feeding is associated with a reduced risk of bronchopulmonary dysplasia (BPD). Secondary outcome measures analyzed were retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC). Study design In an ongoing multicenter cohort study, the data of 1433 very low birth weight infants born before 32 weeks of gestation and discharged in 2013 were analyzed. We compared growth and neonatal complications of infants who received breastmilk exclusively (N = 223) with those who received formula feedings exclusively (N = 239). Logistic regression models were estimated for BPD, ROP, and NEC using nutrition as an independent variable. The Firth logistic regression model and Lasso were used for sensitivity analyses. Results Exclusively breastmilk-fed infants gained less weight compared with formula-fed infants. SDS for weight decreased between birth and discharge (median (Q1-Q3): formula −0.9 (−1.4 to [−0.5]) vs breastmilk −1.1 (−1.7 to [−0.6])). Exclusive formula feeding of very low birth weight infants was associated with increased risks of BPD (OR 2.6) as well as NEC (OR 12.6) and ROP (OR 1.80) after controlling for known risk factors. Conclusions Exclusive breastmilk feeding was associated with lower growth rates and a reduced risk of BPD as well as NEC and ROP.

Importance Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). Objective To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks’ gestational age in extremely preterm infants. Design, Setting, and Participants The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks’ gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. Intervention LISA via a thin catheter. Main Outcomes and Measures Survival without BPD at 36 weeks’ gestational age. Results Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, −5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). Conclusions and Relevance LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. Trial Registration isrctn.org Identifier:ISRCTN64011614

Objective Preterm infants are at risk of acquiring human cytomegalovirus (CMV) infection through breast milk transmission, possibly leading to serious symptoms, as suggested by previous studies. Over a period of 8.5 years, we compared infants infected postnatally with CMV with noninfected controls to determine whether CMV infection transmitted through breast milk poses serious acute risks. Study design CMV monitoring included maternal serologic testing and biweekly viral culture and polymerase chain reaction in breast milk and infant urine. Clinical and laboratory test findings were assessed retrospectively in infected infants and controls matched for gestational age during the initial hospital stay. Results Forty CMV-infected infants met the study criteria. They had lower minimal platelet and neutrophil counts and a higher frequency of C-reactive protein (CRP) elevations to 10 to 20 mg/L than their matched controls ( P ≤ .001). But no association of CMV infection with bronchopulmonary dysplasia, necrotizing enterocolitis, growth, or CRP elevations to > 20 mg/L was found. Cholestasis appeared in 3 infants in the CMV-infected group, but disappeared within 10 weeks. Conclusions Neonatal symptoms related to postnatal CMV infection were transient and had no affect on neonatal outcome in these infants, in contrast with uncontrolled reports. Whether withholding or pasteurizing breast milk is warranted, however, depends on long-term outcome.

Background: After elimination of CMV transmission by blood products we have still observed preterm infants with postnatally acquired CMV infections. 16 preterm infants with CMV infection by breast milk were identified. Methods: CMV-DNA PCR and viral cultures. Criteria of transmission: CMV in breast milk; viruria in preterm infants; exclusions of congenital infection, of donor's breast milk and of CMV seropositive blood transfusions. Results: 8 infants (50 %) had marked symptoms of an acute CMV infection: sepsis-like symptoms with apnoea and bradycardia (4), cholestasis/hepatitis (4/2), thrombocytopenia (6), neutropenia (5). Infection in the latter group occurred at an median postnatal age of 46 vs. 62 days in asymptomatic infected infants (p < 0.01). Conclusion: There is a high incidence of symptomatic CMV infections in preterm infants due to breast milk transmission. An early postnatal CMV infection seems to be associated with a symptomatic clinical course.

Introduction: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. Methods: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. Results: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Discussion: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care. © 2012 Härtel et al. OA gold

Human cytomegalovirus (HCMV) DNA can be detected in different compartments of human milk. A protocol for the preparation of milk whey free of fat and cells for the detection of human cytomegalovirus (HCMV) by nested PCR is presented. This is based upon the experience of the separation of more than 200 milk specimens of healthy seropositive breast feeding mothers. HCMV DNA could be detected in freshly centrifuged and filtrated milk whey specimens without contamination by cellular DNA. In limiting dilution experiments using HCMV plasmid DNA, the effect of different DNA extraction procedures from native milk and milk whey on the detection limit of cytomegaloviral DNA was demonstrated. About 200 viral genome equivalents/ml in milk whey or native milk were detectable by classical organic phenol/chloroform extraction or a spin column method, respectively. The detection of viral DNA in milk cells depended on a minimum number of milk cells (10(5)-2 x 10(5)) available for DNA extraction. In contrast to the findings of cytomegaloviral DNA in native sera or plasma of immunosuppressed patients we failed to amplify low level viral DNA from native breast milk by nested PCR due to an inhibition of Taq polymerase by lipid components. Finally, the course of cell associated and cell free DNAlactia was monitored. Analyzing sequential milk specimens, in some cases the presence of HCMV DNA in colostrum could be demonstrated. DNAlactia of milk cells and whey was partially discordant. Onset (week 1-4 after delivery) and duration (2 weeks up to more than 3 months) of DNAlactia showed distinct individual patterns. The methods described, allow further analysis of the mechanisms involved in the postnatal HCMV transmission by breast feeding seropositive mothers.

To evaluate the rate of virus excretion through breast milk and the incidence and significance of postnatal cytomegalovirus (CMV) transmission from mothers to premature infants.Prospective study of mother-child pairs after preterm delivery before 32 weeks or birth weight1500 g. Exclusion of donor breast milk and of CMV-seropositive blood. Material used was maternal CMV serostatus, ear swab of the infants at birth, sequential screening of breast milk and children's urine. Methods used were CMV-DNA PCR and viral cultures on fibroblasts.During a 12-month period 56 mother-infant pairs with 67 preterm infants were studied. Twenty-seven women (48%) were CMV-seronegative at birth; breast milk samples and the infants' urine remained CMV-negative. Twenty-nine women were CMV IgG-seropositive; 23 of 27 seropositive breast-feeding mothers excreted CMV through milk (85%); 25 of 27 (93%) had CMV DNA-positive results. CMV infection occurred in 17 of 67 infants (25%). CMV transmission was exclusively found in infants of seropositive mothers who excreted CMV and breast-fed their infants; 17 of 29 exposed infants became infected (59%). In 12 patients (gestational age, 29.9 +/- 1.8 weeks) CMV was detected at a postnatal age beyond 8 weeks; 5 of these infants had mild signs of a viral infection. However, 5 extremely low birth weight infants (gestational age, 24.4 +/- 0.5 weeks) were infected at an age of 4 to 7 weeks; 4 of these infants had marked symptoms of an acute CMV infection.In mothers of preterm infants a high incidence of CMV excretion into breast milk was detected. There is evidence that the most immature infants are at the greatest risk to acquire an early and symptomatic CMV infection.

We describe a newborn infant with veno-occlusive disease (VOD) of the liver. Prior to discharge from the hospital, the newborn, who had been treated for suspected neonatal infection, suddenly developed sepsis-like symptoms. The size of the liver as well as serum activity of hepatic enzymes increased progressively. Initial Doppler-flow studies demonstrated an absent flow in the vena portae, a finding that was compatible with vena portae thrombosis or occlusion of other hepatic veins. A therapy with recombinant tissue plasminogen activator (rt-PA) was initiated; due to extensive bleedings from various sides, the fibrinolytic therapy had to be withdrawn 12 hours later, when Doppler-flow examination revealed a reverse flow in hepatofugal direction. Despite supportive therapy, the general condition of the patient deteriorated continuously, finally resulting in liver and renal failure. Our patient died 19 days after birth. The autopsy demonstrated obliterative lesions of the centrilobular and sublobular hepatic veins, the classical signs of VOD of the liver. Despite extensive diagnostics and examinations, the etiology of VOD could not been elucidated in this newborn.

To the Editor: During labor at term, a 23-year-old woman took a 30-minute tub bath for relaxation in the morning, in water with a temperature of 37°C. She gave birth to a 3170-g boy later that day. Mother and child left the clinic three days later. At day 11, the infant had poor suckling, lethargy, and seizures. Meningitis with bacteremia was diagnosed by the isolation of Pseudomonas aeruginosa from cerebrospinal fluid, blood, and a conjunctival swab. In spite of immediate antipseudomonal chemotherapy (ampicillin, cefotaxime, and gentamicin), acute hydrocephalus developed. Ventriculostomy with external drainage and a ventriculoperitoneal shunt were required. Over . . .

Breastfeeding practices strongly influence the epidemiology of human cytomegalovirus infection. By contrast with term neonates, few data are available on transmission of infection from mothers to preterm infants during breastfeeding.151 mothers and their 176 preterm infants (gestational age at birth32 weeks or birthweight1500 g) were prospectively screened for cytomegalovirus infection by serology, virus culture, and PCR. The roles of cell-free and cell-associated cytomegalovirus excretion during lactation were analysed longitudinally in relation to transmission, by maximum-likelihood estimates.Of the 69 seronegative breastfeeding control mothers, none had detectable cytomegalovirus DNA in breastmilk and none of their 80 infants shed the virus in urine. The proportion of cytomegalovirus reactivation in seropositive breastfeeding mothers was 96% (73 of 76). The early appearance of viral DNA in milk whey (median 3.5 days post partum in transmitters; 8 days in non-transmitters; p=0.025) and infectious virus in milk whey (10 days and 16 days, respectively; p=0.005) were risk factors for transmission. The cumulative rate of transmission was 37% (27 of 73 mothers; 33 infants). The infection of the neonates had a mean incubation time of 42 days (95% CI 28-69). About 50% of the infected infants had no symptoms, but four had sepsis-like symptoms.The proportion of cytomegalovirus reactivation during lactation almost equals maternal seroprevalence. Breastfeeding as a source of postnatal cytomegalovirus infection in preterm infants has been underestimated and may be associated with a symptomatic infection.

Objective: Incidence and significance of postnatal CMV transmission by breast milk in premature infants.