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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.

Introduction In the German Neonatal Network (GNN) 10% of very-low-birth weight infants (VLBWI) suffer from blood-culture confirmed sepsis, while 30% of VLBWI develop clinical sepsis. Diagnosis of sepsis is a difficult task leading to potential over-treatment with antibiotics. This study aims to investigate whether the results of blood multiplex-PCR (SeptiFast®) for common sepsis pathogens are relevant for clinical decision making when sepsis is suspected in VLBWI. Methods We performed a prospective, multi-centre study within the GNN including 133 VLBWI with 214 episodes of suspected late onset sepsis (LOS). In patients with suspected sepsis a multiplex-PCR (LightCycler SeptiFast MGRADE-test®) was performed from 100 μl EDTA blood in addition to center-specific laboratory biomarkers. The attending neonatologist documented whether the PCR-result, which was available after 24 to 48 hrs, had an impact on the choice of antibiotic drugs and duration of therapy. Results PCR was positive in 110/214 episodes (51%) and blood culture (BC) was positive in 55 episodes (26%). Both methods yielded predominantly coagulase-negative staphylococci (CoNS) followed by Escherichia coli and Staphylococcus aureus. In 214 BC—PCR paired samples concordant results were documented in 126 episodes (59%; n = 32 were concordant pathogen positive results, n = 94 were negative in both methods). In 65 episodes (30%) we found positive PCR results but negative BCs, with CoNS being identified in 43 (66%) of these samples. Multiplex-PCR results influenced clinical decision making in 30% of episodes, specifically in 18% for the choice of antimicrobial therapy and in 22% for the duration of antimicrobial therapy. Conclusions Multiplex-PCR results had a moderate impact on clinical management in about one third of LOS-episodes. The main advantage of multiplex-PCR was the rapid detection of pathogens from micro-volume blood samples. In VLBWI limitations include risk of contamination, lack of resistance testing and high costs. The high rate of positive PCR results in episodes of negative BC might lead to overtreatment of infants which is associated with risk of mortality, antibiotic resistance, fungal sepsis and NEC.

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.

Thiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.

Background: Early diagnosis of necrotising enterocolitis (NEC) is difficult but essential for timely therapy. The diagnostic hallmarks and specific radiological signs for NEC are pneumatosis intestinalis (PI) and portal venous gas (PVG), but PVG in abdominal ultrasound (PVG-US) has been proposed as an effective tool in the diagnosis of NEC as well. Objective: To prospectively assess the value of PVG-US for the diagnosis of NEC. Methods: The study screened 352 neonates for PVG-US (n = 796 routine examinations) and performed 48 additional screenings in 34/352 neonates with suspected (stage I, n = 28) or definite NEC (stage ⩾II, n = 20). Sensitivity and specificity of PVG-US for detection of NEC were computed by using NEC stage ⩾II as the reference standard. Results: PVG-US was only present in cases of suspected or definite NEC. The study observed PVG-US in 4/28 NEC stage I and in 9/20 NEC stage ⩾II episodes corresponding to a 86% specificity and a 45% sensitivity for diagnosis of NEC stage ⩾II. However, 7/20 patients with NEC stage ⩾II showed intraoperative findings other than NEC and another 3/20 infants presented with radiologically unspecific intestinal dilatation. None of these 10 infants had detectable PVG-US. Thus, with application of specific radiological signs the sensitivity of PVG-US for diagnosis of NEC stage ⩾II increased to 90%. Conclusion: Screening for PVG-US is a useful, easy and quick bedside test with a high specificity for NEC. Moreover, these results question the value of the Walsh criteria in the diagnosis of NEC.

OBJECTIVES Inflammation plays a role in prematurity, in neonatal disorders of the brain, lung, eye, bowel, and in developmental disability among preterm infants. We initiated a pilot study in preterm children to determine the prevalence of single nucleotide polymorphisms (SNPs) in the infection/inflammation-associated genes for interleukin (IL)-10 (- 1082 G/A), IL-1beta (+ 3953 C/T), tumor necrosis factor (TNF)-alpha (- 308 G/A) and toll-like receptor 4 (TLR-4) (Asp299Gly) and whether these SNPs affect the risk for neonatal disorders. STUDY DESIGN We genotyped 73 children >/= 2 years of age whose gestational age at birth was < 32 weeks, and explored the associations between genotypes and neonatal disorders and developmental status at age 2 + years. RESULTS Infants homozygous for the high IL-10 producer - 1082 G-allele (n = 15) were significantly less likely to develop ultrasound-defined periventricular echodensities. A non-significant, but prominent, risk reduction for bronchopulmonary dysplasia, high-grade retinopathy, cerebral palsy, and developmental delay at age 2 + years was present. Polymorphisms in the IL-1beta, TNF-alpha, and TLR-4 genes were too infrequent in our pilot sample to allow for reasonable analysis. CONCLUSION Infants homozygous for the IL-10 high producer - 1082 G allele might be at reduced risk for prematurity-associated disorders.

Spontaneous pneumomediastinum is a rare condition in the newborn, not associated with identifiable trauma or mechanical ventilation. It is diagnosed by a combination of physical examination and confirmatory chest radiograph, with various recognized signs identifiable in this condition. We report the case of a male neonate, who had pneumomediastinum confirmed by the presence of a wind blown spinnaker sail sign and was managed conservatively. We also reviewed the literature.

Purpose: We evaluated the influence of three different dosages of methotrexate (MTX) during consolidation on the incidence of testicular relapse in children with acute lymphoblastic leukemia (ALL). Patients and Methods: One thousand one hundred forty-four boys with newly diagnosed ALL, enrolled in three consecutive trials of the Berlin-Frankfurt-Munster group (ALL-BFM 81, 83, 86), were retrospectively evaluated for the influence of MTX on testicular relapse-free interval. The basic treatment design was similar in all trials. No intravenous MTX was used in trial ALL-BFM 81 in the group who received cranial irradiation (CRT) except for a part of standard risk patients. Four courses of intermediate dose MTX (IDM) (0.5 g/m 2 ) were introduced for all patients in trial ALL-BFM 83 (IDM group), which were replaced by high dose MTX (HDM) (5 g/m 2 ) in trial ALL-BFM 86 (HDM group). The median observation time was > 9 years. Results: The cumulative incidence of isolated testicular relapses was significantly higher in the CRT group as compared to the IDM and HDM groups (6.7% versus 2.5% and 2.3%, p = 0.02 and 0.01). HDM decreased neither the incidence nor the rate of isolated testicular relapses any further. Event-free survival (EFS) for boys was similar between trial ALL-BFM 81 and 86 (64% versus 69%, p = 0.35), but differed significantly between trials ALL-BFM 83 and 86 (61% versus 69%, p = 0.0078). Conclusion: The introduction of IDM reduced the incidence of isolated testicular relapses significantly by a factor two, but had no significant influence on overall survival. HDM did not result in a more effective prevention of testicular relapses, but resulted in better systemic control and hence better survival than IDM.

Background Pulmonary interstitial emphysema (PIE) represents a severe complication of respiratory distress syndrome and can dramatically impair the ventilation of premature infants. Objectives We report three mechanically ventilated premature infants with severe diffuse, unilateral PIE not responding to conventional treatment, whose clinical condition improved dramatically following an ipsilateral pneumothorax. Results In the first two patients, the pneumothoraces occurred spontaneously. In the third patient, the ipsilateral lung was punctured with a pigtail catheter to create and - subsequently drain - a pneumothorax. Thereafter, mechanical ventilation could be discontinued within 3 days in all infants. Conclusions Lung puncture with consecutive tension release of the overinflated lung by drainage is a therapeutic option for premature infants suffering from diffuse PIE in whom other conservative measures fail. It may be considered before proceeding to surgical measures in order to preserve potentially functional lung tissue.

The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6% (± 0.9%). The large standard-risk (SR) group (35% of patients) achieved an excellent 6y-EFS of 89.5% (± 1.1%) despite significant reduction of anthracyclines. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7% (± 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in non–T-ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% (± 3.2%). Compared without previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients.

To establish a multiplex amplification refractory mutation system (ARMS) in fluid and dried whole blood, and to perform a pilot study to examine the role for single-nucleotide polymorphisms (SNPs) of inflammation-associated genes (interleukin [IL]-1 and −10, tumor necrosis factor-alpha [TNFA], and toll-like receptor-4 [TLR4]) and their interaction with clinical chorioamnionitis (CAM) in prematurity. We established a quadruplex ARMS to detect the four above SNPs. Fifty four women delivered at gestational age less than 32 weeks and 83 healthy female volunteers were genotyped. We compared (1) mothers of preterm infants with volunteers, and (2) women delivered before 29 weeks’ gestation (n = 29) with those delivered at 29 to 31 completed weeks (n = 25). Multiplex ARMS is feasible using both fluid and dried whole blood. We found no overall differences in genotype and allele frequencies between mothers of preterm infants and volunteers. Among women who had a preterm delivery, those with both CAM and IL10(–1082)*G allele, the risk for delivery before 29 weeks was markedly increased (odds ratio [OR] 22, 95% confidence interval [CI] 2.5–191). The presence of both CAM and IL 10(-1082)* G might play a role in extreme preterm delivery less than 29 weeks.

We recently found increased temperature and increased bradycardia and desaturation during skin-to-skin care (SSC). We wanted to determine if these effects were related.Twenty-two infants (median gestational age at birth 28.5 weeks [range 24-31], median age at study 25.5 days [range 10-60 days], median birth weight 1025 g [range 550-1525 g], median weight at study 1320 g [range 900-2460 g]) underwent three 2-hour recordings of breathing movements, nasal airflow, heart rate, and pulse oximeter saturation (SpO 2 ): at thermoneutrality (TN) during incubator care, at TN during SSC, and at elevated temperature (ET) during incubator care. Core temperature was measured via a rectal probe. Recordings were analyzed for the summed rate of bradycardia and desaturation (heart rate2/3 of baseline; SpO 2or=80%).Rectal temperature remained unchanged during SSC and increased by 0.6 degrees C during ET ( P.001). The summed rate of bradycardia and desaturation was increased during SSC but not during ET (TN: median 2.2/hour (range, 0-19), ET: median 1.7/hour (range, 0-13), SSC: 3.0/hour (0-25), P.02 SSC vs ET).Bradycardia and desaturation were increased during SSC, even at constant rectal temperature, whereas ET had no effect on these events. Moderate hyperthermia did not increase respiratory instability in preterm infants.

To report our experience with an early initiation of enteral feedings after necrotizing enterocolitis (NEC).Over a 4-year period, all inborn infants with NEC Bell stage II or greater received enteral feedings, increased by 20 mL/kg/d, once no portal vein gas had been detected on ultrasound for 3 consecutive days (group 1). Infants were compared with a historic comparison group (group 2).Necrotizing enterocolitis rates were 5% (26/523) in the early feeding group and 4% (18/436) in the comparison group. One early feeding infant and two comparison group infants died of NEC, whereas two and one, respectively, had recurrent NEC. Enteral feedings were restarted at a median of 4 days (range, 3-14) versus 10 days (range, 8-22) after onset of NEC. Early feeding was associated with shorter time to reach full enteral feedings (10 days [range, 7-31] vs 19 days [range, 9-76], P.001), a reduced duration of central venous access (13.5 days [range, 8-24] vs 26.0 days [range, 8-39], P.01), less catheter-related septicemia (18% vs 29%, P.01), and a shorter duration of hospital stay (63 days [range, 28-133] vs 69 days [range, 36-150], P.05).Early enteral feeding after NEC was associated with significant benefits and no apparent adverse effects. This study was underpowered, however, to exclude a higher NEC recurrence risk potentially associated with this change in practice.

To define prognostic factors in infant acute lymphoblastic leukemia (ALL), the outcome of 106 infants (age ≤12 months) during 3 consecutive multicenter trials of the Berlin-Frankfurt-Münster group (ALL-BFM 83, 86, and 90) was retrospectively analyzed according to presenting features and early in vivo response to prednisone. The prednisone response was defined as the cytoreduction (number of blood blasts per microliter at day 8) to a 7-day prednisone prephase and 1 intrathecal dose of methotrexate on day 1. Prednisone good responder (PGR

In a matched-pair study, we analyzed the association of a phenotypically relevant NQO1 polymorphism (C609T) with risk of secondary malignant neoplasms (SMN) after treatment for childhood acute lymphoblastic leukemia. Patients carrying a variant low-activity NQO1 allele had a significantly increased risk of developing a SMN. The observed effect was restricted to solid tumors.