Active perinatal care of preterm infants in the German Neonatal Network.

OBJECTIVE: To determine if survival rates of preterm infants receiving active perinatal care improve over time. DESIGN: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016. SETTING: 43 German level III neonatal intensive care units (NICUs). PATIENTS: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care. INTERVENTIONS: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (

Clinical Relevance of Pathogens Detected by Multiplex PCR in Blood of Very-Low-Birth Weight Infants with Suspected Sepsis - Multicentre Study of the German Neonatal Network.

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.

Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols.

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.

Immaturity, perinatal inflammation, and retinopathy of prematurity: a multi-hit hypothesis.

OBJECTIVE: To explore the relationship among markers of infection/inflammation in their association with retinopathy of prematurity (ROP). METHODS: We studied clinical characteristics and 4 single nucleotide polymorphisms in infection/inflammation-associated genes in a group of 73 children with a gestational age<32 weeks. Forty-four children (60%) had ROP, of whom 13 (30% of those with ROP) progressed to stage 3 ROP. No child had grade 4 or 5 ROP. We employed both descriptive and analytic statistical methods. RESULTS: Clinical variables of infection/inflammation were consistently associated with an increased risk of ROP. Among infants with ROP, they were also associated with progression to ROP grade 3. Genetic markers were not associated with ROP occurrence, but with progression to high grade disease. In tri-variable analyses exploring the effects of gestational age <29 weeks, clinical chorioamnionitis (CAM) and neonatal systemic inflammatory response syndrome (SIRS) on ROP occurrence, low gestational age was the most important antecedent, while additional individual or joint exposure to SIRS and CAM add appreciably to this risk of progression to high grade disease. CONCLUSION: Both antenatal and neonatal exposure to inflammation appear to contribute to the increased ROP risk in preterm infants.

Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95.

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.

The NQO1 C609T polymorphism is associated with risk of secondary malignant neoplasms after treatment for childhood acute lymphoblastic leukemia: a matched-pair analysis from the ALL-BFM study group.

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.

Multiplex measurement of cytokine/receptor gene polymorphisms and interaction between interleukin-10 (-1082) genotype and chorioamnionitis in extreme preterm delivery.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSION: The presence of both CAM and IL10(-1082)*G might play a role in extreme preterm delivery less than 29 weeks.

Bradycardia and desaturation during skin-to-skin care: no relationship to hyperthermia.

OBJECTIVE: 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. STUDY DESIGN: 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 rate <2/3 of baseline; SpO 2

Randomized, controlled trial of oral creatine supplementation (not effective) for apnea of prematurity.

BACKGROUND: Hypoxic ventilatory depression in mice and muscle fatigue in adult humans are improved by creatine supplementation (CS). Because these issues may be operative in apnea of prematurity (AOP), we hypothesized that CS reduces episodes of hypoxemia and bradycardia in infants with AOP. METHODS: Infants were eligible for this double-blind, controlled trial if gestational age was <32 weeks and AOP was severe enough to require treatment with caffeine. If they had > or = 1 desaturation (pulse oximeter saturation [SpO2] < or = 80%) or bradycardia (heart rate < or = two thirds of baseline) per hour in an initial 6-hour recording, they were randomized to a 2-week course of oral CS (200 mg/kg per day) or placebo (P). Infants then underwent 2 additional 6-hour recordings of breathing movements, nasal airflow, heart rate, pulse oximeter saturation (SpO2) and pulse waveforms after 7 and 14 days of treatment. Urinary creatine excretion was measured also. Recordings were analyzed for the frequency of bradycardia and desaturation, the primary outcome parameter, as well as for apnea (> or =10 seconds), baseline heart and respiratory rate, and SpO2. RESULTS: Of 38 infants enrolled, 34 completed the study (17 in each group). Median (range) gestational age at birth was 27 (25-30) vs 27 (25-30) weeks, and at study 29 (26-36) vs 29 (27-33) weeks. Oral CS was well tolerated; no side effects were noted. Urinary creatine excretion was low in the P group (median: 27 mmol/mol of creatinine; range: 18-102) and increased in the CS group (6949 mmol/mol of creatinine; range: 1427-11807). CS, however, had no effect on the combined rate of bradycardia and desaturation (P: 2.7 per hour [range: 0.2-10.3]; CS: 4.1 per hour [range: 0.6-12.1]), nor was there any decrease in apnea rate (P: 1.7 per hour [range: 0-4.5]; CS: 2.2 per hour [range: 0.2-5.1]). CONCLUSION: Despite a significant increase in creatine excretion, suggesting good enteral absorption, CS did not, in the dose and for the duration given in this study, improve symptoms of AOP in these infants.

Early feeding after necrotizing enterocolitis in preterm infants.

OBJECTIVE: To report our experience with an early initiation of enteral feedings after necrotizing enterocolitis (NEC). STUDY DESIGN: 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). RESULTS: 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). CONCLUSION: 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.