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Introduction: Supplemental oxygen therapy is a mainstay of modern neonatal intensive care for preterm infants. However, both insufficient and excess oxygen delivery are associated with adverse outcomes. Automated or closed loop FiO2 control has been developed to keep SpO2 within a predefined target range more effectively. Methods: The aim of this study was to investigate the feasibility of closed loop FiO2 control by Predictive Intelligent Control of Oxygenation (PRICO) on the Fabian ventilator in maintaining SpO2 within a target range (88/89-95%) in preterm infants on different modes of invasive and noninvasive respiratory support. In two tertiary neonatal intensive care units, preterm infants with an FiO2 >0.21 were included and received an 8 h nonblinded treatment period of closed loop FiO2 control by PRICO, flanked by two 8 h control periods of routine manual control (RMC1 and RMC2). Results: 32 preterm infants were included (median gestational age 26 + 5 weeks [IQR 25 + 5–27 + 6], median birthweight 828 grams [IQR 704–930]). Six patients received invasive respiratory support, while 26 received noninvasive respiratory support (18 CPAP, 4 DuoPAP, and 4 nasal IMV). The time percentage within the SpO2 target range was increased with PRICO (74.4% [IQR 67.8–78.5]) compared to RMC1 (65.8% [IQR 51.1–77.8]; p = 0.011) and RMC2 (60.6% [IQR 56.2–66.6]; p < 0.001) with an estimated median difference of 6.0% (95% CI 1.2–11.5) and 9.8% (95% CI 6.0–13.0), respectively. Conclusion: In preterm infants on invasive and noninvasive respiratory supports, closed loop FiO2 control by PRICO compared to RMC is feasible and superior in maintaining SpO2 within target ranges.

ObjectiveTo investigate the efficacy of automated control of inspired oxygen (FiO2) by Predictive Intelligent Control of Oxygenation (PRICO) on the Fabian ventilator in maintaining oxygen saturation (SpO2) in preterm infants on high flow nasal cannula (HFNC) support.DesignSingle-centre randomised two-period crossover study.SettingTertiary neonatal intensive care unit.Patients27 preterm infants (gestational age (GA) 0.25.InterventionA 24-hour period on automated FiO2-control with PRICO compared with a 24-hour period on routine manual control (RMC) to maintain a SpO2 level within target range of 88%–95% measured at 30 s intervals.Main outcome measuresPrimary outcome: time spent within target range (88%–95%). Secondary outcomes: time spent above and below target range, in severe hypoxia (SpO2 98%), mean SpO2 and FiO2 and manual FiO2 adjustments.Results15 patients received PRICO-RMC and 12 RMC-PRICO. The mean time within the target range increased with PRICO: 10.8% (95% CI 7.6 to 13.9). There was a decrease in time below target range: 7.6% (95% CI 4.2 to 11.0), above target range: 3.1% (95% CI 2.9 to 6.2) and in severe hypoxia: 0.9% (95% CI 1.5 to 0.2). We found no difference in time spent in severe hyperoxia. Mean FiO2 was higher during PRICO: 0.019 (95% CI 0.006 to 0.030). With PRICO there was a reduction of manual adjustments: 9/24 hours (95% CI 6 to 12).ConclusionIn preterm infants on HFNC support, automated FiO2-control by PRICO is superior to RMC in maintaining SpO2 within target range. Further validation studies with a higher sample frequency and different ventilation modes are needed.

Introduction: Less invasive surfactant administration (LISA) to preterm infants is associated with decreased risk for death or BPD. After LISA, a considerable proportion requires a second dose of surfactant because of ongoing respiratory distress syndrome, raising a clinical dilemma between intubation or performing a repeated LISA (re-LISA) procedure. We aim to assess efficacy of re-LISA in avoiding subsequent nasal continuous positive airway pressure failure (need for intubation in the first 72 h of life; CPAP-F), to identify factors associated with subsequent CPAP-F, and to compare short-term outcomes following re-LISA to surfactant retreatment by endotracheal intubation and mechanical ventilation. Methods: This was an observational retrospective study in two Dutch NICUs. Inclusion criterion was infants with gestational age Results: Of 209 infants requiring second surfactant dose, 132 received re-LISA. Subsequent CPAP-F was observed in 56 (42%) infants and was associated with extreme prematurity (OR 2.6, 95% CI: 1.2–5.8) and FiO2>0.5 (OR 5.4, 95% CI: 2.0–14.7). Infants receiving re-LISA had a lower risk of death or BPD compared to infants intubated for the second surfactant dose (OR 0.4, 95% CI: 0.2–0.9). Infants with CPAP-F after re-LISA had similar outcomes compared to those intubated for second surfactant dose. Conclusion: Re-LISA is effective in reducing CPAP-F and is associated with lower risk of death or BPD compared to retreatment via an endotracheal tube. Infants failing CPAP after re-LISA have similar outcomes compared to intubated infants. These findings support the use of re-LISA in preterm infants with ongoing RDS.

Background The role of intestinal microbiota in the pathogenesis of late-onset sepsis (LOS) in preterm infants is largely unexplored but could provide opportunities for microbiota-targeted preventive and therapeutic strategies. We hypothesized that microbiota composition changes before the onset of sepsis, with causative bacteria that are isolated later in blood culture. Methods This multicenter case-control study included preterm infants born under 30 weeks of gestation. Fecal samples collected from the 5 days preceding LOS diagnosis were analyzed using a molecular microbiota detection technique. LOS cases were subdivided into 3 groups: gram-negative, gram-positive, and coagulase-negative Staphylococci (CoNS). Results Forty LOS cases and 40 matched controls were included. In gram-negative LOS, the causative pathogen could be identified in at least 1 of the fecal samples collected 3 days prior to LOS onset in all cases, whereas in all matched controls, this pathogen was absent (P = .015). The abundance of these pathogens increased from 3 days before clinical onset. In gram-negative and gram-positive LOS (except CoNS) combined, the causative pathogen could be identified in at least 1 fecal sample collected 3 days prior to LOS onset in 92% of the fecal samples, whereas these pathogens were present in 33% of the control samples (P = .004). Overall, LOS (expect CoNS) could be predicted 1 day prior to clinical onset with an area under the curve of 0.78. Conclusions Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as an early noninvasive biomarker.

IntroductionCardiorespiratory monitoring is used in the neonatal intensive care unit (NICU) to assess the clinical status of newborn infants and detect critical deteriorations in cardiorespiratory function. Currently, heart rate (HR) is monitored by electrocardiography (ECG) and respiration by chest impedance (CI). Disadvantages of current monitoring techniques are usage of wired adhesive electrodes which may damage the skin and hinder care. The Bambi® belt is a wireless and non-adhesive alternative that enables cardiorespiratory monitoring by measuring electrical activity of the diaphragm via transcutaneous electromyography. A previous study showed feasibility of the Bambi® belt and this study compares the belt performance to ECG and CI.Methods and analysisThis multicentre non-inferiority paired study will be performed in the NICU of the Máxima Medical Center (MMC) in Veldhoven and the Emma Children’s Hospital, Amsterdam University Medical Centre (AmsterdamUMC) in Amsterdam, The Netherlands. 39 infants in different postmenstrual age groups (minimally 10 infants32 weeks) will be recruited. These infants will be monitored with the Bambi® belt in addition to standard ECG and CI for 24 hours. The primary outcome is the HR, studied with three criteria: (1) the limits of agreement of the HR measurements in terms of the second-to-second difference in the HR between the belt and standard ECG, (2) the detection of cardiac events consisting of bradycardia and tachycardia and (3) the quality of HR-monitoring. The secondary outcome is the respiratory rate (RR), studied with the criteria (1) agreement in RR-trend monitoring, (2) apnoea and tachypnoea detection and (3) reliable registrations.Ethics and disseminationThis protocol was approved by the Medical Ethical Committee of the MMC and the Central Committee for Human Research. The MMC started patient recruitment in July and the AmsterdamUMC in August 2021. The results will be presented at conferences and published in peer-reviewed journals.Trial registration numberNL9480.

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics’ effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19–0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35–0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85–0.97]; p = 0.003).Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. What is Known:• Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis.• The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. What is New:• Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged.• A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86–0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04–0.82]), early onset of NEC (0.003, 0.85 [0.77–0.95]), low serum bicarbonate (0.009, 0.85 [0.76–0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03–28.47]) were identified as independent risk factors for sNEC.Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known:• In 27–52% of the infants with NEC, a surgical intervention is indicated during its disease course.• Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New:• Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC.• Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC.

Intussusception of the small intestine has been described in pregnant women with a history of a laparoscopic Roux-en-Y gastric bypass. This study provides a systematic review on the characteristics of intussusception in this population. MEDLINE, Embase, Cochrane Library, and our own hospital's electronics health records were searched for eligible studies/cases. Fifteen papers were eligible, containing 17 cases. Our hospital search included 6 cases. Seventeen of 23 intussusceptions were retrograde and were mostly (18/23) located at the jejunojejunostomy. Six patients were treated successfully with manual reduction only and 17 patients required surgical resection. Fifteen (65%) patients had an ischemic segment. Six (26%) patients delivered during the same hospital admission. One fetal death (1 of twins) was reported. Awareness of this rare but serious complication by obstetricians and bariatric surgeons is necessary to limit maternal and fetal complications.

Pregnant women with a history of bariatric surgery (BS) may develop acute abdominal pain related to this surgery, especially after Roux-en-Y gastric bypass. Studies showed alarming results regarding maternal and foetal morbidity and mortality. The aim of this study was to analyse these outcomes for pregnant women and their offspring. Single-centre retrospective cohort study in a tertiary referral centre for bariatric complications during pregnancy. Pregnant women with a history of BS referred between September 2015 and November 2019 with acute abdominal pain suspected for a bariatric complication were included. Data were retrospectively collected from the patient files, and a questionnaire was sent regarding the postoperative course and childbirth. Fifty women were included. At presentation, mean maternal age was 31 (± 4) years, and median gestational age was 28+4 (25+4, 30+5) weeks. Thirteen women were treated conservatively. Thirty-seven women underwent surgery for, among others, internal herniation (n = 26) and intussusception (n = 6). Six women required small bowel resection. Two women underwent an emergency caesarean section shortly after the surgery due to foetal distress. Eight women delivered preterm of whom five infants required respiratory support. There was one intrauterine foetal death. Surgery > 48 h after the onset of the symptoms was not associated with an increase in small bowel resections or preterm birth. Acute abdominal pain in pregnant women may be related to a bariatric complication. Further awareness of bariatric complications within the obstetric care and transferal to specialized care to prevent diagnostic delay may improve maternal and neonatal outcome.

ObjectiveTo evaluate incidence of minimally invasive surfactant therapy (MIST) failure, identify risk factors and assess the impact of MIST failure on neonatal outcome.DesignRetrospective cohort study. MIST failure was defined as need for early mechanical ventilation (SettingTwo tertiary neonatal intensive care centres in the Netherlands.PatientsInfants born between 24 weeks’ and 31 weeks’ gestational age (GA) (n=185) with MIST for respiratory distress syndrome.InterventionsMIST procedure with poractant alfa (100–200 mg/kg).Main outcome measuresContinuous positive airway pressure (CPAP) failure after MIST in the first 72 hours of life.Results30% of the infants failed CPAP after MIST. In a multivariate logistic regression analysis, four risk factors were independently associated with failure: GA Furthermore, MIST failure was independently associated with an increased risk of severe intraventricular haemorrhage.ConclusionWe observed moderate MIST failure rates in concordance with the results of earlier studies. Absence of corticosteroids and lower surfactant dose are risk factors for MIST failure that may be modifiable in order to improve MIST success and patient outcome.

Preterm birth is associated with increased mortality and morbidity. Tocolytic drugs, such as indomethacin, are often used to postpone preterm delivery. Indomethacin has been proven to be more effective than other tocolytic agents in terms of delaying birth but is often prescribed with caution because of its potential association with adverse neonatal outcomes. We aim to study the effects of antenatal indomethacin on neonatal outcomes after controlling for potential confounders, as compared to nifedipine and/or atosiban.In this cohort study, we performed a retrospective analysis of maternal and neonatal data. Women were included if they received indomethacin, nifedipine or atosiban as a tocolytic drug for imminent preterm labor and gave birth at a gestational age (GA) between 23Four hundred seventy-four women, delivering 610 infants were investigated. The incidence of the following adverse neonatal outcomes were significantly higher after indomethacin use: neonatal death (The presumed association between antenatal indomethacin exposure and several adverse neonatal outcomes may be based upon indication bias. Taking important confounding factors, such as GA at birth and neonatal birth weight into account, antenatal indomethacin exposure does not result in a higher incidence of adverse neonatal outcomes. However, there may be a higher risk for spontaneous intestinal perforation.

Background: Histologic chorioamnionitis is only diagnosed postnatally which prevents interventions. We hypothesized that volatile organic compounds (VOCs) in the amniotic fluid might be useful biomarkers for chorioamnionitis and that VOC profiles differ between amnionitis of different origins.Methods: Time-mated ewes received intra-amniotic injections of media or saline (controls), or live Ureaplasma parvum serovar 3 (Up) 14, 7 or 3d prior to c-section at day 124 gestational age (GA). 100 μg recombinant ovine IL-1α was instilled at 7, 3 or 1d prior to delivery. Headspace VOC profiles were measured from amniotic fluids at birth using ion mobility spectrometer coupled with multi-capillary columns.Results: 127 VOC peaks were identified. 27 VOCs differed between samples from controls and Up- or IL-1α induced amnionitis. The best discrimination between amnionitis by Up vs. IL-1α was reached by 2-methylpentane, with a sensitivity/specificity of 96/95% and a positive predictive value/negative predictive values of 96 and 95%. The concentration of 2-methylpentane in VOCs peaked 7d after intra-amniotic instillation of Up.Discussion: We established a novel method to study headspace VOC profiles of amniotic fluids. VOC profiles may be a useful tool to detect and to assess the duration of amnionitis induced by Up. 2-methylpentane was previously described in the exhalate of women with pre-eclampsia and might be a volatile biomarker for amnionitis. Amniotic fluids analyzed by ion mobility spectrometry coupled with multi-capillary columns may provide bedside diagnosis of amnionitis and understanding inflammatory mechanisms during pregnancy.

The transformation procedure of deriving amplitude-integrated (a)EEG from raw EEG has been well described in a purely analog prototype, however the inherent specifications within the prototype are not established or disclosed. In this paper, we aim at providing an accessible and digitalized aEEG algorithm that is evaluated quantitatively and validated in clinical practice. The algorithms, especially the filter design and envelope detection methods, applied in the transformation procedure, are investigated. The effectiveness and feasibility of the filters namely, symmetric and asymmetric filters followed with four different envelope detection methods (low-pass filtering, squaring and low-pass filtering, Hilbert transform, and moving average) are evaluated on a clinical dataset collected at Children's Hospital of Fudan University which involves 30 infants. Compared to the outputs of the commercial available (a)EEG device NicoletOne, the Spearman rank correlations (SRs) of the upper/lower tracings of aEEG using the asymmetric filter and squaring and low-pass filtering-based envelope detection method can reach over 0.97. Meanwhile, the SRs of the upper and the lower margin amplitude of aEEG can achieve 0.98 and 0.97, respectively. Furthermore, the accuracy of the obtained aEEG tracings in identifying the aEEG background activities can achieve 100%. To our knowledge, this is the first work to present a digital procedure to transform the EEG into aEEG by assessing the impact of different filters and envelope detection methods. With the high performance of the proposed approach, this work can promote the standardization of aEEG transformation procedure and the exploration of the sophisticated automatic aEEG interpretation algorithms.

IEEE access 7, 141766-141781 (2019). doi:10.1109/ACCESS.2019.2944531, Published by IEEE, New York, NY

Introduction Headspace gas chromatography–mass spectrometry (HS-GC–MS) is widely considered the gold standard of quantitative fecal VOC analysis. However, guidelines providing general recommendations for bioanalytical method application in research and clinical setting are lacking. Objectives To propose an evidence-based research protocol for fecal VOC analysis by HS-GC–MS, based on extensive testing of instrumental and sampling conditions on detection and quantification limits, linearity, accuracy and repeatability of VOC outcome. Methods The influence of the following variables were assessed: addition of different salt solutions, injection temperature, injection speed, injection volume, septum use, use of calibration curves and fecal sample mass. Ultimately, the optimal sample preparation was assessed using fecal samples from healthy preterm infants. Fecal VOC analysis in this specific population has potential as diagnostic biomarkers, but available amount of feces is limited here, so optimization of VOC extraction is of importance. Results We demonstrated that addition of lithium chloride enhanced the release of polar compounds (e.g. small alcohols) into the headspace. Second, a linear relationship between injection volume, speed and temperature, and fecal sample mass on the abundance of VOC was demonstrated. Furthermore, the use of a septum preserved 90% of the non-polar compounds. By application of optimal instrumental and sampling conditions, a maximum of 320 unique compounds consisting of 14 different chemical classes could be detected. Conclusions These findings may contribute to standardized analysis of fecal VOC by HS-GC–MS, facilitating future application of fecal VOC in clinical practice.

Background In preterm infants with Respiratory Distress Syndrome (RDS), Less Invasive Surfactant Administration (LISA) has been established to reduce the need of mechanical ventilation and might improve survival rates without bronchopulmonary dysplasia. The aim of this study was to investigate whether NICU care has changed after introduction of less invasive surfactant administration (LISA), with regard to diagnostic and therapeutic procedures in the first week of life. Methods Infants with gestational age n = 169) were retrospectively compared to infants who received surfactant after intubation (January 2012 – May 2014, n = 155). Local protocols on indication for surfactant, early onset sepsis, blood transfusions and enteral feeding did not change between both study periods. Besides, as secondary outcome complications of prematurity were compared. Data was collected from electronic patient files and compared by univariate analysis through Students T-test, Mann Whitney-U test, Pearson Chi-Square test or Linear by Linear Association. Results All baseline characteristics of both groups were comparable. Compared to controls, LISA patients received a higher total surfactant dose (208 vs.160 mg/kg; p p = 0.023), but needed less mechanical ventilation (35.5% vs. 76.8%; p p p p = 0.024), blood transfusions (24.9% vs. 41.9%, p = 0.003) and had shorter duration of antibiotic therapy for suspected early onset sepsis (3.0 vs. 5.0 days, p p = 0.048) at day seven. There were no differences in complications of prematurity. Conclusion The introduction of LISA is associated with significantly fewer diagnostic and therapeutic procedures in the first week of life, which emphasizes the beneficial effects of LISA.

Background: \ud Late onset sepsis (LOS) in preterm infants is preceded by fecal volatile organic compound (VOC) alterations, suggesting an etiological role of gut microbiota in LOS rather than being primarily caused by central venous catheters (CVC). To increase our knowledge about the involvement of the gut microbiota in LOS, we analyzed fecal samples from septic infants without a CVC.\ud Methods: \ud In this prospective multicenter study, fecal samples were collected daily from all infants born at ≤30 weeks gestation. Fecal VOC profiles up to 3 days prior to sepsis onset from infants with non-catheter–related LOS were compared with profiles from non-septic controls by means of High-Field Asymmetric Waveform Ion Mobility Spectrometry.\ud Results: \ud In total, 104 fecal samples were analyzed. Fecal VOC profiles allowed for discrimination between non-catheter–related LOS cases (n = 24) and matched controls (n = 25). Discriminative accuracy increased after focusing on center of origin (area under the curve, sensitivity, specificity; 0.95, 100%, 83%) and after focusing on LOS cases caused by Staphylococcus epidermidis (0.95, 100%, 78%), the most cultured pathogen (n = 11).\ud Conclusions: \ud Fecal VOC profiles of preterm LOS infants without a CVC differed from matched controls underlining the increasing notion that aberrations in gut microbiota composition and activity may play a role in LOS etiology.

Objectives: Several studies associated altered gut microbiota composition in preterm infants with late-onset sepsis (LOS), up to days before clinical onset of sepsis. Microbiota analysis as early diagnostic biomarker is, however, in clinical practice currently not feasible because of logistic aspects and high costs. Therefore, we hypothesized that analysis of fecal volatile organic compounds (VOCs) may serve as noninvasive biomarker to predict LOS at a preclinical stage, because VOC reflect the composition and activity of intestinal microbial communities.Methods: In a prospective multicenter study, fecal samples were collected daily from infants with a gestational age of Results: Fecal VOC profiles of infants with LOS (n = 36) could be discriminated from controls (n = 40) at 3 days (area under the curve [+/- 95% confidence interval], P value, sensitivity, specificity; 70.2 [52.2-88.3], 0.033, 57.1%, 61.5%), 2 days (77.7 [62.7-92.7], 0.050, 75.0%, 70.8%), and 1 day (70.4 [49.6-91.3], 0.037, 64.3%, 64.3%) before the onset of LOS.Conclusions: Fecal VOC profiles of preterm infants with LOS could be discriminated from matched controls, up to 3 days before clinical onset of the disease, underlining the hypothesis that intestinal microbiota may play an etiological role in LOS. Notably, VOC profiling is clinically feasible and the potential of this technique in the early detection of LOS needs to be confirmed in future studies.

In the last 4 decades, advances in neonatology have led to a significant increase in the survival of preterm infants. One of the biggest advances was the introduction of surfactant replacement therapy for the treatment of respiratory distress syndrome. This is the main cause of respiratory insufficiency in preterm infants and is one of the major causes of perinatal morbidity and mortality. Surfactant replacement therapy is already a well-investigated and established therapy in neonatology. However, surfactant replacement therapy has progressed and been refined over recent decades, especially with the increasing care for preterm infants born before 26 weeks' gestational age and the recent clinical focus on avoiding mechanical ventilation. Clinical evidence is evolving on new types of surfactant, surfactant dosages, co-medication given before, with, or after surfactant replacement, and new technical advances regarding the mode of administration. (C) 2017 S. Karger AG, Basel

Brain connectivity is associated with axonal connections between brain structures. Our goal was to quantify the interhemispheric neuronal connectivity in healthy preterm infants by automated quantitative EEG time-correlation analysis. As with advancing postmenstrual age (PMA, gestational age + postnatal age) the neuronal connectivity between left and right hemisphere increases, we expect to observe changes in EEG time-correlation with age. Thirty-six appropriate-for-gestational age preterm infants (PMA between 27-37 weeks) and normal neurodevelopmental follow-up at 5 years of age were included. Of these, 22 infants underwent 3-8 repeated EEG recordings at weekly intervals. The reduced 10-20 EEG electrode system for newborns was used with five sets of bipolar channels: central-temporal, frontal polar-temporal, frontal polar-central, temporal-occipital and central-occipital. We performed EEG time-correlation analysis between homologous channels of the brain hemispheres to identify interhemispheric similarity in EEG signal shape. For each 8 s epoch of the EEG the time-correlation values and the corresponding lag times were calculated for homologous channels on both hemispheres. In all channels, the median correlation value decreased significantly (between -40% and -60% decrease) from 27 to 37 weeks PMA, for gestational maturation. For the postnatal maturation only the central-temporal channel showed a significantly decreasing trend. In contrast, the median lag time showed no uniform change with PMA. The decreasing median correlation values in all homologous channels indicate a decrease in similarity in signal shape with advancing PMA. This finding may reflect greater functional differentiation of cortical areas in the developing preterm brain and may be explained by the increase of complex neural networks with excitatory and inhibitory circuitries.

Since the publication of the results of the Term Breech Trial (TBT) in 2000 the number of planned Caesarean sections for breech presentation has increased dramatically, at the expense of vaginal breech deliveries. The favourable effect of a planned Caesarean section for breech presentation on perinatal outcomes described in the TBT could not, however, be reproduced in later trials. A planned Caesarean section does carry an increased risk of maternal complications; furthermore, a previous Caesarean section leads to higher risks for both mother and child in any subsequent pregnancy. A recent prospective study advocates vaginal breech delivery 'on all fours', a position in which the mother leans on her hands and knees during delivery. A vaginal breech delivery in this position seems to be just as safe for the child as a planned Caesarean section, while a vaginal delivery is safer for the mother than a Caesarean section. This article describes two uncomplicated vaginal breech deliveries in the all fours position.

The conclusion of our recent paper that performance of the STAN device in clinical practice is potentially limited by high false-negative and high false-positive STAN-event rates and loss of ST waveform assessment capacity during severe hypoxemia, evoked comments by Kjellmer, Lindecrantz and Rosen. These comments can be summarized as follows: 1) STAN analysis is based on a unipolar lead but the authors used a negative aVF lead, and they did not validate this methodology; 2) The fetuses used in the study were too young to display the signals that the authors were trying to detect. In response to these comments we now provide both a theoretical and an experimental underpinning of our approach. In an in vivo experiment in human we placed several electrodes over the head (simulating different places of a scalp electrode), simultaneously recorded Einthoven lead I and II, and constructed-aVF from these two frontal leads. Irrespective of scalp electrode placement, the correlation between any of unipolar scalp electrode-derived signals and constructed-aVF was excellent (>= 0.92). In response to the second comment we refer to a study which demonstrated that umbilical cord occlusion resulted in rapid increase in T/QRS ratio that coincided with initial hypertension and bradycardia at all gestational ages which were tested from 0.6-0.8 gestation. The animals of our study were in this gestational range and, hence, our experimental setup can be used to assess STAN's quality to detect fetal hypoxia. In conclusion, we have clearly demonstrated the appropriateness of using-aVF as a proxy for a scalp electrode-derived signal in STAN in these preterm lambs. Investigation why STAN could not detect relevant ST-changes and instead produced erroneous alarms in our experimental setup is hampered by the fact that the exact STAN algorithm (signal processing and analysis) is not in the public domain.

Background: Late-onset sepsis (LOS) in preterm infants is a leading cause of mortality and morbidity. Timely recognition and initiation of antibiotics are important factors for improved outcomes. Identification of risk factors could allow selection of infants at an increased risk for LOS. Objectives: The aim was to identify risk factors for LOS. Methods: In this multicenter case-control study, preterm infants born at ≤30 weeks of gestation were included at 9 neonatal intensive care units. Detailed demographical and clinical data were collected daily up to day 28 postnatally. Clinical and demographic risk factors were identified using univariate and multivariate regression analyses in a 1: 1 matched case-control cohort. Results: In total, 755 infants were included, including 194 LOS cases (41 gram-negative cases, 152 gram-positive cases, and 1 fungus). In the case-control cohort, every additional day of parenteral feeding increased the risk for LOS (adjusted OR = 1.29; 95% CI 1.07–1.55; p = 0.006), whereas antibiotics administration decreased this risk (OR = 0.08; 95% CI 0.01–0.88; p = 0.039). These findings could largely be attributed to specific LOS-causative pathogens, since these predictive factors could be identified for gram-positive, but not for gram-negative, LOS cases. Specifically cephalosporins administration prior to clinical onset was inversely related to coagulase-negative staphylococcus LOS (CoNS-LOS) development. Formula feeding was an independent risk factor for development of CoNS-LOS (OR = 3.779; 95% CI 1.257–11.363; p = 0.018). Conclusion: The length of parenteral feeding was associated with LOS, whereas breastmilk administration was protective against CoNS-LOS. A rapid advancement of enteral feeding, preferably with breastmilk, may proportionally reduce the number of parenteral feeding days and consequently the risk for LOS.

Background: Although sedative premedication for endotracheal intubation is considered standard of care, less invasive surfactant administration (LISA) is often performed without sedative premedication. The aim of this study was to assess success rates, technical quality and vital parameters in LISA without sedative premedication. Methods: Prospective observational study in 86 neonates

BACKGROUND:Current methods for assessing perinatal hypoxic conditions did not improve infant outcomes. Various waveform-based and interval-based ECG markers have been suggested, but not directly compared. We compare performance of ECG markers in a standardized ovine model for fetal hypoxia.METHODS:Sixty-nine fetal sheep of 0.7 gestation had ECG recorded 4 h before, during, and 4 h after a 25-min period of umbilical cord occlusion (UCO), leading to severe hypoxia. Various ECG markers were calculated, among which were heart rate (HR), HR-corrected ventricular depolarization/repolarization interval (QTc), and ST-segment analysis (STAN) episodic and baseline rise markers, analogue to clinical STAN device alarms. Performance of interval- and waveform-based ECG markers was assessed by correlating predicted and actual hypoxic/normoxic state.RESULTS:Of the markers studied, HR and QTc demonstrated high sensitivity (≥86%), specificity (≥96%), and positive predictive value (PPV) (≥86%) and detected hypoxia in ≥90% of fetuses at 4 min after UCO. In contrast, STAN episodic and baseline rise markers displayed low sensitivity (≤20%) and could not detect severe fetal hypoxia in 65 and 28% of the animals, respectively.CONCLUSION:Interval-based HR and QTc markers could assess the presence of severe hypoxia. Waveform-based STAN episodic and baseline rise markers were ineffective as markers for hypoxia.

BACKGROUND: Surfactant replacement therapy is the gold standard treatment of neonatal respiratory distress (RDS). Nebulization is a noninvasive mode of surfactant administration. We administered Poractant alfa (Curosurf) via a vibrating perforated membrane nebulizer (eFlow Neonatal Nebulizer) to spontaneously breathing preterm lambs during binasal continuous positive pressure ventilation (CPAP).METHODS: Sixteen preterm lambs were operatively delivered at a gestational age of 133 ± 1 d (term ~150 d), and connected to CPAP applied via customized nasal prongs. Nebulization was performed (i) with saline or (ii) with surfactant for 3 h in humidified or (iii) nonhumidified air, and with surfactant (iv) for 60 min or (v) for 30 min. We measured arterial oxygenation, lung gas volumes and surfactant pool size and deposition.RESULTS: Nebulization of surfactant in humidified air for 3 h improved oxygenation and lung function, and surfactant was preferentially distributed to the lower lung lobes. Shorter nebulization times and 3 h nebulization in dry air did not show these effects. Nebulized surfactant reached all lung lobes, however the increase of surfactant pool size missed statistical significance.CONCLUSION: Positive effects of surfactant nebulization to spontaneously breathing preterm lambs depend on treatment duration, surfactant dose, air humidity, and surfactant distribution within the lung.

Pregnant women who previously had bariatric surgery may develop acute abdominal pain during pregnancy that may be related to previous operations. Two patients, a 38-year-old twin-primigravida who had a gestation period of 24+6 weeks and a 26-year-old woman who had a gestation period of 24 weeks, both of whom had laparoscopic gastric bypass (RYGB) surgery 2 and 3 years previously, developed abdominal pain. The patients were not ill, but had diffuse abdominal pain in combination with normal blood tests and imaging. Patient B had undergone laparoscopy at another centre after 5 weeks of gestation for internal herniation. After referral to our multidisciplinary Bariatric-Obstetric-Neonatal (MD-BON) team, diagnostic laparoscopy was advised as internal herniation was deemed possible. In both patients, internal herniation was indeed found in Petersen's space and jejunal mesenteric defect, which was closed using laparoscopic surgery. Both women delivered healthy offspring afterwards. The presence of a MD-BON team allows for an increased awareness of potential long-term complications associated with earlier bariatric surgery in pregnancy.

Fecal volatile organic compound (VOC) analysis has shown great potential as a noninvasive diagnostic biomarker for a variety of diseases. Before clinical implementation, the factors influencing the outcome of VOC analysis need to be assessed. Recent studies found that the sampling conditions can influence the outcome of VOC analysis. However, the dietary influences remains unknown, especially in (preterm) infants. Therefore, we assessed the effects of feeding composition on fecal VOC patterns of preterm infants (born at &lt, 30 weeks gestation). Two subgroups were defined: (1) daily intake &gt, 75% breastmilk (BM) feeding and (2) daily intake &gt, 75% formula milk (FM) feeding. Fecal samples, which were collected at 7, 14 and 21 days postnatally, were analyzed by an electronic nose device (Cyranose 320&reg, ). In total, 30 preterm infants were included (15 FM, 15 BM). No differences in the fecal VOC patterns were observed at the three predefined time-points. Combining the fecal VOC profiles of these time-points resulted in a statistically significant difference between the two subgroups although this discriminative accuracy was only modest (AUC [95% CI], p-value, sensitivity, and specificity of 0.64 [0.51&ndash, 0.77], 0.04, 68%, and 51%, respectively). Our results suggest that the influence of enteral feeding on the outcome of fecal VOC analysis cannot be ignored in this population. Furthermore, in both subgroups, the fecal VOC patterns showed a stable longitudinal course within the first month of life.

Background. The intestinal microbiota has increasingly been considered to play a role in the etiology of late-onset sepsis (LOS). We hypothesize that early alterations in fecal volatile organic compounds (VOCs), reflecting intestinal microbiota composition and function, allow for discrimination between infants developing LOS and controls in a preclinical stage.Methods. In 9 neonatal intensive care units in the Netherlands and Belgium, fecal samples of preterm infants born at a gestational age ≤30 weeks were collected daily, up to the postnatal age of 28 days. Fecal VOC were measured by high-field asymmetric waveform ion mobility spectrometry (FAIMS). VOC profiles of LOS infants, up to 3 days prior to clinical LOS onset, were compared with profiles from matched controls.Results. In total, 843 preterm born infants (gestational age ≤30 weeks) were included. From 127 LOS cases and 127 matched controls, fecal samples were analyzed by means of FAIMS. Fecal VOCs allowed for preclinical discrimination between LOS and control infants. Focusing on individual pathogens, fecal VOCs differed significantly between LOS cases and controls at all predefined time points. Highest accuracy rates were obtained for sepsis caused by Escherichia coli, followed by sepsis caused by Staphylococcus aureus and Staphylococcus epidermidis.Conclusions. Fecal VOC analysis allowed for preclinical discrimination between infants developing LOS and matched controls. Early detection of LOS may provide clinicians a window of opportunity for timely initiation of individualized therapeutic strategies aimed at prevention of sepsis, possibly improving LOS-related morbidity and mortality.

Introduction: Although the exact pathophysiological mechanisms of both necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in preterm infants are yet to be elucidated, evidence is emerging that the gut microbiota plays a key role in their pathophysiology. Areas covered: In this review, initial microbial colonization and factors influencing microbiota composition are discussed. For both NEC and LOS, an overview of studies investigating preclinical alterations in gut microbiota composition and fecal volatile organic compounds (VOCs) is provided. Fecal VOCs are considered to reflect not only gut microbiota composition, but also their metabolic activity and concurrent interaction with the host. Expert review: Heterogeneity in study protocols and applied analytical techniques hampers reliable comparison between outcomes of different microbiota studies, limiting the ability to draw firm conclusions. This dilemma is illustrated by the finding that study results often cannot be reproduced, or even contradict each other. A NEC- and sepsis specific microbial or metabolic signature has not yet been discovered. Identification of ‘disease-specific’ VOCs and microbiota composition may increase understanding on pathophysiological mechanisms and may allow for development of an accurate screening tool, opening avenues towards timely identification and initiation of targeted treatment for preterm infants at increased risk for NEC and sepsis.

BackgroundThe aim of this study was to evaluate the potential of fecal volatile organic compounds (VOCs), obtained by means of an electronic nose device (Cyranose 320), as early non-invasive biomarker for BPD.MethodsIn this nested case-control study performed at three Neonatal Intensive Care Units, fecal samples obtained at postnatal age of 7, 14, 21, and 28 days from preterm infants with severe bronchopulmonary dysplasia (BPD) were compared with fecal VOC profiles from matched controls. Microbiota analysis was performed by means of IS-pro technique on fecal samples collected at 28 days postnatally.ResultsVOC profiles of infants developing severe BPD (n=15) could be discriminated from matched controls (n=15) at postnatal age of 14 days (area under the curve (±95% confidence interval), P-value, sensitivity, specificity; 0.72 (0.54-0.90), 0.040, 60.0%, 73.3%), 21 days (0.71 (0.52-0.90), 0.049, 66.7%, 73.3%) and 28 days (0.77 (0.59-0.96), 0.017, 69.2%, 69.2%) but not at 7 days. Intestinal microbiota did not differ between BPD subjects and controls.ConclusionFecal VOC profiles of infants developing BPD could be differentiated from controls at postnatal day 14, 21, and 28. VOC differences could not be directed to intestinal microbiota alterations but presumably reflect local and systemic metabolic and inflammatory pathways associated with BPD.Pediatric Research advance online publication, 22 November 2017; doi:10.1038/pr.2017.268.

Background: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. Objective: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. Methods: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age ≤30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. Results: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. Conclusions: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC.

Introduction The inconclusive clinical results for ST-waveform analysis (STAN) in detecting fetal hypoxemia may be caused by the signal processing of the STAN-device itself. We assessed the performance of a clinical STAN device in signal processing and in detecting hypoxemia in a fetal sheep model exposed to prolonged umbilical cord occlusion (UCO). Methods Eight fetal lambs were exposed to 25 minutes of UCO. ECG recordings were analyzed during a baseline period and during UCO. STAN-event rates and timing of episodic T/QRS rise, baseline T/QRS rise and the occurrence of biphasic ST-waveforms, as well as signal loss, were assessed. Results During baseline conditions of normoxemia, a median of 40 (IQR, 25–70) STAN-events per minute were detected, compared to 10 (IQR, 2–22) during UCO. During UCO STAN-events were detected in five subjects within 10 minutes and in six subjects after 18 minutes, respectively. Two subjects did not generate any STAN-event during UCO. Biphasic ST event rate was reduced during UCO (median 0, IQR 0–5), compared to baseline (median 32, IQR, 6–55). ST-waveforms could not be assessed in 62% of the recording time during UCO, despite a good quality of the ECG signal. Conclusions The STAN device showed limitations in detecting hypoxemia in fetal sheep after prolonged UCO. The STAN device produced high false positive event rates during baseline and did not detect T/QRS changes adequately after prolonged fetal hypoxemia. During 14% of baseline and 62% of the UCO period, the STAN-device could not process the ECG signal, despite its good quality. Resolving these issues may improve the clinical performance of the STAN device.

As an approach of unobtrusive assessment of neonatal sleep state we aimed at an automated sleep state coding based only on heart rate variability obtained from electrocardiography used for regular patient monitoring. We analyzed active and quiet sleep states of preterm infants between 30 and 37 weeks postmenstrual age. To determine the sleep states we used a nonlinear kernel support vector machine for sleep state separation based on known heart rate variability features. We used unweighted and weighted misclassification penalties for the imbalanced distribution between sleep states. The validation was performed with leave-one-out-cross-validation based on the annotations of three independent observers. We analyzed the classifier performance with receiver operating curves leading to a maximum mean value for the area under the curve of 0.87. Using this sleep state separation methods, we show that automated active and quiet sleep state separation based on heart rate variability in preterm infants is feasible.

Necrotizing enterocolitis (NEC) remains one of the most frequent gastrointestinal diseases in the neonatal intensive care unit, with a continuing unacceptable high mortality and morbidity rates. Up to 20% to 40% of infants with NEC will need surgical intervention at some point. Although the exact pathophysiology is not yet elucidated, prematurity, use of formula feeding, and an altered intestinal microbiota are supposed to induce an inflammatory response of the immature intestine. The clinical picture of NEC has been well described. However, an early diagnosis and differentiation against sepsis is challenging. Besides, it is difficult to timely identify NEC cases that will deteriorate and need surgical intervention. This may interfere with the most optimal treatment of infants with NEC. In this review, we discuss the pathogenesis, diagnosis, and treatment of NEC with a focus on the role of microbiota in the development of NEC. An overview of different clinical prediction models and biomarkers is given. Some of these are promising tools for accurate diagnosis of NEC and selection of appropriate therapy.