Reduction in Perinatal Mortality after Implementation of HBB Training at a District Hospital in Mali.

BACKGROUND: Mali has a high neonatal mortality rate of 38/1000 live births; in addition the fresh stillbirth rate (FSR) is 23/1000 births and of these one-third are caused by intrapartum events. OBJECTIVES: The aims are to evaluate the effect of helping babies breathe (HBB) on mortality rate at a district hospital in Kati district, Mali. METHODS: HBB first edition was implemented in April 2016. One year later the birth attendants were trained in HBB second edition and started frequent repetition training. This is a before and after study comparing the perinatal mortality during the period before HBB training with the period after HBB training, the period after HBB first edition and the period after HBB second edition. Perinatal mortality is defined as FSR plus neonatal deaths in the first 24 h of life. RESULTS: There was a significant reduction in perinatal mortality rate (PMR) between the period before and after HBB training, from 21.7/1000 births to 6.0/1000 live births; RR 0.27, (95% CI 0.19-0.41; p < 0.0001). Very early neonatal mortality rate (24 h) decreased significantly from 6.3/1000 to 0.8/1000 live births; RR 0.12 (95% CI 0.05-0.33; p = 0.0006). FSR decreased from 15.7/1000 to 5.3/1000, RR 0.33 (95% CI 0.22-0.52; p < 0.0001). No further reduction occurred after introducing the HBB second edition. CONCLUSION: HBB may be effective in a local first-level referral hospital in Mali.

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide.

BACKGROUND: After perinatal asphyxia, the cerebellum presents more damage than previously suggested. OBJECTIVES: To explore if the antioxidant N-acetylcysteine amide (NACA) could reduce cerebellar injury after hypoxia-reoxygenation in a neonatal pig model. METHODS: Twenty-four newborn pigs in two intervention groups were exposed to 8% oxygen and hypercapnia, until base excess fell to -20 mmol/l or the mean arterial blood pressure declined to <20 mmHg. After hypoxia, they received either NACA (NACA group, n = 12) or saline (vehicle-treated group, n = 12). One sham-operated group (n = 5) served as a control and was not subjected to hypoxia. Observation time after the end of hypoxia was 9.5 hours. RESULTS: The intranuclear proteolytic activity in Purkinje cells of asphyxiated vehicle-treated pigs was significantly higher than that in sham controls (p = 0.03). Treatment with NACA was associated with a trend to decreased intranuclear proteolytic activity (p = 0.08), There were significantly less mutations in the mtDNA of the NACA group compared with the vehicle-treated group, 2.0 × 10-4 (±2.0 × 10-4) versus 4.8 × 10-5(±3.6 × 10-4, p < 0.05). CONCLUSION: We found a trend to lower proteolytic activity in the core of Purkinje cells and significantly reduced mutation rate of mtDNA in the NACA group, which may indicate a positive effect of NACA after neonatal hypoxia. Measuring the proteolytic activity in the nucleus of Purkinje cells could be used to assess the effect of different neuroprotective substances after perinatal asphyxia.

Physical activity and the risk of preterm birth: a systematic review and meta-analysis of epidemiological studies.

BACKGROUND: Physical activity has been inconsistently associated with risk of preterm birth, and the strength of the association and the shape of the dose-response relationship needs clarification. OBJECTIVES: To conduct a systematic review and dose-response meta-analysis to clarify the association between physical activity and risk of preterm birth. SEARCH STRATEGY: PubMed, Embase and Ovid databases were searched for relevant studies up to 9 February 2017. SELECTION CRITERIA: Studies with a prospective cohort, case-cohort, nested case-control or randomized study design were included. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked for accuracy by a second reviewer. Summary relative risks (RRs) were estimated using a random effects model. MAIN RESULTS: Forty-one studies (43 publications) including 20 randomized trials and 21 cohort studies were included. The summary RR for high versus low activity was 0.87 [95% confidence interval (CI): 0.70-1.06, I2 = 17%, n = 5] for physical activity before pregnancy, and it was 0.86 (95% CI: 0.78-0.95, I2 = 0%, n = 30) for early pregnancy physical activity. The summary RR for a 3 hours per week increment in leisure-time activity was 0.90 (95% CI: 0.85-0.95, I2 = 0%, n = 5). There was evidence of a nonlinear association between physical activity and preterm birth, Pnonlinearity < 0.0001, with the lowest risk observed at 2-4 hours per week of activity. CONCLUSION: This meta-analysis suggests that higher leisure-time activity is associated with reduced risk of preterm birth. Further randomized controlled trials with sufficient frequency and duration of activity to reduce the risk and with larger sample sizes are needed to conclusively demonstrate an association. TWEETABLE ABSTRACT: Physically active compared with inactive women have an 10-14% reduction in the risk of preterm birth.

The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy.

Neonatal hypoxemic respiratory failure (HRF), a deficiency of oxygenation associated with insufficient ventilation, can occur due to a variety of etiologies. HRF can result when pulmonary vascular resistance (PVR) fails to decrease at birth, leading to persistent pulmonary hypertension of newborn (PPHN), or as a result of various lung disorders including congenital abnormalities such as diaphragmatic hernia, and disorders of transition such as respiratory distress syndrome, transient tachypnea of newborn and perinatal asphyxia. PVR changes throughout fetal life, evident by the dynamic changes in pulmonary blood flow at different gestational ages. Pulmonary vascular transition at birth requires an interplay between multiple vasoactive mediators such as nitric oxide, which can be potentially inactivated by superoxide anions. Superoxide anions have a key role in the pathophysiology of HRF. Oxygen (O2) therapy, used in newborns long before our knowledge of the complex nature of HRF and PPHN, has continued to evolve. Over time has come the discovery that too much O2 can be toxic. Recommendations on the optimal inspired O2 levels to initiate resuscitation in term newborns have ranged from 100% (pre 1998) to the currently recommended use of room air (21%). Questions remain about the most effective levels, particularly in preterm and low birth weight newborns. Attaining the appropriate balance between hypoxemia and hyperoxemia, and targeting treatments to the pathophysiology of HRF in each individual newborn are critical factors in the development of improved therapies to optimize outcomes.

Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate.

Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.

Development of a reliable analytical method to determine lipid peroxidation biomarkers in newborn plasma samples.

This paper describes a reliable analytical method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry to determine F2-isoprostanes and other total byproducts (isoprostanes, isofurans, neuroprostanes and neurofurans) as lipid peroxidation biomarkers in newborn plasma samples. The proposed procedure is characterized by a simple sample treatment employing a reduced sample volume (100µL). Also, it shows a high throughput and high selectivity to determine simultaneously different isoprostane isomers in a large number of samples. The reliability of the described method was demonstrated by analysis of spiked plasma samples, obtaining recoveries between 70% and 130% for most of the analytes. Taking into account the implementation of further clinical studies, it was demonstrated the proper sensitivity of the method by means of the analysis of few human newborn plasma samples. In addition to this, newborn piglet plasma samples (n=80) were analyzed observing that the developed method was suitable to determine the analyte levels present in this kind of samples. Therefore, this analytical method could be applied in further clinical research about establishment of reliable lipid peroxidation biomarkers employing this experimental model.

Estimation of time since death by vitreous humor hypoxanthine, potassium, and ambient temperature.

Measurement of vitreous humor potassium (K(+)) has since the 1960s been recognized as an adjunct for estimation of time since death. In 1991 we introduced hypoxanthine (Hx) as a new marker. Furthermore we demonstrated that time since death estimation was more accurate when ambient temperature was included in the calculations, both for K(+) and for Hx. In this paper we present a refined method. The subjects consist of 132 cases with known time of death and ambient temperature. One sample from each subject was used in the calculations. Vitreous humor Hx levels were available in all subjects, while K(+) was measured in 106 of the subjects, due to insufficient volume of vitreous humor. Linear regression analysis was applied to model the correlation between vitreous humor Hx and K(+), taking the interactions with temperature into consideration. The diagrams published in 1991, which also included ambient temperature, estimated median time since death with range between the 10th and 90th percentile, whereas the linear regression analysis presented in this paper estimates mean time since death with a corresponding 95% interval of confidence. We conclude that time since death may be estimated with relatively high precision applying vitreous humor Hx and K(+) concentrations combined with ambient temperature.

Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air.

AIM: The starting fraction of inspired oxygen for preterm resuscitation is a matter of debate, and the use of room air in full-term asphyxiated infants reduces oxidative stress. This study compared oxidative stress in preterm infants randomised for resuscitation with either 100% oxygen or room air titrated to internationally recommended levels of preductal oxygen saturations. METHODS: Blood was collected at birth, two and 12 hours of age from 119 infants <32 weeks of gestation randomised to resuscitation with either 100% oxygen (n = 60) or room air (n = 59). Oxidative stress markers, including advanced oxidative protein products (AOPP) and isoprostanes (IsoP), were measured with high-performance liquid chromatography and mass spectrometry. RESULTS: Significantly higher levels of AOPP were found at 12 hours in the 100% oxygen group (p < 0.05). Increases between two- and 12-hour AOPP (p = 0.004) and IsoP (p = 0.032) concentrations were significantly higher in the 100% oxygen group. CONCLUSION: Initial resuscitation with room air versus 100% oxygen was associated with lower protein oxidation at 12 hour and a lower magnitude of increase in AOPP and IsoP levels between two and 12 hours of life. Correlations with clinical outcomes will be vital to optimise the use of oxygen in preterm resuscitation.

Detection of batch effects in liquid chromatography-mass spectrometry metabolomic data using guided principal component analysis.

Metabolomics based on liquid chromatography-mass spectrometry (LC-MS) is a powerful tool for studying dynamic responses of biological systems to different physiological or pathological conditions. Differences in the instrumental response within and between batches introduce unwanted and uncontrolled data variation that should be removed to extract useful information. This work exploits a recently developed method for the identification of batch effects in high throughput genomic data based on the calculation of a δ statistic through principal component analysis (PCA) and guided PCA. Its applicability to LC-MS metabolomic data was tested on two real examples. The first example involved the repeated analysis of 42 plasma samples and 6 blanks in three independent batches, and the second data set involved the analysis of 101 plasma and 18 blank samples in a single batch with a total runtime of 50h. The first and second data set were used to evaluate between and within-batch effects using the δ statistic, respectively. Results obtained showed the usefulness of using the δ statistic together with other approaches such as summary statistics of peak intensity distributions, PCA scores plots or the monitoring of IS peak intensities, to detect and identify instrumental instabilities in LC-MS.

New guidelines for newborn resuscitation--a critical evaluation.

UNLABELLED: The 2010 International Liaison Committee on Resuscitation guidelines for newborn resuscitation represent important progress. The criteria for assessment are simplified based on heart rate and respiration only and there is no timing of stages after the first 60 sec. Instead of giving supplemental oxygen, the guidelines state that 'it is best to start with air'. However, the optimal oxygen concentration later in the process and for premature babies is not yet clear. A description of an adequate heart rate response is not given, and the cut-off of 100 bpm may be arbitrary. There are still no clear recommendations regarding ventilation, inspiratory time, use of positive end expiratory pressure or continuous positive airway pressure. The guidelines do not mention which paCO2 level might be optimal. As colour pink assessment and routine suctioning of airways are not recommended anymore, there is an urgent need to obtain international consensus and create a new and revised Apgar score without these two variables. CONCLUSION: In spite of improved guidelines for newborn resuscitation, there is still a number of unanswered questions and a need for more delivery room studies.

A new tool for the validation of umbilical cord acid-base data.

OBJECTIVE: To identify the distribution of carbon dioxide tension (pCO(2) ) relative to pH in validated umbilical cord acid-base data. DESIGN: Observational study. SETTING: European hospital labour wards. POPULATION: Data for 36,432 term newborns were obtained from three sources: two trials of fetal monitoring with electrocardiography (ECG; the Swedish randomised controlled trial and the European Union Fetal ECG trial) and data from Mölndal Hospital. METHODS: From the total study population, cases with missing values or obvious typing errors were excluded. The remaining data were validated based on specified criteria. Percentiles of arterial pCO(2) by pH were calculated using multilevel regression modelling. MAIN OUTCOME MEASURES: Umbilical cord pH, pCO(2) and base deficit. RESULTS: Acid-base values were considered invalid in one out of seven cases. Percentiles for arterial pCO(2) corresponding to specified values of arterial pH were developed from the validated data of 26, 690 cases. CONCLUSIONS: Percentiles for arterial pCO(2) for a specified arterial pH can be used as a tool to identify cases with erroneously low pCO(2) values, and thus avoid an incorrect interpretation of the newborn's acid-base status.

Why are we still using oxygen to resuscitate term infants?

This article summarizes the historical background for the use of oxygen during newborn resuscitation and describes some of the research and the process of changing the previous practice from a high- to a low-oxygen approach. Findings of a recent Cochrane review suggest that more than 100,000 newborn lives might be saved globally each year by changing from 100 to 21% oxygen for newborn resuscitation. This estimate represents one of the largest yields for a simple therapeutic approach to decrease neonatal mortality in the history of pediatric research. Available data also suggest that, for the very low birth weight infant, use of the low-oxygen approach should be considered with the understanding that some of the smallest and sickest preterm neonates will need some level of oxygen supplementation during the first minutes of postnatal life. As more data are needed for the very preterm population, creation of strict guidelines for these infants would be premature at present. However, it can be stated that term and late preterm infants in need of resuscitation should, in general, be started on 21% oxygen, and if resuscitation is not started with 21% oxygen, a blender should be available, enabling the administration of the lowest FiO(2) possible to keep heart rate and SaO(2) within the target range. For extremely low birth weight infants, initial FiO(2) could be between 0.21 and 0.30 and adjusted according to the response in SaO(2) and heart rate.

Resuscitation of the term and preterm infant.

Resuscitation is one of the most frequently performed procedures in the neonatal period. Since the most recent guidelines from the International Liaison Committee on Resuscitation (ILCOR) appeared in 2005, experimental and clinical research has introduced changes regarding the different components of the procedure, with the common denominator being the least aggressive to the baby. Babies should be kept warm, avoiding suctioning as a general rule, adjusting pressure, volume and oxygen to the minimum to achieve stabilisation without causing harm to the airways or oxidative stress, and applying all the available technology in the delivery room before transportation to the neonatal intensive care unit. The response to ventilation should primarily be assessed by the heart rate. Babies of gestational age >or=32 weeks should be ventilated initially with 21% oxygen and if <32 weeks with 21-30% oxygen. Intubation, chest compressions, use of drugs or volume therapy are rarely needed in term or near term babies in need of resuscitation. The first minutes of life are decisive, and what we do during these minutes will have unequivocal influence later on.

Toxic effects of different meconium fractions on lung function: new therapeutic strategies for meconium aspiration syndrome?

To review and summarize experimental data examining the effects of different fractions of meconium, and to test the effect of albumin on meconium aspiration both as prophylactic and rescue treatment. Newborn piglets 2 to 5 days of age were made hypoxic and then instilled meconium or fractions of meconium intratracheally. Meconium-added albumin and albumin instilled after meconium were also tested. Lung function and inflammatory cytokines were measured. Both the lipid- and water-soluble fractions induce inflammation in the lungs with elevation of inflammatory cytokines. When meconium was mixed with albumin, the inflammatory effects of meconium were significantly ameliorated. Rescue therapy with intratracheal albumin 5 min after the meconium aspiration syndrome was induced also improved lung function. These results indicate that at least part of the symptoms seen in the meconium aspiration syndrome could be prevented by blocking the active substances of meconium such as bile acids and free fatty acids.

The role of complement in meconium aspiration syndrome.

The complement system is part of the host defense with a number of biological effects, most of which contribute to the inflammatory reaction by activation of cells like leukocytes and endothelial cells. An intact complement system is required for protection against infection and for maintaining internal inflammatory homeostasis. However, the system is a double-edged sword as improperly or uncontrolled activation is disadvantageous and potentially harmful for the host. Meconium aspiration syndrome (MAS) is associated with a local inflammatory reaction in the lungs, frequently described as a chemical pneumonitis. Cytokines, arachidonic acid metabolites and reactive oxygen species are involved in this reaction. We have recently documented that meconium is a potent activator of complement in vitro and in an experimental piglet model of MAS, the latter presenting with an inflammatory profile closely resembling systemic inflammatory response syndrome. We postulate that complement activation may contribute to the pathogenesis of MAS.