Impact of a Multi-Strain Probiotic on Healthcare-Associated Bloodstream Infection Incidence and Severity in Preterm Neonates

Aim:Hospital acquired bloodstream infection (HA-BSI) is a major contributor to morbidity and mortality in preterm, very low birthweight infants, especially in low-to-middle- income countries.Materials and Methods:We conducted a double-blind, placebo-controlled, randomized clinical trial to investigate the effect of a multi-strain probiotic formulation (LabinicTM) on the incidence and severity of HA-BSI in preterm neonates.Results:Two hundred neonates (100 per arm) were included in this trial. Fifteen neonates developed HA-BSI events (2 in the probiotic arm and 13 in the placebo arm). The median day of life at HA-BSI onset for the probiotic group was 10.5±3.5, and for the placebo group, it was 11.2±6.4. The incidence of HA-BSI in neonates receiving the probiotic was significantly lower compared to those receiving the placebo [0.93 versus 5.99 HA-BSI events/1,000 neonate-days; incidence rate ratio (IRR) of 0.156 [95% confidence interval (CI): 0.017 to 0.691], p=0.0046]. Calculating the incidence rate of the combined outcome (sepsis/death) was also lower in the probiotic group versus the placebo group [2.34 versus 6.45 events/1,000 neonate days; IRR 0.33 (95% CI: 0.11 to 0.97), p=0.043].Conclusion:The use of a multi-strain probiotic significantly reduced HA-BSI incidence in this cohort of preterm neonates

Amniotic Fluid: A Perspective on Promising Advances in the Prevention and Treatment of Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a common and potentially fatal disease that typically affects preterm (PIs) and very low birth weight infants (VLBWIs). Although NEC has been extensively studied, the current therapeutic approaches are unsatisfactory. Due to the similarities in the composition between human amniotic fluid (AF) and human breast milk (BM), which plays a protective role in the development of NEC in PIs and VLBWIs, it has been postulated that AF has similar effects on the outcome of NEC and potential therapeutic implications. AF has been long used for its diagnostic purposes and is often discarded after birth as “biological waste”. However, researchers have started to elucidate its therapeutic potential. Experimental studies in animal models have shown that diseases of various organ systems can possibly benefit from AF-based therapy. Hence, we have identified three approaches which show promising results for future clinical application in the prevention and/or treatment of NEC: (1) administration of processed AF (PAF) isolated from donor mothers, (2) administration of AF stem cells (AFSCs), and (3) administration of simulated AF (SAF) formulated to mimic the composition of physiological AF. We have highlighted the most important aspects that should be taken into account to guide further research on the clinical application of AF-based therapy. We hope that this review can provide a framework to identify the challenges of AF-based therapy and help to design future studies to better evaluate AF-based approaches for the treatment and/or prevention of NEC in PIs and VLBWIs

Effect of a Multi-Strain Probiotic on Growth and Time to Reach Full Feeds in Preterm Neonates

Background: The main nutritional goal for premature neonates is to achieve a postnatal growth rate that the neonate would have experienced in utero. Postnatal growth failure is, however, very common in very and extremely low birth weight neonates. The use of probiotics shows promising results in reducing the time for full feeds, as well as in increased weight gain. The optimal probiotic strain has, however, not been elucidated. The aim of the present study was to evaluate the difference in the growth and time to reach full feeds between the two treatment arms, using LabinicTM as a multi-strain probiotic and a placebo. Methods: We conducted a double-blind, placebo-controlled, randomized clinical trial investigating the effect of a multi strain probiotic (LabinicTM) on various outcomes in preterm neonates. The results on the time to reach full feeds and the growth will be discussed in this paper. A probiotic or placebo was given once daily to the neonates for 28 days. Weight and feeding volume were measured daily, and length and head circumference were measured weekly. Results: The probiotic group reached full feeds earlier 8.7 days; ± 2.0 than the placebo group 9.7 days; ±4.3 (p = 0.04) and regained their birthweight earlier than the placebo group 11.5 days ± 6.3 vs. 13.3 days ± 6.3 (p = 0.06). From day 21 onwards, the probiotic group showed a significantly greater crude gain in weight (p < 0.001) than the placebo group (estimated difference between the two groups day 21: 56.7 g and at day 28: 83.7 g. There was a significant improvement observed in the weight Z-score change in the probiotic group over the 28-day period. Conclusion: The use of a multi-strain probiotic (LabinicTM) shows great potential as a low-cost, low-risk intervention in reducing the time to reach full feeds as well as shortening the time to regain birthweight. The probiotic had an additional beneficial impact on Z-score change in weight potentially decreasing post-natal growth restriction

Effect of a Multi-Strain Probiotic on the Incidence and Severity of Necrotizing Enterocolitis and Feeding Intolerances in Preterm Neonates

Background: Necrotizing enterocolitis (NEC) is a multifactorial disease, causing inflammation of the bowel. The exact root of NEC is still unknown, but a low weight and gestational age at birth are known causes. Furthermore, antibiotic use and abnormal bacterial colonization of the premature gut are possible causes. Premature neonates often experience feeding intolerances that disrupts the nutritional intake, leading to poor growth and neurodevelopmental impairment. Methods: We conducted a double-blind, placebo-controlled, randomized clinical trial to investigate the effect of a multi-strain probiotic formulation (Labinic TM) on the incidence and severity of NEC and feeding intolerances in preterm neonates. Results: There were five neonates in the placebo group who developed NEC (Stage 1A–3B), compared to no neonates in the probiotic group. Further, the use of probiotics showed a statistically significant reduction in the development of feeding intolerances, p < 0.001. Conclusion: A multi-strain probiotic is a safe and cost-effective way of preventing NEC and feeding intolerances in premature neonates

Development and internal validation of a Neonatal Healthcare-associated infectiOn Prediction score (NeoHoP score) for very low birthweight infants in low-resource settings: a retrospective case–control study

Background and objectives Early diagnosis of neonatal infection is essential to prevent serious complications and to avoid unnecessary use of antibiotics. The prevalence of healthcare-associated infections (HAIs) among very low birthweight (VLBW; &lt;1500 g) infants is 20%; and the mortality in low-resource settings can be as high as 70%. This study aimed to develop an Infection Prediction Score to diagnose bacterial HAIs.Methods A retrospective cohort of VLBW infants investigated for HAI was randomised into two unmatched cohorts. The first cohort was used for development of the score, and the second cohort was used for the internal validation thereof. Potential predictors included risk factors, clinical features, interventions, and laboratory data. The model was developed based on logistic regression analysis.Results The study population of 655 VLBW infants with 1116 episodes of clinically suspected HAIs was used to develop the model. The model had five significant variables: capillary refill time &gt;3 s, lethargy, abdominal distention, presence of a central venous catheter in the previous 48 hours and a C reactive protein ≥10 mg/L. The area below the receiver operating characteristic curve was 0.868. A score of ≥2 had a sensitivity of 54.2% and a specificity of 96.4%.Conclusion A novel Infection Prediction Score for HAIs among VLBW infants may be an important tool for healthcare providers working in low-resource settings but external validation needs to be performed before widespread use can be recommended

Impact of a multi-strain probiotic administration on peri-rectal colonization with drug-resistant Gram-negative bacteria in preterm neonates

Background: Infections caused by drug resistant Gram-negative bacteria (DR-GNB) are a major health concern for hospitalized preterm neonates, globally. The aim of this study was to investigate the effect of a multi-strain probiotic on the incidence of rectal colonization with DR-GNB in preterm neonates. Methods: A double-blind, placebo-controlled, randomized clinical trial was conducted including 200 neonates, randomly allocated to a multi-strain probiotic (n = 100) or placebo (n = 100). Results: Fifteen percent of the neonates showed peri-rectal colonization with DR-GNB on the day of enrolment indicating probable maternal-to-neonate (vertical) bacterial transmission or environmental acquisition at time of delivery, with no difference between groups. Acquisition of further DR-GNB colonization was rapid, with an increase from 15% on the day enrolment to 77% by day 7 and 83% by day 14 of life. By day 7 (corresponding to early gut colonization), neonates in the probiotic group were 57% less likely to have peri-rectal DR-GNB colonization [OR: 0.43 (0.20–0.95); p = 0.04] and by day 14 (corresponding to late gut colonization), neonates in the probiotic group were 93% less likely to have peri-rectal DR-GNB colonization [OR: 0.07 (0.02–0.23); p < 0.001]. Conclusion: Hospitalized neonates showed substantial peri-rectal colonization with DR-GNB at enrolment and further rapid acquisition of DR-GNB in the first 2 weeks of life. The use of a multi-strain probiotic was effective in reducing early and late neonatal gut colonization with DR-GNB. Clinical Trial Registration: The trial was registered at the Pan African Clinical Trial Registry (PACTR202011513390736)

Care Pathway for Foetal Joint Contractures, Foetal Akinesia Deformation Sequence, and Arthrogryposis Multiplex Congenita

INTRODUCTION: The majority of arthrogryposis multiplex congenita (AMC) and lethal forms of AMC such as foetal akinesia deformation sequence (FADS) cases are missed prenatally. We have demonstrated the additional value of foetal motor assessment and evaluation in a multidisciplinary team for the period 2007-2016. An applied care pathway was developed for foetuses presenting with joint contracture(s) in one anatomic region (e.g., talipes equinovarus [TEV]), more than one body part with non-progressive contractures and motility (AMC) and with deterioration over time (FADS). METHODS: The multidisciplinary team of Amsterdam University Medical Centre Expertise Centre FADS and AMC developed the care pathway. Additional tools are provided including a motor assessment by ultrasound examination and a post-mortem assessment form. RESULTS: An eight-step care pathway is presented with a proposed timing for prenatal sonographic examination, genetic examinations, multidisciplinary meetings, prenatal and postnatal counselling of the parents by a specialist also treating after birth, and the follow-up of prenatal and postnatal findings with counselling for future pregnancies. DISCUSSION/CONCLUSION: The scheduled serial structural and motor sonograpahic assessment together with follow-up examinations and genetic analysis should be tailored per prenatal centre per available resources. The multidisciplinary care pathway may pave the way to increase the detection rate and diagnosis of isolated contracture(s), TEV with underlying genetic causes, and the rare phenotypes AMC/FADS and prompt treatment after birth within expertise teams

Outcome of isolated gastroschisis; an international study, systematic review and meta-analysis

To determine outcome of children born with isolated gastroschisis (no extra-gastrointestinal congenital abnormalities). International cohort study and meta-analysis. time to full enteral feeding (TFEF); secondary outcomes: Duration of mechanical ventilation, length of stay (LOS), mortality and differences in outcome between simple and complex gastroschisis (complex; born with bowel atresia, volvulus, perforation or necrosis). To compare the cohort study results with literature three databases were searched. Studies were eligible for inclusion if cases were born in developed countries with isolated gastroschisis after 1990, number of cases >20 and TFEF was reported. The cohort study included 204 liveborn cases of isolated gastroschisis. The TFEF, median duration of ventilation and LOS was, 26days (range 6-515), 2days (range 0-90) and 33days (range 11-515), respectively. Overall mortality was 10.8%. TFEF and LOS were significantly longer (P <0.0001) and mortality was fourfold higher in the complex group. Seventeen studies, amongst the current study, were included for further meta-analysis comprising a total of 1652 patients. Mean TFEF was 35.3±4.4days, length of ventilation was 5.5±2.0days, LOS was 46.4±5.2days and mortality risk was 0.06 [0.04-0.07 95%CI]. Outcome of simple and complex gastroschisis was described in five studies. TFEF, ventilation time, LOS were significant longer and mortality rate was 3.64 [1.95-6.83 95%CI] times higher in complex cases. These results give a good indication of the expected TFEF, ventilation time and LOS and mortality risk in children born with isolated gastroschisis, although ranges remain wide. This study shows the importance of dividing gastroschisis into simple and complex for the prediction of outcom

Real-time continuous glucose monitoring in preterm infants (REACT): an international, open-label, randomised controlled trial

Background Hyperglycaemia and hypoglycaemia are common in preterm infants and have been associated with increased risk of mortality and morbidity. Interventions to reduce risk associated with these exposures are particularly challenging due to the infrequent measurement of blood glucose concentrations, with the potential of causing more harm instead of improving outcomes for these infants. Continuous glucose monitoring (CGM) is widely used in adults and children with diabetes to improve glucose control, but has not been approved for use in neonates. The REACT trial aimed to evaluate the efficacy and safety of CGM in preterm infants requiring intensive care. Methods This international, open-label, randomised controlled trial was done in 13 neonatal intensive care units in the UK, Spain, and the Netherlands. Infants were included if they were within 24 h of birth, had a birthweight of 1200 g or less, had a gestational age up to 33 weeks plus 6 days, and had parental written informed consent. Infants were randomly assigned (1:1) to real-time CGM or standard care (with masked CGM for comparison) using a central web randomisation system, stratified by recruiting centre and gestational age (<26 or ≥26 weeks). The primary efficacy outcome was the proportion of time sensor glucose concentration was 2·6–10 mmol/L for the first week of life. Safety outcomes related to hypoglycaemia (glucose concentrations <2·6 mmol/L) in the first 7 days of life. All outcomes were assessed on the basis of intention to treat in the full analysis set with available data. The study is registered with the International Standard Randomised Control Trials Registry, ISRCTN12793535. Findings Between July 4, 2016, and Jan 27, 2019, 182 infants were enrolled, 180 of whom were randomly assigned (85 to real-time CGM, 95 to standard care). 70 infants in the real-time CGM intervention group and 85 in the standard care group had CGM data and were included in the primary analysis. Compared with infants in the standard care group, infants managed using CGM had more time in the 2·6–10 mmol/L glucose concentration target range (mean proportion of time 84% [SD 22] vs 94% [11]; adjusted mean difference 8·9% [95% CI 3·4–14·4]), equivalent to 13 h (95% CI 5–21). More infants in the standard care group were exposed to at least one episode of sensor glucose concentration of less than 2·6 mmol/L for more than 1 h than those in the intervention group (13 [15%] of 85 vs four [6%] of 70). There were no serious adverse events related to the use of the device or episodes of infection. Interpretation Real-time CGM can reduce exposure to prolonged or severe hyperglycaemia and hypoglycaemia. Further studies using CGM are required to determine optimal glucose targets, strategies to obtain them, and the potential effect on long-term health outcomes

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

BACKGROUND: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. METHODS: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. DISCUSSION: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. TRIAL REGISTRATION: NCT03162653, www.ClinicalTrials.gov , May 22, 2017.status: publishe