How frequent is routine use of probiotics in UK neonatal units?

OBJECTIVE: There is a lack of UK guidance regarding routine use of probiotics in preterm infants to prevent necrotising enterocolitis, late-onset sepsis and death. As practices can vary, we aimed to determine the current usage of probiotics within neonatal units in the UK. DESIGN AND SETTING: Using NeoTRIPS, a trainee-led neonatal research network, an online survey was disseminated to neonatal units of all service levels within England, Scotland, Northern Ireland and Wales in 2022. Trainees were requested to complete one survey per unit regarding routine probiotic administration. RESULTS: 161 of 188 (86%) neonatal units responded to the survey. 70 of 161 (44%) respondents routinely give probiotics to preterm infants. 45 of 70 (64%) use the probiotic product Lactobacillus acidophilus NCFM/Bifidobacterium bifidum Bb-06/B. infantis Bi-26 (Labinic™). 57 of 70 (81%) start probiotics in infants ≤32 weeks' gestation. 33 of 70 (47%) had microbiology departments that were aware of the use of probiotics and 64 of 70 (91%) had a guideline available. Commencing enteral feeds was a prerequisite to starting probiotics in 62 of 70 (89%) units. The majority would stop probiotics if enteral feeds were withheld (59 of 70; 84%) or if the infant was being treated for necrotising enterocolitis (69 of 70; 99%). 24 of 91 (26%) units that did not use probiotics at the time of the survey were planning to introduce them within the next 12 months. CONCLUSIONS: More than 40% of all UK neonatal units that responded are now routinely administering probiotics, with variability in the product used. With increased probiotic usage in recent years, there is a need to establish whether this translates to improved clinical outcomes.

Paediatric research in the times of COVID-19.

The COVID-19 pandemic poses many direct and indirect consequences for children's health and associated research. Direct consequences include participation of children in COVID-19 research trials, pausing other research in children and the potential implications of a global economic downturn on future research funding. Collaborative and networked research together with streamlined research processes and use of remote technology have been central to efforts by clinicians and scientists around the world and have proved essential for reducing COVID-19 morbidity and mortality. IMPACT: Maintain streamlined and efficient approaches to research governance and data sharing to facilitate high-quality collaborative research. Ensure early inclusion of children in trials of therapies for diseases that affect all age groups. Paediatric Research Societies should co-ordinate effective processes to define key research questions and develop multinational clinical trials for diagnostics, therapeutics and preventative strategies for infants, children and young people.

Bifidobacterium breve BBG-001 and intestinal barrier function in preterm babies: Exploratory Studies from the PiPS Trial.

BACKGROUND: Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential. METHODS: Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic. RESULTS: Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC. CONCLUSIONS: That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials. IMPACT: Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.

Evaluating preterm care across Europe using the eNewborn European Network database.

BACKGROUND: The inefficiency of recording data repeatedly limits the number of studies conducted. Here we illustrate the wider use of data captured as part of the European eNewborn benchmarking programme. METHODS: We extracted data on 39,529 live-births from 22 weeks 0 days to 31 weeks 6 days gestational age (GA) or ≤1500 g birth weight. We explored relationships between delivery room care and Apgar scores on mortality and bronchopulmonary dysplasia (BPD) and calculated the time needed for each country to detect a clinically relevant change in these outcomes following a hypothetical intervention. RESULTS: Early neonatal, neonatal, and in-hospital mortality were 3.90% (95% CI 3.71, 4.09), 6.00% (5.77, 6.24) and 7.57% (7.31, 7.83), respectively. The odds of death were greater with decreasing GA, lower Apgar scores, growth restriction, male sex, multiple birth and no antenatal steroids. Relationships for BPD were similar. The time required for participating countries to achieve 80% power to detect a relevant change in outcomes following a hypothetical intervention in 23-25 weeks' GA infants ranged from 12 years for neonatal mortality and 22 years for BPD compared to 1 year for the whole network. CONCLUSIONS: The eNewborn platform offers opportunity to drive efficiencies in benchmarking, quality control and research.

Historical aspects of probiotic use to prevent necrotising enterocolitis in preterm babies.

Over the last few decades, numerous studies have evaluated probiotic use for the prevention of necrotising enterocolitis in preterm babies. Early 'proof of concept' studies evaluating whether probiotics are capable of colonising the preterm gut have translated into multiple observational studies, small and large randomised controlled trials. Some show evidence of benefit while others have produced disappointing results. In this paper, we review the history of probiotic use in preterm babies for NEC prevention in an attempt to explain why uncertainty exists and why this intervention has not been universally adopted into routine neonatal practice.

The United Kingdom National Neonatal Research Database: A validation study.

BACKGROUND: The National Neonatal Research Database (NNRD) is a rich repository of pre-defined clinical data extracted at regular intervals from point-of-care, clinician-entered electronic patient records on all admissions to National Health Service neonatal units in England, Wales, and Scotland. We describe population coverage for England and assess data completeness and accuracy. METHODS: We determined population coverage of the NNRD in 2008-2014 through comparison with data on live births in England from the Office for National Statistics. We determined the completeness of seven data items on the NNRD. We assessed the accuracy of 44 data items (16 patient characteristics, 17 processes, 11 clinical outcomes) for infants enrolled in the multi-centre randomised controlled trial, Probiotics in Preterm Study (PiPs). We compared NNRD to PiPs data, the gold standard, and calculated discordancy rates using predefined criteria, and sensitivity, specificity and positive predictive values (PPV) of binary outcomes. RESULTS: The NNRD holds complete population data for England for infants born alive from 25+0 to 31+6 (completed weeks) of gestation; and 70% and 90% for those born at 23 and 24 weeks respectively. Completeness of patient characteristics was over 90%. Data were linked for 2257 episodes of care received by 1258 of the 1310 babies recruited to PiPs. Discordancy rates were <5% for 13/16 patient characteristics (exceptions: mode of delivery 8.7%; maternal ethnicity 10.2%, Lower layer Super Output Area 16.5%); <5% for 9/16 processes (exceptions: medical treatment for Patent ductus arteriosus 6.1%, high-dependency days 10.2%, central line days 11.2%, type of first milk 22.3%; and during first 14 days, summary of types of milk 13.8%; number of days of antibiotics 9.0%; whether antacid given 5.1%); and <5% for 10/11 clinical outcomes (exception: Bronchopulmonary dysplasia, defined as oxygen dependency at 36 weeks postmenstrual age 3.3%). The specificity of NNRD data was >85% for all outcomes; sensitivity ranged from 50-100%; PPV ranged from 58.8 (95% CI 40.8-75.4%) for porencephalic cyst to 99.7 (95% CI 99.2, 99.9%) for survival to discharge. CONCLUSIONS: The completeness and quality of data held in the NNRD is high, providing assurance in relation to use for multiple purposes, including national audit, health service evaluations, quality improvement, and research.

Incidence of neonatal necrotising enterocolitis in high-income countries: a systematic review.

OBJECTIVE: To conduct a systematic review of neonatal necrotising enterocolitis (NEC) rates in high-income countries published in peer-reviewed journals. METHODS: We searched MEDLINE, Embase and PubMed databases for observational studies published in peer-reviewed journals. We selected studies reporting national, regional or multicentre rates of NEC in 34 Organisation for Economic Co-operation and Development countries. Two investigators independently screened studies against predetermined criteria. For included studies, we extracted country, year of publication in peer-reviewed journal, study time period, study population inclusion and exclusion criteria, case definition, gestation or birth weight-specific NEC and mortality rates. RESULTS: Of the 1888 references identified, 120 full manuscripts were reviewed, 33 studies met inclusion criteria, 14 studies with the most recent data from 12 countries were included in the final analysis. We identified an almost fourfold difference, from 2% to 7%, in the rate of NEC among babies born <32 weeks' gestation and an almost fivefold difference, from 5% to 22%, among those with a birth weight <1000 g but few studies covered the entire at-risk population. The most commonly applied definition was Bell's stage ≥2, which was used in seven studies. Other definitions included Bell's stage 1-3, definitions from the Centers for Disease Control and Prevention, International Classification for Diseases and combinations of clinical and radiological signs as specified by study authors. CONCLUSION: The reasons for international variation in NEC incidence are an important area for future research. Reliable inferences require clarity in defining population coverage and consistency in the case definition applied. PROSPERO INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS REGISTRATION NUMBER: CRD42015030046.

The Microbiome of Infants Recruited to a Randomised Placebo-controlled Probiotic Trial (PiPS Trial).

The microbial dysbiosis associated with necrotizing enterocolitis (NEC) in preterm infants suggests that early exposure to probiotics may decrease and antibiotics may increase NEC risk. However, administration of Bifidobacterium breve strain BBG-001 to preterm infants did not affect NEC incidence in a multicenter randomised controlled phase 3 trial (PiPS trial). Using a subset of these subjects we compared the fecal microbiome of probiotic and placebo groups and assessed the impact of early antibiotic treatment. Extracted DNA from 103 fecal samples collected at 36weeks post-menstrual age underwent PCR amplification of a fragment of the 16S rRNA gene. Heatmaps were constructed showing the proportions of sequences from bacterial families present at >1% of the community. Stepwise logistic regression assessed the association between early antibiotic exposure and microbiome group. There was no difference in the microbial richness and diversity of the microbiome of preterm infants following treatment with probiotic or a placebo. Conversely, early antimicrobial exposure was associated with different patterns of colonisation, specifically a relative abundance of Proteobacteria. These findings highlight that the potential influence of probiotics on the microbiome of preterm infants remains unclear whereas the modulatory effect of antibiotic exposure on microbial colonisation requires further research.

Incidence and enteral feed antecedents of severe neonatal necrotising enterocolitis across neonatal networks in England, 2012-13: a whole-population surveillance study.

BACKGROUND: Necrotising enterocolitis is a neonatal gastrointestinal inflammatory disease with high mortality and severe morbidity. This disorder is growing in global relevance as birth rates and survival of babies with low gestational age improve. Population data are scant and pathogenesis is incompletely understood, but enteral feed exposures are believed to affect risk. We aimed to quantify the national incidence of severe necrotising enterocolitis, describe variation across neonatal networks, and investigate enteral feeding-related antecedents of severe necrotising enterocolitis. METHODS: We undertook a 2-year national surveillance study (the UK Neonatal Collaborative Necrotising Enterocolitis [UKNC-NEC] Study) of babies born in England to quantify the burden of severe or fatal necrotising enterocolitis confirmed by laparotomy, leading to death, or both. Data on all liveborn babies admitted to neonatal units between Jan 1, 2012, and Dec 31, 2013, were obtained from the National Neonatal Research Database. In the subgroup of babies born before a gestational age of 32 weeks, we did a propensity score analysis of the effect of feeding in the first 14 postnatal days with own mother's milk, with or without human donor milk and avoidance of bovine-origin formula, or milk fortifier, on the risk of developing necrotising enterocolitis. FINDINGS: During the study period, 118 073 babies were admitted to 163 neonatal units across 23 networks, of whom 14 678 were born before a gestational age of 32 weeks. Overall, 531 (0·4%) babies developed severe necrotising enterocolitis, of whom 247 (46·5%) died (139 after laparotomy). 462 (3·2%) of 14 678 babies born before a gestational age of 32 weeks developed severe necrotising enterocolitis, of whom 222 (48·1%) died. Among babies born before a gestational age of 32 weeks, the adjusted network incidence of necrotising enterocolitis ranged from 2·51% (95% CI 1·13-3·60) to 3·85% (2·37-5·33), with no unusual variation from the adjusted national incidence of 3·13% (2·85-3·42), despite variation in feeding practices. The absolute risk difference for babies born before a gestational age of 32 weeks who received their own mother's milk within 7 days of birth was -0·88% (95% CI -1·15 to -0·61; relative risk 0·69, 95% CI 0·60 to 0·78; number needed to treat to prevent one case of necrotising enterocolitis 114, 95% CI 87 to 136). For babies who received no compared with any bovine-origin products within 14 days of birth, the absolute risk difference was -0·65% (-1·01 to -0·29; relative risk 0·61, 0·39 to 0·83; number needed to treat 154, 99 to 345). We were unable to assess the effect of human donor milk as use was low. INTERPRETATION: Early feeding of babies with their own mother's milk and avoidance of bovine-origin products might reduce the risk of necrotising enterocolitis, but the absolute reduction is small. Owing to the rarity of severe necrotising enterocolitis, international collaborations are needed for adequately powered preventive trials. FUNDING: National Institute for Health Research.

Development of a Gestational Age-Specific Case Definition for Neonatal Necrotizing Enterocolitis.

Importance: Necrotizing enterocolitis (NEC) is a major cause of neonatal morbidity and mortality. Preventive and therapeutic research, surveillance, and quality improvement initiatives are hindered by variations in case definitions. Objective: To develop a gestational age (GA)-specific case definition for NEC. Design, Setting, and Participants: We conducted a prospective 34-month population study using clinician-recorded findings from the UK National Neonatal Research Database between December 2011 and September 2014 across all 163 neonatal units in England. We split study data into model development and validation data sets and categorized GA into groups (group 1, less than 26 weeks' GA; group 2, 26 to less than 30 weeks' GA; group 3, 30 to less than 37 weeks' GA; group 4, 37 or more weeks' GA). We entered GA, birth weight z score, and clinical and abdominal radiography findings as candidate variables in a logistic regression model, performed model fitting 1000 times, averaged the predictions, and used estimates from the fitted model to develop an ordinal NEC score and cut points to develop a dichotomous case definition based on the highest area under the receiver operating characteristic curves [AUCs] and positive predictive values [PPVs]. Exposures: Abdominal radiography performed to investigate clinical concerns. Main Outcomes and Measures: Ordinal NEC likelihood score, dichotomous case definition, and GA-specific probability plots. Results: Of the 3866 infants, the mean (SD) birth weight was 2049.1 (1941.7) g and mean (SD) GA was 32 (5) weeks; 2032 of 3663 (55.5%) were male. The total included 2978 infants (77.0%) without NEC and 888 (23.0%) with NEC. Infants with NEC in group 1 were less likely to present with pneumatosis (31.1% vs 47.2%; P = .01), blood in stool (11.8% vs 29.6%; P < .001), or mucus in stool (2.1% vs 5.6%; P = .048) but more likely to present with gasless abdominal radiography findings (6.3% vs 0.9%; P = .009) compared with infants with NEC in group 3. In the ordinal NEC score analysis, we allocated 3 points to pneumatosis, 2 points to blood in stool, and 1 point each to abdominal tenderness and abdominal discoloration; 1 point was assigned if 1 or more of pneumoperitoneum, fixed loop, and portal venous gas were present, and 1 point was assigned if both increased and/or bilious aspirates and abdominal distension were present. The cutoff scores for the dichotomous GA-specific case definition were 2 or greater for infants in groups 1 and 2, 3 or greater for infants in group 3, and 4 or greater for infants in group 4. The ordinal NEC score and dichotomous case definition discriminated well between infants with (AUC, 87%) and without (AUC, 80%) NEC. The case definition has a sensitivity of 66.2% (95% CI, 63.0-69.4), a specificity of 94.4% (95% CI, 93.2-95.4), an AUC of 80.0% (95% CI, 79-82), and a PPV of 85.5% (95% CI, 82.6-88.1). Applying the cut points to the 431 infants who underwent a laparotomy yielded a sensitivity of 76.5% (95% CI, 70.0-82.1), a specificity of 74.4% (95% CI, 68.3-80.0), an AUC of 75.0% (95% CI, 71.0- 80.0), and a PPV of 72.9% (95% CI, 66.4-78.7). Conclusions and Relevance: The risk of NEC and clinical presentation are associated with GA. Adoption of a consistent GA-specific case definition would strengthen global efforts to reduce the population burden of this devastating neonatal disease.

Impact of obstetric interventions on condition at birth in extremely preterm babies: evidence from a national cohort study.

BACKGROUND: To investigate perinatal decision-making and the use of obstetric interventions, we examined the effects of antenatal steroids, tocolysis, and delivery mode on birth in a good condition (defined as presence of an infant heart rate >100 at five minutes of age) and delivery-room (DR) death in extremely preterm deliveries. METHODS: Prospective cohort of all singleton births in England in 2006 at 22-26 weeks of gestation where the fetus was alive at the start of labour monitoring or decision to perform caesarean section. Odds ratios adjusted for potential confounders (aOR) were calculated using logistic regression. RESULTS: One thousand seven hundred twenty two singleton pregnancies were included. 1231 women received antenatal steroids, 437 tocolysis and 356 delivered by Caesarean section. In babies born vaginally, aOR between a partial course of steroids and improved condition at birth was 1.84, 95% CI: 1.20 to 2.82 and, for a complete course, 1.63, 95% CI: 1.08 to 2.47; for DR death, aORs were 0.34 (0.21 to 0.55) and 0.41 (0.26 to 0.64) for partial and complete courses of steroids. No association was seen for steroid use in babies delivered by Caesarean section. Tocolysis was associated with improved condition at birth (aOR 1.45, 95% CI: 1.05 to 2.0) and lower odds of death (aOR 0.48, 95% CI: 0.32 to 0.73). In women without spontaneous labour, Caesarean delivery at ≤24 and 25 weeks was associated with improved condition at birth ((aORs 12.67 (2.79 to 57.60) and 4.94 (1.44 to 16.90), respectively) and lower odds of DR death (aORs 0.03 (0.01 to 0.21) and 0.13 (0.03 to 0.55)). There were no differences at 26 weeks gestation or in women with spontaneous labour. CONCLUSIONS: Antenatal steroids are strongly associated with improved outcomes in babies born vaginally. Tocolysis was associated with improvements in all analyses. Effects persisted after adjustment for perinatal decision-making. However, associations between delivery mode and birth outcomes may be attributable to case selection.

A randomised controlled trial of the probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial.

BACKGROUND: Necrotising enterocolitis (NEC) and late-onset sepsis remain important causes of death and morbidity in preterm babies. Probiotic administration might strengthen intestinal barrier function and provide protection; this is supported by published meta-analyses, but there is a lack of large well-designed trials. OBJECTIVE: To test the use of the probiotic Bifidobacterium breve strain BBG-001 to prevent NEC, late-onset sepsis and death in preterm babies while monitoring probiotic colonisation of participants. DESIGN: Double-blind, randomised, placebo-controlled trial. SETTING: Recruitment was carried out in 24 hospitals, and the randomisation programme used a minimisation algorithm. Parents, clinicians and outcome assessors were blinded to the allocation. PARTICIPANTS: Babies born between 23 and 30 weeks' gestation and randomised within 48 hours of birth. Exclusions included life-threatening or any gastrointestinal malformation detected within 48 hours of birth and no realistic chance of survival. INTERVENTIONS: Active intervention: 1 ml of B. breve BBG-001 in one-eighth-strength infant formula Neocate(®) (Nutricia Ltd, Trowbridge, UK), (6.7 × 10(7) to 6.7 × 10(9) colony-forming units) per dose administered enterally. Placebo: 1 ml of one-eighth-strength infant formula Neocate. Started as soon as practicable and continued daily until 36 weeks' postmenstrual age. MAIN OUTCOME MEASURES: Primary outcomes were an episode of bloodstream infection, with any organism other than a skin commensal, in any baby between 72 hours and 46 weeks' postmenstrual age; an episode of NEC Bell stage ≥ 2 in any baby; and death before discharge from hospital. Secondary outcomes included stool colonisation with B. breve. RESULTS: In total, 654 babies were allocated to receive probiotic and 661 to receive placebo over 37 months from July 2010. Five babies were withdrawn; 650 babies from the probiotic group and 660 from the placebo group were included in the primary analysis. Baseline characteristics were well balanced. There was no evidence of benefit for the primary outcomes {sepsis: 11.2% vs. 11.7% [adjusted relative risk (RR) 0.97, 95% confidence interval (CI) 0.73 to 1.29]; NEC Bell stage ≥ 2: 9.4% vs. 10.0% [adjusted RR 0.93, 95% CI 0.68 to 1.27]; and death: 8.3% vs. 8.5% [adjusted RR 0.93, 95% CI 0.67 to 1.30]}. B. breve colonisation status was available for 1186 (94%) survivors at 2 weeks' postnatal age, of whom 724 (61%) were positive: 85% of the probiotic group and 37% of the placebo group. There were no differences for subgroup analyses by minimisation criteria and by stool colonisation with B. breve at 2 weeks. No harms associated with the interventions were reported. LIMITATIONS: Cross-colonisation of the placebo arm could have reduced statistical power and confounded results; analyses suggest that this did not happen. CONCLUSIONS: This is the largest trial to date of a probiotic intervention. It shows no evidence of benefit and does not support routine use of probiotics for preterm infants. FUTURE WORK RECOMMENDATIONS: The increasing understanding of the pathogenesis of NEC and sepsis will inform the choice of probiotics for testing and better define the target population. Future Phase III trials should incorporate monitoring of the quality and viability of the intervention and colonisation rates of participants; cluster design should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05511098 and EudraCT 2006-003445-17. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 66. See the NIHR Journals Library website for further project information.

Investigating increased admissions to neonatal intensive care in England between 1995 and 2006: data linkage study using Hospital Episode Statistics.

BACKGROUND: A 44 % increase was observed in admissions to neonatal intensive care of babies born ≤26 weeks completed gestational age in England between 1995 and 2006. Hospital Episode Statistics (HES) may provide supplementary information to investigate this. The methods and results of a probabilistic data linkage exercise are reported. METHODS: Two data sets were linked for each year (1995 and 2006) using 3 different algorithms (Fellegi and Sunter, Contiero and estimation-maximisation). RESULTS: In 1995, linkage was performed between 668 EPICure and 486,705 HES records; 1,820 linked pairs were identified of which 422 (63.17 %) were confirmed. In 2006, from 2,750 EPICure and 631,401 HES records, 8,913 linked pairs were identified with 1,662 (60.40 %) confirmed as true. Reported births in HES at <26 weeks gestation increased 37.0 % from 867 to 1188. CONCLUSIONS: Results support the EPICure findings that there was an increase in the birth rate for extremely premature babies between 1995 and 2006. There were insufficient data available for detailed investigation. Routine data sources may not be suitable for investigations at the margins of viability.

ESBL-producing Enterobacteriaceae in 24 neonatal units and associated networks in the south of England: no clustering of ESBL-producing Escherichia coli in units or networks.

OBJECTIVES: The objectives of this study were to characterize ESBL-producing Enterobacteriaceae present in 24 neonatal units (NNUs) in eight networks participating in a multicentre probiotic study and to test the hypothesis that specific strains would cluster within individual units and networks. METHODS: We performed analysis of stool samples for the presence of ESBL-producing Enterobacteriaceae at 2 weeks post-natal age and 36 weeks post-menstrual age. ESBL-producing Enterobacteriaceae were characterized and typed using molecular methods. RESULTS: ESBL-producing Enterobacteriaceae (n = 71) were isolated from 67/1229 (5.5%) infants from whom we received a sample at either sampling time or both sampling times, and from infants in 18 (75%) of the 24 recruiting NNUs. Thirty-three Escherichia coli, 23 Klebsiella spp. and 6 Enterobacter spp. strains were characterized. ESBL-producing E. coli were all distinguishable within individual NNUs by antibiotic resistance genotype, serogroup (O25b), phenotype, phylotype or ST. Ten of the 33 were ST131 and 9 of the 10 ST131 isolates were ciprofloxacin resistant. Seven of the 10 ST131 isolates carried genes encoding CTX-M group 1 enzymes. ST131 isolates were isolated from centres within five of the eight NNU networks. There were clusters of indistinguishable ESBL-producing Klebsiella and Enterobacter isolates associated with specific NNUs. CONCLUSIONS: Strains of E. coli ST131 were distributed across neonatal networks in the south of England. There was no evidence of clustering of clonally related ESBL-producing E. coli strains, by contrast with Klebsiella spp. and Enterobacter spp., which did cluster within units. The possibility that ESBL-producing E. coli strains are spread by vertical transmission requires further investigation.

Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial.

BACKGROUND: Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants. METHODS: In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17. FINDINGS: Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68-1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73-1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67-1·30]). No probiotic-associated adverse events were reported. INTERPRETATION: There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants. FUNDING: UK National Institute for Health Research Health Technology Assessment programme.

Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants.

In spite of their precipitous encounter with the environment, newborn infants cannot readily mount T helper type 1 (TH1) cell antibacterial and antiviral responses. Instead, they show skewing toward TH2 responses, which, together with immunoregulatory functions, are thought to limit the potential for inflammatory damage, while simultaneously permitting intestinal colonization by commensals. However, these collective capabilities account for relatively few T cells. Here we demonstrate that a major T cell effector function in human newborns is interleukin-8 (CXCL8) production, which has the potential to activate antimicrobial neutrophils and γδ T cells. CXCL8 production was provoked by antigen receptor engagement of T cells that are distinct from those few cells producing TH1, TH2 and TH17 cytokines, was co-stimulated by Toll-like receptor signaling, and was readily apparent in preterm babies, particularly those experiencing neonatal infections and severe pathology. By contrast, CXCL8-producing T cells were rare in adults, and no equivalent function was evident in neonatal mice. CXCL8 production counters the widely held view that T lymphocytes in very early life are intrinsically anti-inflammatory, with implications for immune monitoring, immune interventions (including vaccination) and immunopathologies. It also emphasizes qualitative distinctions between infants' and adults' immune systems.

Impact of ethnicity and extreme prematurity on infant pulmonary function.

The impact of birth before 27 completed weeks of gestation on infant pulmonary function (PF) was explored in a multi-ethnic population in comparison to more mature preterm controls (PTC) and healthy fullterm infants. Plethysmographic lung volume (FRCpleth ) and forced expired volume (FEV0.5 ) were obtained at ∼12 months post-term age in 52 extremely preterm (EP) infants (median [range] gestational age [GA]: 26 [23-27] weeks; 40% White mothers; 79% with BPD), 41 PTC (GA:35 [30-36] weeks; 37% White mothers) and 95 fullterm infants (GA:40 [37-42] weeks; 86% White mothers). Using reference equations based on identical equipment and techniques, results were expressed as z-scores to adjust for age, sex and body size. FEV0.5 was significantly lower in EP infants when compared with PTC (mean difference [95% CI]: -1.02[-1.60; -0.44] z-scores, P < 0.001), as was forced vital capacity (FVC) but there were no significant differences in FRCpleth or FEV0.5 /FVC ratio. FEV0.5 , FVC, and FEV0.5 /FVC were significantly lower in both preterm groups when compared with fullterm controls. On multivariable analyses of the combined preterm dataset: FEV0.5 at ∼1 year was 0.11 [0.05; 0.17] z-scores higher/week GA, and 1.28 (0.49; 2.08) z-scores lower in EP infants with prior BPD. Among non-white preterm infants, FEV0.5 was 0.70 (0.17; 1.24) z-scores lower, with similar reductions in FVC, such that there were no ethnic differences in FEV0.5 /FVC. Similar ethnic differences were observed among fullterm infants. These results confirm the negative impact of preterm birth on subsequent lung development, especially following a diagnosis of BPD, and emphasize the importance of taking ethnic background into account when interpreting results during infancy as in older subjects.

Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies.

OBJECTIVE: To determine outcomes at age 3 years in babies born before 27 completed weeks' gestation in 2006, and to evaluate changes in outcome since 1995 for babies born between 22 and 25 weeks' gestation. DESIGN: Prospective national cohort studies, EPICure and EPICure 2. SETTING: Hospital and home based evaluations, England. PARTICIPANTS: 1031 surviving babies born in 2006 before 27 completed weeks' gestation. Outcomes for 584 babies born at 22-25 weeks' gestation were compared with those of 260 surviving babies of the same gestational age born in 1995. MAIN OUTCOME MEASURES: Survival to age 3 years, impairment (2008 consensus definitions), and developmental scores. Multiple imputation was used to account for the high proportion of missing data in the 2006 cohort. RESULTS: Of the 576 babies evaluated after birth in 2006, 13.4% (n=77) were categorised as having severe impairment and 11.8% (n=68) moderate impairment. The prevalence of neurodevelopmental impairment was significantly associated with length of gestation, with greater impairment as gestational age decreased: 45% at 22-23 weeks, 30% at 24 weeks, 25% at 25 weeks, and 20% at 26 weeks (P<0.001). Cerebral palsy was present in 83 (14%) survivors. Mean developmental quotients were lower than those of the general population (normal values 100 (SD 15)) and showed a direct relation with gestational age: 80 (SD 21) at 22-23 weeks, 87 (19) at 24 weeks, 88 (19) at 25 weeks, and 91 (18) at 26 weeks. These results did not differ significantly after imputation. Comparing imputed outcomes between the 2006 and 1995 cohorts, the proportion of survivors born between 22 and 25 weeks' gestation with severe disability, using 1995 definitions, was 18% (95% confidence interval 14% to 24%) in 1995 and 19% (14% to 23%) in 2006. Fewer survivors had shunted hydrocephalus or seizures. Survival of babies admitted for neonatal care increased from 39% (35% to 43%) in 1995 to 52% (49% to 55%) in 2006, an increase of 13% (8% to 18%), and survival without disability increased from 23% (20% to 26%) in 1995 to 34% (31% to 37%) in 2006, an increase of 11% (6% to 16%). CONCLUSION: Survival and impairment in early childhood are both closely related to gestational age for babies born at less than 27 weeks' gestation. Using multiple imputation to account for the high proportion of missing values, a higher proportion of babies admitted for neonatal care now survive without disability, particularly those born at gestational ages 24 and 25 weeks.

Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies).

OBJECTIVE: To determine survival and neonatal morbidity for babies born between 22 and 26 weeks' gestation in England during 2006, and to evaluate changes in outcome since 1995 for babies born between 22 and 25 weeks' gestation. DESIGN: Prospective national cohort studies. SETTING: Maternity and neonatal units in England. PARTICIPANTS: 3133 births between 22 and 26 weeks' gestation in 2006; 666 admissions to neonatal units in 1995 and 1115 in 2006 of babies born between 22 and 25 weeks' gestation. MAIN OUTCOME MEASURES: Survival to discharge from hospital, pregnancy and delivery outcomes, infant morbidity until discharge. RESULTS: In 2006, survival of live born babies was 2% (n=3) for those born at 22 weeks' gestation, 19% (n=66) at 23 weeks, 40% (n=178) at 24 weeks, 66% (n=346) at 25 weeks, and 77% (n=448) at 26 weeks (P<0.001). At discharge from hospital, 68% (n=705) of survivors had bronchopulmonary dysplasia (receiving supplemental oxygen at 36 weeks postmenstrual age), 13% (n=135) had evidence of serious abnormality on cerebral ultrasonography, and 16% (n=166) had laser treatment for retinopathy of prematurity. For babies born between 22 and 25 weeks' gestation from March to December, the number of admissions for neonatal care increased by 44%, from 666 in 1995 to 959 in 2006. By 2006 adherence to evidence based practice associated with improved outcome had significantly increased. Survival increased from 40% to 53% (P<0.001) overall and at each week of gestation: by 9.5% (confidence interval -0.1% to 19%) at 23 weeks, 12% (4% to 20%) at 24 weeks, and 16% (9% to 23%) at 25 weeks. The proportions of babies surviving in 2006 with bronchopulmonary dysplasia, major cerebral scan abnormality, or weight and/or head circumference <-2 SD were similar to those in 1995, but the proportion treated for retinopathy of prematurity had increased from 13% to 22% (P=0.006). Predictors of mortality and morbidity were similar in both cohorts. CONCLUSION: Survival of babies born between 22 and 25 weeks' gestation has increased since 1995 but the pattern of major neonatal morbidity and the proportion of survivors affected are unchanged. These observations reflect an important increase in the number of preterm survivors at risk of later health problems.