Cheryl Battersby

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 mothers 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 mothers 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 mothers 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.

The impact of a regional care bundle on maternal breast milk use in preterm infants: outcomes of the East of England quality improvement programme

Objective To evaluate a quality improvement (QI) programme to increase the use of maternal breast milk (MBM) in preterm infants. Design Interrupted time series analysis. Setting 17 neonatal units in the East of England (EoE) Perinatal Network; 144 in the rest of the UK Neonatal Collaborative (UKNC). Patients Infants born ≤32+6 weeks gestation admitted to neonatal care between 2009 and 2012. Intervention A ‘care bundle’ to promote MBM in the EoE. Outcomes Percentage of infants receiving exclusive or any MBM at discharge and care days where any MBM was received. Methods Data were extracted from the National Neonatal Research Database; outcomes were compared preintervention and postintervention, and in relation to the rest of the UKNC. Results Exclusive and any MBM use at discharge increased from 26% to 33% and 50% to 57% respectively in the EoE, though there was no evidence of a step or trend change following the introduction of the care bundle. Exclusive MBM use at discharge improved significantly faster in EoE than the rest of the UKNC; 0.22% (95% CI 0.11 to 0.34) increase per month versus 0.05% (95% CI 0.01 to 0.09, p=0.007 for difference). The percentage of infants receiving MBM at discharge and care days where any MBM was received was not significantly different between EoE and the rest of the UKNC. Conclusions This QI programme was associated with some improvement in MBM use in preterm infants that would not have been evident without the use of routinely recorded national comparator data.

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.

Survival of very preterm infants admitted to neonatal care in England 2008–2014: time trends and regional variation

Objective To analyse survival trends and regional variation for very preterm infants admitted to neonatal care. Setting All neonatal units in England. Patients Infants born at 22+0–31+6 weeks+daysgestational age (GA) over 2008–2014 and admitted to neonatal care; published data for admitted infants 22+0–25+6 weeks+days GA in 1995 and 2006, and for live births at 22+0–31+6 weeks+days GA in 2013. Methods We obtained data from the National Neonatal Research Database. We used logistic regression to model survival probability with birth weight, GA, sex, antenatal steroid exposure and multiple birth included in the risk adjustment model and calculated annualpercentage change (APC) for trends using joinpoint regression. We evaluated survival over a 20-year period for infants <26 weeks’ GA using additional published data from the EPICure studies. Results We identified 50 112 eligible infants. There was an increase in survival over 2008–2014 (2008: 88.0%; 2014: 91.3%; adjusted APC 0.46% (95% CI 0.30 to 0.62) p<0.001). The greatest improvement was at 22+0–23+6 weeks (APC 6.03% (95% CI 2.47 to 3.53) p=0.002). Improvement largely occurred in London and South of England (APC: London 1.26% (95% CI 0.60 to 1.96); South of England 1.09% (95% CI 0.36 to 1.82); Midlands and East of England 0.15% (95% CI −0.56 to 0.86); and North of England 0.26% (95% CI −0.54 to 1.07)). Survival at the earliest gestations improved at a similar rate over 1995–2014 (22+0–25+6 weeks, APC 2.73% (95% CI 2.35 to 3.12), p value for change=0.25). Conclusions Continued national improvement in the survival of very preterm admissions masks important regional variation. Timely assessment of preterm survival is feasible using electronic records.

Term admissions to neonatal units in England: a role for transitional care? A retrospective cohort study

Objective To identify the primary reasons for term admissions to neonatal units in England, to determine risk factors for admissions for jaundice and to estimate the proportion who can be cared for in a transitional setting without separation of mother and baby. Design Retrospective observational study using neonatal unit admission data from the National Neonatal Research Database and data of live births in England from the Office for National Statistics. Setting All 163 neonatal units in England 2011–2013. Participants 133 691 term babies born ≥37 weeks gestational age and admitted to neonatal units in England. Primary and secondary outcomes Primary reasons for admission, term babies admitted for the primary reason of jaundice, patient characteristics, postnatal age at admission, total length of stay, phototherapy, intravenous fluids, exchange transfusion and kernicterus. Results Respiratory disease was the most common reason for admission overall, although jaundice was the most common reason for admission from home (22% home vs 5% hospital). Risk factors for admission for jaundice include male, born at 37 weeks gestation, Asian ethnicity and multiple birth. The majority of babies received only a brief period of phototherapy, and only a third received intravenous fluids, suggesting that some may be appropriately managed without separation of mother and baby. Admission from home was significantly later (3.9 days) compared with those admitted from elsewhere in the hospital (1.7 days) (p<0.001). Conclusion Around two-thirds of term admissions for jaundice may be appropriately managed in a transitional care setting, avoiding separation of mother and baby. Babies with risk factors may benefit from a community midwife postnatal visit around the third day of life to enable early referral if necessary. We recommend further work at the national level to examine provision and barriers to transitional care, referral pathways between primary and secondary care, and community postnatal care.

O-045 Incidence And Outcomes Of Severe Necrotising Enterocolitis In Infants Less Than 32 Weeks Gestation: A Prospective Population Study

Objectives Population data for Necrotising Enterocolitis (NEC) are sparse. We determined the incidence, short-term outcomes and antecedent feed exposures of severe NEC in preterm infants in England. Methods The study comprised infants 23+0 to 31+6 weeks gestation born in 2012 and admitted to 129 (80%) neonatal units in England. Infants with severe NEC (defined as requirement for surgery, histology, or post-mortem) were identified from the National Neonatal Research Database (www.imperial.ac.uk/ndau). Results Of 6468 infants, 167 (2.6%) had severe NEC; incidence (95% confidence interval) for 23 to 25+6, 26 to 28+6, 29 to 31+6 weeks gestation infants was 8% (6.4, 10), 3.5% (2.7, 4.4) and 0.8% (0.6, 1.0) respectively. Relative Risk reduced with each additional gestational week (0.70 (0.66, 0.74); Poisson regression, p < 0.001). Of infants requiring surgery, 60% received surgery and survived, 30% received surgery and died, and 10% did not receive surgery; all died. Figure 1 illustrates the inverse relationship between gestation and postnatal age at surgery; median days (interquartile range) 23 to 25+6: 27 (13–44); 26 to 28+6:24 (11–35); 29 to 31+6:12 (8–25) (log-rank test, p = 0.02). Antecedent feeding exposures were 8% never fed; 41% exclusively maternal milk; 13% maternal and donor milk; 35% human milk and formula; 3% exclusively formula. Fortifier was used in 12%. Conclusions Severe NEC remains a devastating disease affecting preterm infants in the first postnatal month. Novel findings are that 1 in 10 affected infants die having been considered too unwell for surgery, and over half were exclusively fed human milk prior to onset. Abstract O-045 Figure 1 Postnatal age at NEC surgery.

PC.15 The UK Neonatal Collaborative Necrotising Enterocolitis (NEC) Study: development of an evidence-based case-definition for NEC

Objective Lack of a universal case-definition hinders (NEC) surveillance and clinical trials. Bell’s staging, although widely used, was devised to guide surgical management after diagnosis1. We aimed to develop an evidence-based NEC case-definition. Methods We used the National Neonatal Research Database, that holds data extracted from the electronic records of babies admitted to NHS neonatal units, to obtain variables for infants receiving a laparotomy between November 2011–May 2013 (gestation, clinical signs (abdominal distension, tenderness, discolouration, mass, increased and/or bilious aspirates, bloody and/or mucousy stools), radiological signs (pneumatosis, air in the liver, pneumoperitoneum, fixed loop, gasless), confirmed NEC (at surgery or post-mortem). We developed case-definitions using logistic regression and classification trees2, and calculated sensitivity, specificity and area under the receiver operating characteristic curve (AUC). Interim validation was conducted using a separate dataset covering June–December 2013. Results We identified 142 infants from 40 neonatal units; 60 had confirmed NEC. The logistic regression definition comprised “pneumatosis OR two or more of (a) abdominal discolouration, (b) gasless X-ray (c) pneumoperitoneum” (sensitivity 0.72, specificity 0.88, AUC 0.8) and classification tree definition “pneumatosis OR abdominal discolouration OR [pneumoperitoneum AND aspirates]” (sensitivity 0.85, specificity 0.78, AUC 0.82). Validation showed logistic regression: sensitivity 0.64, specificity 0.95, AUC 0.85; classification tree sensitivity 0.67, specificity 0.91, AUC 0.79. Conclusion Our interim analysis shows that the two methods derived similar definitions identifying a similar proportion of cases; pneumatosis was the strongest predictor. The final analysis will include data from June 2013-April 2014 and will investigate gestation-specific effects. References Bell MJ, Ternberg JL, Feigin RD , et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7 Online First: 1978/01/01] Crichton NJ, Hinde JP, Marchini J. Models for diagnosing chest pain: is CART helpful? Stat Med. 1997;16:717–27 Online

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.

Use of pasteurised human donor milk across neonatal networks in England

OBJECTIVES To describe the use of pasteurised human donor milk (pHDM) in England and the influence of a human milk bank in the network. DESIGN Prospective observational study SETTING: All 163 neonatal units (23 networks) in England 2012-2013. PATIENTS Preterm infants born at <32 weeks gestational age (GA). MAIN OUTCOME MEASURES Proportion of infants and care-days fed pHDM during the first 30 postnatal days by network METHODS: We extracted daily patient-level data from the National Neonatal Research Database (NNRD). We fitted a logistic regression of pHDM exposure on the presence of a pHDM bank within the network, with GA, BW z score and network as covariates. Significance was assessed by the likelihood ratio (chi-squared) test. RESULTS Data for 13,463 infants were included in the study. Across the networks, the proportion (95%CI) of infants ranged from 2.0% (1.0, 3.0) to 61.0% (57.4%, 64.6%), and the proportion of care-days in which pHDM was fed from 0.08% (0.04%, 0.10%) to 21.9% (19.9%, 24.0%). In three networks <5%, and in seven networks >30% of infants received any pHDM. Variation in the use of pHDM across networks remained significant after adjustment for presence of a human milk bank within the network and all covariates (p < 0.001). CONCLUSIONS Wide variation of pHDM use in England is not fully explained by presence of a pHDM bank or patient characteristics. This suggests clinical uncertainty about the use of pHDM.