microbiome serially over time and might serve as a useful adjunct in the management of patients with Barrett’s oesophagus.
Julian A Abrams Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York 10032, NY, USA [email protected]
I declare no competing interests. 1
Abrams JA, Sharaiha RZ, Gonsalves L, Lightdale CJ, Neugut AI. Dating the rise of esophageal adenocarcinoma: analysis of Connecticut Tumor Registry data, 1940–2007. Cancer Epidemiol Biomarkers Prev 2011; 20: 183–86. Yang L, Lu X, Nossa CW, Francois F, Peek RM, Pei Z. Inﬂammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 2009; 137: 588–97. Gall A, Fero J, McCoy C, et al. Bacterial composition of the human upper gastrointestinal tract microbiome is dynamic and associated with genomic instability in a Barrett’s esophagus cohort. PLoS One 2015; 10: e0129055.
Elliott DRF, Walker AW, O’Donovan M, Parkhill J, Fitzgerald RC. Use of non-endoscopic sampling device to sample the oesophageal microbiota: a case-control study. Lancet Gastroenterol Hepatol 2016; published online Nov 11. http://dx.doi.org/10.1016/S2468-1253(16)30086-3. Ross-Innes CS, Debiram-Beecham I, O’Donovan M, et al. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett’s esophagus: a multi-center case-control study. PLoS Med 2015; 12: e1001780. Pei Z, Bini EJ, Yang L, Zhou M, Francois F, Blaser MJ. Bacterial biota in the human distal esophagus. Proc Natl Acad Sci USA 2004; 101: 4250–55. Kianoush N, Adler CJ, Nguyen KA, Browne GV, Simonian M, Hunter N. Bacterial proﬁle of dentine caries and the impact of pH on bacterial population diversity. PLoS One 2014; 9: e92940. Byun R, Nadkarni MA, Chhour KL, Martin FE, Jacques NA, Hunter N. Quantitative analysis of diverse Lactobacillus species present in advanced dental caries. J Clin Microbiol 2004; 42: 3128–36. Blackett KL, Siddhi SS, Cleary S, et al. Oesophageal bacterial bioﬁlm changes in gastro-oesophageal reﬂux disease, Barrett’s and oesophageal carcinoma: association or causality? Aliment Pharmacol Ther 2013; 37: 1084–92. Salter SJ, Cox MJ, Turek EM, et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC biology 2014; 12: 87.
Simon Fraser/Department of Child Health, RVI, Newcastle/SPL
Necrotising enterocolitis: better data, still many questions
Published Online November 7, 2016 http://dx.doi.org/10.1016/ S2468-1253(16)30158-3 See Articles page 43
Despite real advances in the care of neonates, necrotising enterocolitis remains one of the greatest scourges of neonatal intensive care and is associated with substantial morbidity and mortality.1,2 However, the precise nature of necrotising enterocolitis, its causes, how best to treat it, and which babies would beneﬁt from surgical as opposed to medical treatment remain unclear. The inability to deﬁnitively answer these questions undoubtedly hinders progress despite eﬀorts to improve outcomes for these vulnerable babies. The UK National Conﬁdential Enquiry into Patient Outcome and Death report on paediatric surgery in 20113 highlighted the gaps in understanding of incidence, epidemiology, and outcomes of necrotising enterocolitis in the UK. In The Lancet Gastroenterology & Hepatology, Cheryl Battersby and colleagues4 start to ﬁll in some of these gaps in knowledge by providing an up-to-date epidemiological picture of severe necrotising enterocolitis among babies born before a gestational age of 32 weeks in England over a 2-year period. The importance of this study is in its completeness, with data captured from 118 073 babies admitted to all 163 neonatal units in England. Consequently, reliable data are now available that will help to inform research and service delivery. As an aside, this study also serves as an excellent example of how the (electronic) capture of routinely collected data can be used eﬀectively and
eﬃciently for research purposes, and is a model that should undoubtedly be replicated. Within the dataset, several findings might be surprising, and should certainly give pause for thought about how to care for babies with necrotising enterocolitis. For instance, 108 (20·3%) of 531 babies with the disease died without undergoing surgery, and of these babies, only seven (6·5%) were assessed by autopsy. Perhaps the low frequency of surgery was because the babies were too sick to transfer to a surgeon, or because the decision to treat with surgery should have been made earlier. An option might be for babies at the highest risk of necrotising enterocolitis to be cared for in a surgical centre, although whether surgery would have made any difference to their outcomes is unclear. The frequency of neonatal autopsy also needs to be increased to learn more about the causes of death and improve care in the future. The particular group of babies who had neither surgery nor autopsy is also problematic from a data analysis point of view, because necrotising enterocolitis was not confirmed by a surgeon or a pathologist. The investigation of Battersby and colleagues into the role that type of milk (maternal milk, human donor milk, bovine-origin formula, or bovine-origin milk fortiﬁer) might play in the development of necrotising enterocolitis is topical because of the www.thelancet.com/gastrohep Vol 2 January 2017
availability of human-derived milk fortiﬁer5 and increasing recognition that the gut in preterm babies can be particularly sensitive to bovine-origin peptides.6 With use of the statistical technique of propensity score analysis, these researchers created comparable groups to assess the risk of necrotising enterocolitis by early milk exposure. Headline ﬁndings are largely in keeping with the accepted knowledge that early feeding with own mother’s milk reduces risk of necrotising enterocolitis.7 The absolute risk diﬀerence for any feeding with 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). Avoidance of a bovine milk product within the ﬁrst 14 days of life also appears to reduce the risk of necrotising enterocolitis (absolute risk diﬀerence –0·65%, –1·01 to –0·29; relative risk 0·61, 0·39 to 0·83). Unfortunately, the propensity score analysis included less than half of the babies who developed severe necrotising enterocolitis (220 [41·4%] of 531). The rest were excluded from the analysis on the basis of concern over necrotising enterocolitis in the ﬁrst 14 days of life. Babies who have relevant symptoms in the early days of life are precisely those who often end up developing necrotising enterocolitis later, so the exclusion of such a high proportion of cases inevitably leaves questions about the potential role of feed type in a high proportion of cases. A further limitation of the analysis is that only feed type in the ﬁrst 14 days was included. Any later change in milk type or the addition of breastmilk fortiﬁer (which happened at median of 20 days) that could conceivably have precipitated severe necrotising enterocolitis remains unaccounted for. These exclusions might have had an eﬀect on the ﬁnal statistical analysis, which reports a very large number needed to treat with either early milk from the baby’s own mother (114) or avoidance of bovine-origin formula (154) to prevent one case of necrotising enterocolitis. The implications of Battersby and colleagues’ ﬁndings for clinical practice are to remind us of the burden of necrotising enterocolitis and that breastmilk remains the best feeding option and should be given exclusively for at least the ﬁrst 14 days if at all possible. Further research is necessary to determine the precise role of bovine-origin formula (including breastmilk fortiﬁer) in the development of necrotising www.thelancet.com/gastrohep Vol 2 January 2017
enterocolitis and whether use of human-based substitutes will be beneﬁcial. All feeding advice, of course, must be given on a background of maintaining acceptable postnatal growth and longer-term neurodevelopmental outcomes. One key issue remains to be addressed to ensure progress in understanding necrotising enterocolitis: the definition that should be used in the context of methodologically robust research studies. Battersby and colleagues’ definition of severe necrotising enterocolitis as being confirmed at surgery, histology, or autopsy or when reported on the death certificate as the primary cause of death sounds attractive because it excludes less-severe and suspected cases. Nevertheless, the difficulties in separating necrotising enterocolitis from similar conditions clinically, intraoperatively, and histologically are well recognised. A lack of standardisation of indications for surgical intervention and low autopsy rates confound this issue further. I certainly support Battersby and colleagues’ call for large-scale collaborative research, which should be based on the starting point of a robust definition of what we really mean by necrotising enterocolitis. Nigel J Hall University of Southampton, Southampton, UK; and Southampton Children’s Hospital, Southampton, UK [email protected]
I have received personal fees from Danone Nutricia Early Life Nutrition. 1 2
Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009; 44: 1072–75. Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed 2007; 92: F193–98. Mason DG, Wilkinson K, Gough MJ, et al. Surgery in children: are we there yet? London: National Conﬁdential Enquiry into Patient Outcome and Death, 2011. Battersby C, Longford N, Mandalia S, Costeloe K, Modi N, on behalf of the UK Neonatal Collaborative Necrotising Enterocolitis (UKNC-NEC) study group. Incidence and enteral feed antecedents of severe neonatal necrotising enterocolitis across neonatal networks in England, 2012–13: a whole-population surveillance study. Lancet Gastroenterol Hepatol 2016; published online Nov 7. http://dx.doi.org/10.1016/S24681253(16)30117-0. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010; 156: 562–67. Abrams S, Cristofalo EA, Schanler RJ, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr 2013; 163: 1592–95. e1. Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol 2009; 29: 57–62.