Preventive Strategies and Factors Associated With
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Open access Original research BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis Mark Adams,1,2 Dirk Bassler,1 Brian A Darlow,3 Kei Lui,4 Brian Reichman,5 Stellan Hakansson,6 Mikael Norman,7 Shoo K Lee,8 Kjell K Helenius,9 Liisa Lehtonen,10 Laura San Feliciano ,11 Maximo Vento,12 Marco Moroni,13 Marc Beltempo,14 Junmin Yang,8 Prakesh S Shah,8 on behalf of the International Network for EvaluatingOutcomes (iNeo) of Neonates To cite: Adams M, Bassler D, ABSTRACT Strengths and limitations of this study Darlow BA, et al. Preventive Objectives To compare necrotising enterocolitis (NEC) strategies and factors prevention practices and NEC associated factors between ► We report on a large, multinational patient database associated with surgically units from eight countries of the International Network for treated necrotising enterocolitis and high survey response rate, enabling a snapshot Evaluation of Outcomes of Neonates, and to assess their in extremely preterm infants: of contemporary necrotising enterocolitis outcome association with surgical NEC rates. an international unit survey and practices. Design Prospective unit-level survey combined with linked with retrospective cohort ► Survey was completed by a single representative at retrospective cohort study. data analysis. BMJ Open each site rather than all practitioners, whereas re- Setting Neonatal intensive care units in Australia/ 2019;9:e031086. doi:10.1136/ sponses were based on neonatal intensive care unit bmjopen-2019-031086 New Zealand, Canada, Finland, Israel, Spain, Sweden, policies rather than personal opinion. Switzerland and Tuscany (Italy). ► Prepublication history and ► As individual patient data for NEC prevention were http://bmjopen.bmj.com/ Patients Extremely preterm infants born between 240 additional material for this not available, we applied a pragmatic approach link- to 286 weeks’ gestation, with birth weights<1500 g, and paper are available online. To ing unit level survey data on prevention with patient admitted between 2014–2015. view these files, please visit level cohort data on outcome and risk factors to re- Exposures NEC prevention practices (probiotics, feeding, the journal online (http:// dx. doi. port on a possible association between NEC preven- org/ 10. 1136/ bmjopen- 2019- donor milk) using responses of an on-line pre-piloted tion and outcome. 031086). questionnaire containing 10 questions and factors ► When linking survey with cohort study data we have associated with NEC in literature (antenatal steroids, assumed that all neonates within a unit were treated Received 15 April 2019 c-section, indomethacin treated patent ductus arteriosus Revised 23 August 2019 equally, which is an assumption and needs confir- and sepsis) using cohort data. on October 8, 2021 by guest. Protected copyright. Accepted 13 September 2019 mation but is acceptable for generating a hypothesis. Outcome measures Surgical NEC rates and death following NEC using cohort data. Results The survey response rate was 91% (153 units). of consensus surrounding the use of preventive strategies Both probiotic provision and donor milk availability varied for NEC and emphasises the need for research. between 0%–100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to INTRODUCTION © Author(s) (or their link survey results and cohort outcomes, revealed similar Necrotising enterocolitis (NEC) remains a employer(s)) 2019. Re-use baseline characteristics but considerable differences potentially devastating complication with permitted under CC BY-NC. No in factors associated with NEC between networks. 397 variable treatment success rates. In the USA commercial re-use. See rights (4.1%) neonates underwent NEC surgery, ranging from and permissions. Published by and Canada, NEC affects approximately 7% 2.4%–8.4% between networks. Standardised ratios for BMJ. of babies weighing between 500–1500 g with surgical NEC were lower for Australia/New Zealand, higher 1 For numbered affiliations see for Spain, and comparable for the remaining six networks. approximately 20%–30% of mortality rate. end of article. Conclusions The variation in implementation of NEC A recent systematic review revealed similar Correspondence to prevention practices and in factors associated with NEC or lower incidence rates for Japan (1.6%), Dr Mark Adams; in literature could not be associated with the variation in Italy (3%), Korea (6.4%) and Spain (6.9%) mark. adams@ usz. ch surgical NEC incidence. This corroborates the current lack for infants born <1500 g.2 In a study from the Adams M, et al. BMJ Open 2019;9:e031086. doi:10.1136/bmjopen-2019-031086 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from National Institute of Child Health and Human Devel- probiotic usage (five questions), start and advancement of opment (NICHD) of extremely preterm infants born enteral feeding (three questions), donor-milk availability between 2000–2011, NEC related deaths rose from 23% and donor-milk handling (two questions). The survey was to 30%, whereas overall mortality declined.3 In survivors, distributed in English and is provided as a supplementary NEC and surgery for NEC have been associated with file (see online supplement 1). increased risk of adverse neurodevelopmental outcome at 2 years of age.4–6 The financial impact of NEC is esti- Cohort study (patient level data) mated at US$1 billion per year in the USA alone.7 Patient data collected from infants born between 240 NEC is considered a multifactorial disease that results in to 286 weeks’ gestation, weighing <1500 g and admitted profound inflammation and intestinal injury.7 8 Research to same neonatal units between 1 January 2014 and 31 in preventive measures is progressing but a unanimously December 2015 were compared between the eight partic- accepted approach is yet to be identified. Probiotics ipating countries. Extremely preterm infants of <24 supplementation reduced rates of NEC in multiple weeks’ gestation were excluded from the current study, as studies; however, results of two large randomised clinical admission to care and care provision to such infants varies trials are contradictory with no consensus on which probi- considerably among the eight collaborating countries. otic may effectively prevent NEC.9 10 Donor milk and Infants with major congenital anomalies and those born exclusive human milk diets are also proposed as preven- outside any of the participating hospitals and admitted tive measures, however, the evidence for NEC reduction after 1 week of age were excluded, as these infants may is tentative at best.11 12 Early initiation and rapid advance- not have received all described preventive measures. ment of feeds have not been shown to cause harm, but All networks have obtained ethical/regulatory approval standard practice in many units has not changed due to or its equivalent from their local granting agencies to fear of NEC.13 allow for de-identified data to be collated and sent to the In this context, our objective was to investigate what International Network for Evaluation of Outcomes of the uptake of preventative approaches at various units Neonates (iNeo) Coordinating Centre. Overall coordina- was and whether different approaches to prevention and tion of the project is also approved by the Research Ethics different incidences of factors associated with NEC in Board at the Mount Sinai Hospital, Toronto, Ontario literature were associated also with variations in the inci- Canada for the development, compilation, hosting and dence of surgical NEC in the participating eight high-in- management of the iNeo dataset at the MiCare Research come countries. Centre (12–0336-E). Privacy and confidentiality of patient data is of prime importance to the iNeo collaboration and data handling is in accordance with the Privacy Commis- METHODS sioner’s guidelines. Study design, questionnaire and population http://bmjopen.bmj.com/ In this mixed methods study, we used a survey to deter- Covariate definitions mine unit level NEC prevention practices in each country, Gestational age (GA) was determined by the best esti- and a retrospective patient cohort to obtain patient level mate based on early prenatal ultrasound, last menstrual NEC associated factors and rates for surgical NEC and period, or physical examination of infants at birth, in that mortality following NEC. order. Birth weight z scores were calculated relative to population-specific and sex-specific birth weight for GA Survey (unit level data) references selected by each network as most appropriate In 2016, an online pre-piloted, anonymous questionnaire for the comparison. Antenatal steroid use was defined as was sent to the directors of 168 tertiary neonatal intensive any administration before birth, regardless of the time on October 8, 2021 by guest. Protected copyright. care units (NICUs) from eight collaborating networks: interval, patent ductus arteriosus (PDA) by clinical or Australia/New Zealand Neonatal Network, Canadian echocardiographic diagnosis and sepsis by clear clinical Neonatal Network, Finish Medical Birth Register, Israel evidence of infection as well as at least one relevant posi- Neonatal Network, Spanish