BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available

BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available.

When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to.

The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript.

BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com).

If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 27, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

International variations in preventive strategies and factors associated with surgically treated necrotizing enterocolitis in extremely preterm infants ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-031086

Article Type: Research

Date Submitted by the 15-Apr-2019 Author:

Intervention and Technology http://bmjopen.bmj.com/ Lee, Shoo; Mount Sinai Hospital and University of Toronto, Department of Paediatrics Helenius, Kjell; Turku University Hospital, Department of Pediatrics Lehtonen, Liisa; University of Turku Finland, Department of Pediatrics San Feliciano, Laura; University Hospital Salamanca, Division of Neonatology Vento, Maximo; University of Valencia, Division of Neonatology and Health Research Institute La Fe

Moroni, Marco; Anna Meyer Children’s University Hospital, Neonatal on September 27, 2021 by guest. Protected copyright. Intensive Care Unit Beltempo, Marc; Montreal Children’s Hospital, McGill University, Department of Pediatrics Yang, Junmin; Mount Sinai Hospital and University of Toronto, Department of Paediatrics Shah, Prakesh; Mount Sinai Hospital and University of Toronto, Department of Paediatrics

NEONATOLOGY, Paediatric gastroenterology < PAEDIATRICS, Keywords: PERINATOLOGY, PAEDIATRICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 71 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 27, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 71

1 2 International variations in preventive strategies and factors associated with surgically

3 treated necrotizing enterocolitis in extremely preterm infants BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 5 Mark Adams, PhD1, Dirk Bassler, MD, MSc1, Brian A Darlow, MD2, Kei Lui, MD3, Brian 6 4 5 6 7 Reichman, MBChB , Stellan Håkansson, MD , Mikael Norman, MD , Shoo K Lee, MBBS, 7,8 9 9 10 8 PhD , Kjell K Helenius, MD , Liisa Lehtonen, MD , Laura San Feliciano, MD , Maximo 9 Vento, MD, PhD11, Marco Moroni, MD12, Marc Beltempo, MD13, Junmin Yang, PhD7, 10 Prakesh S Shah, MD, MSc7,8; on behalf of the International Network for Evaluating 11 Outcomes (iNeo) of Neonatesǂ 12 ǂGroup Information: Investigators of the International Network for Evaluating Outcomes 13 14 (iNeo) of Neonates are provided in the Acknowledgements 15 16 Affiliations: 17 1Department of Neonatology, University Hospital Zurich, University of Zurich, Switzerland; 18 Department of Paediatrics,For University peer of reviewOtago, Christchurch, only New Zealand; 3Royal Hospital 19 for Women, National Perinatal Epidemiology and Statistic Unit, University of New South 20 Wales, Randwick, Australia; 4Gertner Institute for Epidemiology and Health Policy Research, 21 5 22 Sheba Medical Centre, Israel; Department of Clinical Sciences/Pediatrics, Umeå University 6 23 Hospital, Umeå, Sweden; Department of Neonatal Medicine, Karolinska University Hospital 24 and Karolinska Institutet, Stockholm, Sweden; 7Department of Paediatrics, Mount Sinai 25 Hospital and University of Toronto, Toronto, Canada; 8Maternal-Infant Care Research 26 Centre, Mount Sinai Hospital, Toronto, Canada; 9Department of Pediatrics, Turku University 27 Hospital and University of Turku, Turku, Finland; 10Division of Neonatology, University 28 Hospital Salamanca, Salamanca, Spain; 11Division of Neonatology and Health Research 29 12 30 Institute La Fe, University of Valencia, Valencia, Spain; Neonatal Intensive Care Unit, 13 31 Anna Meyer Children’s University Hospital, Florence, Italy; Department of Pediatrics, 32 Montreal Children’s Hospital, McGill University, Montreal, QC, Canada. 33 34 Address correspondence to: Mark Adams, Department of Neonatology, University Hospital 35 Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland; Tel. +4143 253 3034; 36

37 E-mail: [email protected]. http://bmjopen.bmj.com/ 38 39 Short title: NEC prevention practices and their impact on outcome 40 41 Financial Disclosure Statement 42 Mark Adams receives a salary as network coordinator for the Swiss Neonatal Network. The 43 remaining authors have indicated they have no financial relationships relevant to this article to 44

45 disclose. on September 27, 2021 by guest. Protected copyright. 46 47 Funding Sources: Funding for iNeo has been provided by a Canadian Institutes of Health 48 Research Chair in Reproductive and Child Health Services and Policy Research (APR- 49 126340) held by PSS. The Australian and New Zealand Neonatal Network is predominantly 50 funded by membership contributions from participating centres. The Canadian Neonatal 51 Network is supported by a team grant from the Canadian Institutes of Health Research (CTP 52 53 87518), the Ontario Ministry of Health, and individual participating centres. The Finnish 54 Medical Birth Register is governmentally funded and kept by the National Institute for Health 55 and Welfare (THL). The Israel Neonatal Network very low birth weight infant database is 56 partially funded by the Israel Center for Disease Control and the Ministry of Health. The 57 Neonatal Research Network of Japan is partly funded by a Health Labour Sciences Research 58 Grant from the Ministry of Health, Labour and Welfare of Japan. SEN1500 is supported by 59 60 funds from the Spanish Neonatal Society (SENeo). The Swedish Neonatal Quality Register is funded by the Swedish Government (Ministry of Health and Social Affairs) and the body of

1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 71 BMJ Open

1 2 regional health care providers (County Councils). SwissNeoNet is partially funded by

3 participating units in the form of membership fees. Tuscany Neonatal Network is funded by BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 the Tuscany Region. The United Kingdom Neonatal Collaborative receives no core funding. 5 6 7 Role of the Funders/Sponsors: The funding bodies played no role in the design and conduct 8 of the study; collection, management, analysis, and interpretation of the data; preparation, 9 review, or approval of the manuscript; and decision to submit the manuscript for publication. 10 11 12 Conflict of Interest Statement: Mark Adams receives a salary as network coordinator for the 13 Swiss Neonatal Network. The remaining authors have indicated they have no potential 14 conflicts of interest relevant to this article to disclose 15 16 List of abbreviations 17 ANZNN: Australia/New Zealand Neonatal Network; CNN: Canadian Neonatal Network; 18 For peer review only 19 FINMBR: Finish Medical Birth Register; GA: gestational age; INN: Israel Neonatal Network; 20 NEC: Necrotizing enterocolitis; NICU: neonatal intensive care unit; OR: odds ratio; PDA: 21 patent ductus arteriosus; SEN1500 Spanish Neonatal Network; SNQ: Swedish Neonatal 22 Quality Register; SR: standardized ratio; SwissNeoNet: Swiss Neonatal Network; TuscanNN: 23 Tuscany Neonatal Network in Italy. 24 25 26 27 ABSTRACT 28 Objectives: To compare necrotizing enterocolitis (NEC) prevention practices and NEC 29 30 associated factors between units from eight countries of the International Network for 31 Evaluation of Outcomes of Neonates (iNeo), and to assess their association with surgical NEC 32 rates. 33 Design: Prospective unit-level survey combined with retrospective cohort study. 34 Setting: Neonatal intensive care units (NICUs) in Australia/New Zealand, Canada, Finland, 35 Israel, Spain, Sweden, Switzerland and Tuscany (Italy). 36 0 6 37 Patients: Extremely preterm infants born between 24 to 28 weeks’ gestation, with birth http://bmjopen.bmj.com/ 38 weights <1500 g, and admitted between 2014-2015. 39 Exposures: NEC prevention practices (probiotics, feeding, donor milk) using responses of an 40 on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in 41 literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and 42 sepsis) using cohort data. 43 Outcome measures: Surgical NEC rates and death following NEC using cohort data. 44

45 Results: The survey response rate was 91% (153 units). Both probiotic provision and donor on September 27, 2021 by guest. Protected copyright. 46 milk availability varied between 0-100% among networks whereas feeding initiation and 47 advancement rates were practically similar in most networks. The 9792 infants included in the 48 cohort study to link survey results and cohort outcomes, revealed similar baseline 49 characteristics but considerable differences in factors associated with NEC between networks. 50 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4-8.4% between networks. 51 Standardized ratios for surgical NEC were lower for Australia/ New Zealand, higher for 52 53 Spain, and comparable for the remaining six networks. 54 Conclusions: The variation in implementation of NEC prevention practices and in factors 55 associated with NEC in literature could not be associated with the variation in surgical NEC 56 incidence. This corroborates the current lack of consensus surrounding the use of preventive 57 strategies for NEC and emphasizes the need for research. 58 59 60

2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 71

1 2 ARTICLE SUMMARY

3 Strengths and limitations of this study BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 5 6  We report on a large, multinational patient database and high survey response rate, 7 enabling a snapshot of contemporary necrotizing enterocolitis outcome and practices. 8  Survey was completed by a single representative at each site rather than all 9 practitioners, whereas responses were based on NICU policies rather than personal 10 opinion. 11  As individual patient data for NEC prevention were not available, we applied a 12 13 pragmatic approach linking unit level survey data on prevention with patient level 14 cohort data on outcome and risk factors to report on a possible association between 15 NEC prevention and outcome. 16  When linking survey with cohort study data we have assumed that all neonates within 17 a unit were treated equally, which is an assumption and needs confirmation but is 18 acceptable forFor generating peer a hypothesis. review only 19 20 21 Keywords 22 Very preterm infants, necrotising enterocolitis, surgery, prevention, risk factors 23 24 Word count 25 3207 26 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 71 BMJ Open

1 2 INTRODUCTION

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Necrotizing enterocolitis (NEC) remains a potentially devastating complication with variable 5 6 7 treatment success rates. In the US and Canada, NEC affects approximately 7% of babies 8 9 weighing between 500-1500 g with approximately 20–30% of mortality rate.[1] A recent 10 11 systematic review revealed similar or lower incidence rates for Japan (1.6%), Italy (3%), 12 13 14 Korea (6.4%) and Spain (6.9%) for infants born <1500g.[2] In a study from the National 15 16 Institute of Child Health and Human Development (NICHD) of extremely preterm infants 17 18 born between 2000-2011,For NEC peer related deaths review rose from 23% only to 30%, whereas overall 19 20 mortality declined.[3] In survivors, NEC and surgery for NEC have been associated with 21 22 23 increased risk of adverse neurodevelopmental outcome at two years of age.[4–6] The financial 24 25 impact of NEC is estimated at $1 billion per year in the US alone.[7] 26 27 28 NEC is considered a multifactorial disease that results in profound inflammation and 29 30 intestinal injury.[7,8] Research in preventive measures is progressing but a unanimously 31 32 33 accepted approach is yet to be identified. Probiotics supplementation reduced rates of NEC in 34 35 multiple studies; however, results of two large randomized clinical trials are contradictory 36 37 with no consensus on which probiotic may effectively prevent NEC.[9,10] Donor milk and http://bmjopen.bmj.com/ 38 39 exclusive human milk diets are also proposed as preventive measures, however, the evidence 40 41 42 for NEC reduction is tentative at best.[11,12] Early initiation and rapid advancement of feeds 43 44 have not been shown to cause harm, but standard practice in many units has not changed due

45 on September 27, 2021 by guest. Protected copyright. 46 to fear of NEC.[13] 47 48 49 In this context, our objective was to investigate what the uptake of preventative approaches at 50 51 52 various units was and whether different approaches to prevention and different incidences of 53 54 factors associated with NEC in literature were associated also with variations in the incidence 55 56 of surgical NEC in the participating eight high-income countries. 57 58 59 60

4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 71

1 2 METHODS

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Study design, questionnaire and population 5 6 7 In this mixed methods study, we used a survey to determine unit level NEC prevention 8 9 practices in each country, and a retrospective patient cohort to obtain patient level NEC 10 11 associated factors and rates for surgical NEC and mortality following NEC. 12 13 14 Survey (unit level data): In 2016, an online pre-piloted, anonymous questionnaire was sent 15 16 to the directors of 168 tertiary neonatal intensive care units (NICUs) from 8 collaborating 17 18 For peer review only 19 networks: Australia/New Zealand Neonatal Network (ANZNN), Canadian Neonatal Network 20 21 (CNN), Finish Medical Birth Register (FINMBR), Israel Neonatal Network (INN), Spanish 22 23 Neonatal Network (SEN1500), Swedish Neonatal Quality Register (SNQ), Swiss Neonatal 24 25 26 Network (SwissNeoNet), and the Tuscany Neonatal Network in Italy (TuscanNN). The 27 28 questionnaire contained questions about treatment practices relating to extremely preterm 29 30 infants under 29 weeks’ gestation. The methodology for this survey was as published 31 32 33 previously.[14] Reminders were sent twice (at a monthly interval) to units that did not 34 35 respond. The survey was first sent in August 2016 and was closed in December 2016. 36 37 Responders were instructed to answer all questions based on their practices in the year 2015. http://bmjopen.bmj.com/ 38 39 One response per unit (usually the director) was collected. The 10 questions relevant to NEC 40 41 42 comprised 4 domains, including probiotic usage (5 questions), start and advancement of 43 44 enteral feeding (3 questions), donor-milk availability, and donor-milk handling (2 questions).

45 on September 27, 2021 by guest. Protected copyright. 46 The survey was distributed in English and is provided as a supplementary file (see online 47 48 49 supplement 1). 50 51 0 52 Cohort study (patient level data): Patient data collected from infants born between 24 to 53 54 286 weeks’ gestation, weighing <1500g, and admitted to same neonatal units between January 55 56 1, 2014- December 31, 2015 were compared between the eight participating countries. 57 58 59 Extremely preterm infants of <24 weeks’ gestation were excluded from the current study, as 60 admission to care and care provision to such infants varies considerably amongst the 8

5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 71 BMJ Open

1 2 collaborating countries. Infants with major congenital anomalies and those born outside any

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 of the participating hospitals and admitted after 1 week of age were excluded, as these infants 5 6 7 may not have received all described preventive measures. Each individual network obtained 8 9 approval for primary data collection. Separate data sharing agreements were obtained from 10 11 the Executive Committees of each network and the iNeo Coordinating Centre at Mount Sinai 12 13 14 Hospital, Toronto, Canada. Approval for this project was granted by the iNeo Steering 15 16 Committee and respective Ethics Boards. 17 18 For peer review only 19 Covariate Definitions 20 21 22 Gestational age (GA) was determined by the best estimate based on early prenatal ultrasound, 23 24 last menstrual period, or physical examination of infants at birth, in that order. Birth weight z 25 26 scores were calculated relative to population- and sex-specific birth weight for gestational age 27 28 29 references selected by each network as most appropriate for the comparison. Antenatal steroid 30 31 use was defined as any administration before birth, regardless of the time interval, PDA by 32 33 clinical or echocardiographic diagnosis, and sepsis by clear clinical evidence of infection as 34 35 36 well as at least 1 relevant positive result from blood cultures.

37 http://bmjopen.bmj.com/ 38 39 Outcomes and Measures 40 41 A lack of consensus on defining NEC among the 8 participating countries led us to use 42 43 surgical NEC as primary outcome. Surgical NEC was defined as laparotomy, laparoscopy, 44 45 bowel resection, or intraperitoneal drain placement for NEC or suspected NEC. Indication to on September 27, 2021 by guest. Protected copyright. 46 47 48 operate was pneumoperitoneum or clinical deterioration despite maximal medical 49 50 therapy.[15–17]. Using surgical NEC as primary outcome also allows exclusion of potential 51 52 cases of spontaneous intestinal perforations as they can be identified reliably only at surgery. 53 54 55 Mortality following NEC was defined as death after receiving a diagnosis of NEC stage 2 or 56 57 above, according to Bell’s criteria[18], and was analyzed to ensure that the comparison of 58 59 surgical NEC among countries was not biased by a high proportion of potential surgical NEC 60

6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 71

1 2 cases missing due to higher NEC death rates. As Sweden does not collect NEC data according

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 to Bell's criteria, its mortality following NEC may be somewhat lower than reported. 5 6 7 8 Statistical analysis 9 10 11 Unit level analyses: Unit level survey responses were reported using descriptive statistics and 12 13 reported as percentages or displayed graphically. 14 15 Mixed level analyses: Unit level data for preventative approaches of probiotic usage, early 16 17 18 feeding and donor milkFor availability peer were reviewanalyzed for their only association with patient level data 19 20 of surgical NEC. A multi-level logistic regression model was developed with surgical NEC as 21 22 dependent variable, and unit-level practices (probiotics, early feeding and donor milk use) and 23 24 25 individual patient level data (GA, male sex, multiple births, and birth-weight z-score) as 26 27 independent variables. Adjusted odds ratios (ORs) and 95% confidence interval (CI) were 28 29 calculated. This analysis was not possible for Australia/New Zealand and Spain, as 30 31 permission for linking survey information and patient data were not available. No model 32 33 34 could be developed for networks where all units provided any of the prophylactic approach to 35 36 all or to none of their patients. Generalized estimation equation was used to account for auto-

37 http://bmjopen.bmj.com/ 38 correlation within units. 39 40 41 Patient level analyses: Patient level data were used to calculate variations in baseline 42 43 characteristics, factors associated with NEC in literature, surgical NEC rates and mortality 44 45 following NEC for participating networks. Standardized ratios (SRs) for participating on September 27, 2021 by guest. Protected copyright. 46 47 48 networks were calculated as the observed number of infants who received NEC surgery 49 50 divided by the number of infants expected to receive NEC surgery, based on the sum of 51 52 predicted probabilities from a multivariable adjusted logistic regression model using data 53 54 from all other countries in the study. Adjustment was made for the same parameters as for the 55 56 57 odds ratios. SR estimates were graphically displayed. As the SR estimate are calculated in 58 59 relation to all other countries combined, it is not directly comparable between contributors. 60

7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 71 BMJ Open

1 2 Data management and statistical analyses were performed at the iNeo Coordinating Centre in

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Toronto, Canada using SAS version 9.2 (SAS Institute Inc., Cary, NC). 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 71

1 2 RESULTS

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 5 Unit level analyses of survey 6 7 8 Probiotics 9 10 11 Out of a total of 168 network units, 153 (91%) responded to the online survey (Table 1). 12 13 Probiotic provision for infants born <29 weeks’ gestation ranged from 0% of units in Israel 14 15 16 and Sweden to 100% of units in Finland. Among units providing probiotics, initiation of 17 18 therapy ranged fromFor 0 to 3 days peer of age in review most units. Lactobacillus only and/or Bifidobacterium 19 20 were the preferred probiotic species; however, other species were provided as well (see online 21 22 supplement 2). In most units in Australia/New Zealand, Finland and Tuscany, probiotic 23 24 25 supplementation was continued in cases of culture positive sepsis, whereas most units in 26 27 Switzerland stopped providing probiotics. 28 29 30 Enteral feeding 31 32 33 Table 1 summarizes enteral feeding initiation and advancement practices for infants 34 35 <26 weeks’ gestation and between 26-28 weeks’ gestation. Figure 1 summarizes feeding 36

37 http://bmjopen.bmj.com/ 38 initiation in both age groups. The majority of units began enteral feeding on first or second 39 40 day of life. In Finland, Sweden and Switzerland, all units reported initiating feeding on first 41 42 day of life. There was some variation in daily rates of advancement between and within all 43 44 networks, with a majority of units advancing at rates between 10 to 25 ml/kg/day. No overall 45 on September 27, 2021 by guest. Protected copyright. 46 47 preference in enteral feeding volume was seen in infants who received milk fortifier, with a 48 49 range in administration varying between 70-120 ml/kg/day. 50 51 52 Donor Milk 53 54 55 Donor milk availability ranged between 0% of units in Israel to 100% of units in Finland, 56 57 Sweden and Tuscany. A majority of units in Spain, Switzerland and Tuscany had initiation 58 59 60 criteria at <32 weeks’ gestation or <1501g weight, whereas in Sweden most units provided

9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 71 BMJ Open

1 2 donor milk at <34 weeks’ gestation. No uniform stopping criteria for donor milk use were

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 applied by most units, except for Tuscany where the majority of units stopped at 1800g. Units 5 6 7 in Finland and Spain used variable criteria other than age or weight for starting and stopping 8 9 donor milk provision. 10 11 12 Mixed level analyses of surveyed practices and surgical NEC 13 14 15 Probiotics: We could only compare units in Canada which showed no difference in surgical 16 17 NEC with probiotics and Switzerland which showed lower odds with probiotics (Table 1). 18 For peer review only 19 The adjusted OR combining all units from the six networks allowing linkage between unit 20 21 22 survey and cohort study revealed no significant association of probiotics provision with 23 24 surgical NEC (0.84, 95% CI 0.61-1.16). 25 26 27 Early initiation of feeding: Data from Canada, Israel and Tuscany were available for 28 29 comparative analyses (Table 1). Except for neonates of 26-28 weeks’ GA in Tuscany there 30 31 32 was no difference in odds of surgical NEC in group who were initiated feeds on day of birth 33 34 compared to units which started feeds later. The adjusted OR combining all units providing 35 36 enteral feeding on day 0 revealed no significant association to surgical NEC (1.16, 95% CI 37 http://bmjopen.bmj.com/ 38 39 0.83-1.63). 40 41 Donor milk: Data from Canada and Switzerland were available for comparative analyses. 42 43 44 There was no difference in odds of surgical NEC between units which provided donor milk

45 on September 27, 2021 by guest. Protected copyright. 46 compared to those units which did not provide donor milk. The adjusted OR combining all 47 48 units also revealed no association (Table 1). 49 50 51 Patient level analyses of cohort study 52 53 54 A total of 9792 infants were included in the analysis. The baseline characteristics in table 2 55 56 57 reveal a small variation among networks in their overall mean GA (range 26.3-26.5 weeks), 58 59 mean birth weight z-score (-0.22 to +0.18), SGA-ratios (8.8%-12.8%), and male sex 60 distribution (51.5%-55.3%). There was considerable variation between networks among

10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 71

1 2 factors associated with NEC in literature: receipt of antenatal steroids ranged from 82.9% in

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Israel to 97.3% in Finland, caesarean section ranged from 60.0% in Canada to 82.7% in 5 6 7 Switzerland, patent ductus arteriosus (PDA) treated with indomethacin ranged from 0% in 8 9 countries exclusively administering ibuprofen or paracetamol to treat PDA (Spain, Sweden, 10 11 Tuscany) to 39.6% in Switzerland, and sepsis ranged from 14.6% in Switzerland to 46.2% in 12 13 14 Spain. 15 16 Overall, average surgical NEC incidence rate in all countries combined was 4.1%, (ranging 17 18 For peer review only 19 from 2.4% in Australia and New Zealand and 8.4% in Spain) whereas death following NEC 20 21 diagnosis occurred in 2.4% of all infants (ranging from 1.4% in Sweden to 3.3% in Spain) 22 23 (Table 2, Figure 2). As none of the countries had higher rates of mortality following NEC in 24 25 26 relation to their surgical NEC incidence rate, we ruled out the possibility that the surgical 27 28 NEC incidence rate of any country is underreported due to death before surgery can take 29 30 place. Australia/New Zealand had lowest adjusted standardized ratios for surgical NEC 31 32 33 whereas Spain had the highest standardized ratio among participating networks (Figure 3). 34 35 36 37 DISCUSSION http://bmjopen.bmj.com/ 38 39 40 In this large multi-center, multi-national, mixed methods study linking unit level survey and 41 42 43 retrospective patient level cohort data, we identified that, on a unit level, NEC preventive 44

45 practices of using probiotics or donor milk varied from 0-100% between networks, whereas on September 27, 2021 by guest. Protected copyright. 46 47 feeding start age and advancement had minor variation between the units of each network. In 48 49 50 mixed level analyses, probiotics were associated with reduced odds of surgical NEC in 51 52 Switzerland and early feeding was associated with reduced odds of surgical NEC in Tuscany 53 54 for neonates of 26-28 weeks’ gestation. Donor milk provision was not associated with 55 56 57 surgical NEC. Patient level analyses revealed that 1 in every 25 admitted infants at 24-28 58 59 weeks’ gestation received surgical intervention for NEC with some variation between 60 networks in incidence and NEC associated mortality. Standardized ratios for surgical NEC

11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 71 BMJ Open

1 2 were lower in Australia/New Zealand, higher in Spain and comparable for the remaining six

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 networks. 5 6 7 Multiple meta-analyses of randomized studies have shown that probiotics are associated with 8 9 10 reduced rates of NEC and sepsis.[19,20] However, a lack of consensus regarding the strain(s), 11 12 dose, and duration and timing of use has prevented many units from adopting it as a strategy. 13 14 Moreover, the long-term effects on immune function and metabolism following replacement 15 16 of a maternally derived intestinal microbiome with a dominant exogenous bacterial species is 17 18 For peer review only 19 not known.[21] The wide variation in units that participated in this study regarding their use, 20 21 strains, start and stop time and the lack of association with surgical NEC rate may be due to 22 23 the very high-risk population, different strains and the fact that this study involves the entire 24 25 26 population at unit-level rather than a select population enrolled in randomized trial. The 27 28 difference in results between systematic reviews and this study could be due to pooling of 29 30 inhomogeneous studies into meta-analyses as concerns raised by several investigators 31 32 33 indicate. Further pragmatic studies from multiple countries are needed. 34 35 36 There is evidence that implementing evidence-based standardized feeding guidelines reduces

37 http://bmjopen.bmj.com/ 38 the incidence of NEC.[8] Although such guidelines are not uniform, they have generally 39 40 incorporated an early minimal enteral nutrition phase during which 10-20 ml/kg/d of enteral 41 42 nutrition is provided without increase, followed by daily advancement based on continued 43 44

45 tolerance. Older practices withheld feedings for days to weeks after birth in an attempt to on September 27, 2021 by guest. Protected copyright. 46 47 avoid an assumed association of NEC with the start of enteral feeding.[22] The majority of 48 49 units amongst the 8 participating countries initiate early feeding with rapid rates of 50 51 52 advancement, with few units continuing to favor the slower approach. We found no 53 54 association between feeding start and surgical NEC. This may be due to the very small 55 56 number of units which delay feeds. 57 58 59 Although using donor milk in lieu of formula feedings has led to reduced NEC rates in recent 60 studies, it is unclear whether donor milk itself protected against NEC or whether the

12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 71

1 2 avoidance of formula acted as a protective factor.[8] We identified a large variation between

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 networks regarding availability and provision of donor milk and varying preferences for 5 6 7 initiation and stopping criteria. At unit level analyses, there was no association between donor 8 9 milk and surgical NEC. One explanation may be that units without donor milk available may 10 11 actually have more active programs to help mothers provide breast milk. 12 13 14 Recent publications, several of them population-based, report NEC rates for very low birth 15 16 weight infants (VLBW, 500-1500g) in the range of 2-12%.[15,23–28] In a previous review, 17 18 For peer review only 19 variations in rates across different NICHD centers and periods ranged from 1-22% of VLBW 20 21 infants between 1987-2000.[29] Reported mortality of infants with NEC continues to remain 22 23 high at approximately 15-30%.[15,30]. Incidences of surgical intervention are less often 24 25 26 reported but usually occur in 30-50% of patients acquiring NEC.[15,16,28,31] Considering 27 28 these rates, the proportions of surgical NEC and death following NEC diagnosis in the current 29 30 study are within the middle to upper range of previously published values, as expected given 31 32 0- 6 33 the lower GA range (24 28 ) of our study versus previously reported VLBW references. They 34 35 correlate well with the NEC rates reported for infants < 28 weeks GA in a recent review.[2] 36

37 http://bmjopen.bmj.com/ 38 The risk of acquiring NEC is inversely proportional to GA.[8,16,31–34] Fetal growth 39 40 restriction and male sex may be additional risk factors.[27,31] In our study, GA and birth 41 42 weight z-score were comparable and therefore they did not explain outcome variation 43 44

45 between networks. Given the association between NEC and antenatal steroid on September 27, 2021 by guest. Protected copyright. 46 47 administration,[23,31,35] caesarean section,[34,36,37] sepsis[6,16,38] and PDA treated with 48 49 indomethacin,[36,39,40] we expected surgical NEC incidence to be affected by the variation 50 51 52 of these factors between networks. However, there was no association in networks with up to 53 54 10% lower proportions of antenatal steroid use (Sweden, Israel), up to 17% lower proportions 55 56 of vaginal delivery (Switzerland), and up to twice as many indomethacin-treated PDA 57 58 59 patients (Switzerland). The only association observed was for the two networks with the 60 highest proportions of surgical NEC (Tuscany, Spain), which also had the highest proportions

13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 71 BMJ Open

1 2 of sepsis. However, sepsis occurs simultaneously in certain NEC cases, rather than as a risk

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 factor for acquiring NEC.[6] 5 6 7 The lack of consensus on defining NEC has led to variable definitions in research databases 8 9 10 and clinical trials.[41] This challenge is reflected in the participating 8 networks as well, 11 12 where most networks used Bell's stage 2 as the defining threshold, whilst one network 13 14 included “mild” or “initial” cases, corresponding to Bell’s stage 1.[18] The current study 15 16 therefore included iNeo networks collecting data on surgical NEC based on laparotomy or 17 18 For peer review only 19 drainage, according to the accepted indication to operate in cases of pneumoperitoneum or 20 21 clinical deterioration despite maximal medical therapy.[15–17] Nevertheless, variation in 22 23 threshold to operate in NEC may exist and contribute to variations in surgical NEC. The study 24 25 26 is further restricted to infants <29 weeks’ gestation whose risk of acquiring NEC is enhanced 27 28 and who are more likely to have a common pathogenesis.[33,34,41] 29 30 31 The current study is strengthened by the large, multinational patient database and high survey 32 33 response rate, enabling a snapshot of contemporary outcome and practices. However, not all 34 35 36 reporting networks are population based.[42] Moreover, the survey was completed by a single

37 http://bmjopen.bmj.com/ 38 representative at each site rather than all practitioners, but responses were based on NICU 39 40 policies rather than personal opinion. We would have liked the analyses of individual per 41 42 patient practices as this would have been the most ideal pragmatic scenario; however, in our 43 44

45 database these items are not collected. Thus, in linking survey with cohort study we have on September 27, 2021 by guest. Protected copyright. 46 47 assumed that all neonates within a unit were treated equally, which is an assumption and 48 49 needs confirmation. However, it is acceptable for generating a hypothesis. 50 51 52 In conclusion, the variation in NEC preventive practices between 8 regionally defined 53 54 55 networks of high-income nations was high for probiotic use and donor milk use, but less so 56 57 for feeding practices. Despite large variabilities in factors known to influence NEC outcome, 58 59 there was no significant relationship between the NEC preventive practice usage by units and 60 surgical NEC rates. Overall, one in 25 extremely preterm neonates received NEC surgery.

14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 71

1 2 The standardized ratios for NEC surgery were significantly lower in Australia/New Zealand

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 and significantly higher in Spain. Our results identify several areas of urgent research need 5 6 7 and generates several hypotheses for studies aimed at improving outcome of this devastating 8 9 disease. It also provides a platform for evaluating practices using a construct of comparative 10 11 effectiveness research whereby pragmatic evaluation of two or more strategies can be 12 13 14 conducted under the umbrella of a registry-based pragmatic clinical trial.[43,44] 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 71 BMJ Open

1 2 Author Contributions

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 5 6 Drs. Adams, Bassler and Shah conceptualized and designed the study and interpreted the data 7 and wrote first draft and prepared final draft. Mr. Yang performed the statistical evaluations. 8 Dr. Adams drafted the first manuscript. Drs. Darlow, Lui, Reichman, Håkansson, Norman, 9 Lee, Helenius, Lehtonen, San Feliciano, Vento, Moroni, and Beltempo critically reviewed the 10 study protocol. All authors reviewed, discussed and approved the final manuscript as 11 submitted and agree to be accountable for all aspects of the work. Author Access to Data: Dr. 12 13 Shah and Mr. Yang had full access to all the data in the study and take responsibility for the 14 integrity of the data and accuracy of the data analysis. 15 16 17 Data sharing statement 18 All data relevant to Forthe study peer are included review in the article or uploadedonly as supplementary 19 20 information. 21 22 23 Patient and Public Involvement 24 25 Patients or public were not involved in the development of the research question, the outcome 26 measures or the study design. The results of this study will be disseminated to study 27 participants, as well as to other patients, through the patient and public page of the Swiss 28 29 neonatal and follow-up website and the iNeo network website. 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

16 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 71

1 2 ACKNOWLEDGEMENTS

3 The authors gratefully acknowledge all investigators and data abstractors of the networks BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 participating in the iNeo consortium for their diligent work. We thank Iris Kulbatski, PhD and 5 Sarah Hutchinson, PhD from the Maternal-Infant Care Research Centre (MiCare) in Toronto, 6 7 Ontario, Canada, for editorial support for this manuscript and other MiCare staff for 8 organizational and statistical support. We also acknowledge other networks which contributed 9 to the survey but did not have information on patient outcomes available: the Neonatal 10 Research Network Japan and the Illinois Neonatal Network. 11 12 13 iNeo Investigators 14 15 ANZNN (Australia and New Zealand Neonatal Network): Ross Haslam* Chair of the 16 Executive Committee; Flinders Medical Centre, SA: Peter Marshall. Gold Coast University 17 Hospital, QLD: Peter Schmidt. Gosford District Hospital, NSW: Adam Buckmaster*. John 18 Hunter Children’s Hospital,For NSW:peer Paul Craven,review Koert de Waal*.only King Edward Memorial and 19 Princess Margaret Hospitals, WA: Karen Simmer, Andy Gill*, Jane Pillow*. Liverpool 20 Hospital, NSW: Jacqueline Stack. Mater Mothers' Hospital, QLD: Lucy Cooke. Mercy 21 Hospital for Women, VIC: Dan Casalaz, Jim Holberton*. Monash Medical Centre, VIC: 22 23 Charles Barfield. Nepean Hospital, NSW: Lyn Downe, Vijay Shingde. Newborn Emergency 24 Transport Service (VIC): Michael Stewart. NSW Pregnancy and Newborn Services Network: 25 Barbara Bajuk*. NSW Newborn & Paediatric Emergency Transport Service: Andrew Berry. 26 Royal Children's Hospital, VIC: Rod Hunt. Royal Darwin Hospital, NT: Charles Kilburn. 27 Royal Hobart Hospital, Tasmania: Tony De Paoli. Royal Hospital for Women, NSW: Kei 28 Lui*. Royal North Shore Hospital, NSW: Mary Paradisis. Royal Prince Alfred Hospital, 29 NSW: Ingrid Rieger, Shelley Reid*. Royal Brisbane and Women's Hospital, QLD: David 30 31 Cartwright, Pieter Koorts. Royal Women's Hospital, VIC: Carl Kuschel, Lex Doyle. Sydney 32 Children's Hospital, NSW: Andrew Numa. The Canberra Hospital, ACT: Hazel Carlisle. The 33 Children's Hospital at Westmead, NSW: Nadia Badawi, Robert Halliday. The Townsville 34 Hospital, QLD: Guan Koh*. Western Australia Neonatal Transport Service: Steven Resnick. 35 Westmead Hospital, NSW: Melissa Luig. Women's & Children's Hospital, SA: Chad 36 Andersen. National Perinatal Epidemiology and Statistics Unit, University of New South 37 http://bmjopen.bmj.com/ 38 Wales: Georgina Chambers*. New Zealand: Christchurch Women's Hospital: Adrienne Lynn, 39 Brian Darlow. Dunedin Hospital: Roland Broadbent*. Middlemore Hospital: Lindsay 40 Mildenhall. Auckland City Hospital: Mariam Buksh, Malcolm Battin. North Shore and 41 Waitakere Hospitals: Jutta van den Boom*. Waikato Hospital: David Bourchier, Lee 42 Carpenter*. Wellington Women's Hospital: Vaughan Richardson. Singapore: KK Women's 43 and Children's Hospital, Singapore: Victor Samuel Rajadurai*. 44 * denotes the ANZNN Executive Committee 45 on September 27, 2021 by guest. Protected copyright. 46 CNN (Canadian Neonatal Network): Prakesh S Shah, MD, MSc (Director, Canadian 47 Neonatal Network and site investigator), Mount Sinai Hospital, Toronto, Ontario; Adele 48 49 Harrison, MD, MBChB, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, 50 MDCM, MHSC, and Joseph Ting, MD, B.C. Women’s Hospital and Health Centre, 51 Vancouver, British Columbia; Zenon Cieslak, MD, Royal Columbian Hospital, New 52 Westminster, British Columbia; Rebecca Sherlock, MD, Surrey Memorial Hospital, Surrey, 53 British Columbia; Wendy Yee, MD, Foothills Medical Centre, Calgary, Alberta; Khalid Aziz, 54 MBBS, MA, MEd, and Jennifer Toye, MD, Royal Alexandra Hospital, Edmonton, Alberta; 55 Carlos Fajardo, MD, Alberta Children’s Hospital, Calgary, Alberta; Zarin Kalapesi, MD, 56 57 Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, MBBS, and 58 Sibasis Daspal, MD, Royal University Hospital, Saskatoon, Saskatchewan; Mary Seshia, 59 MBChB, Winnipeg Health Sciences Centre, Winnipeg, Manitoba; Ruben Alvaro, MD, St. 60 Boniface General Hospital, Winnipeg, Manitoba; Amit Mukerji, MD, Hamilton Health Sciences Centre, Hamilton, Ontario; Orlando Da Silva, MD, MSc, London Health Sciences

17 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 71 BMJ Open

1 2 Centre, London, Ontario; Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor,

3 Ontario; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, Ontario; Michael BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Dunn, MD, Sunnybrook Health Sciences Centre, Toronto, Ontario; Brigitte Lemyre, MD, 5 Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario; 6 7 Kimberly Dow, MD, Kingston General Hospital, Kingston, Ontario; Ermelinda Pelausa, MD, 8 Jewish General Hospital, Montréal, Québec; Keith Barrington, MBChB, Hôpital Sainte- 9 Justine, Montréal, Québec; Christine Drolet, MD, and Bruno Piedboeuf, MD, Centre 10 Hospitalier Universitaire de Québec, Sainte Foy Québec; Martine Claveau, MSc, LLM, NNP, 11 and Marc Beltempo, MD, McGill University Health Centre, Montréal, Québec; Valerie 12 Bertelle, MD, and Edith Masse, MD, Centre Hospitalier Universitaire de Sherbrooke, 13 14 Sherbrooke, Québec; Roderick Canning, MD, Moncton Hospital, Moncton, New Brunswick; 15 Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah, 16 MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New 17 Brunswick; Akhil Deshpandey, MBBS, MRCPI, Janeway Children’s Health and 18 Rehabilitation Centre,For St. John’s, peer Newfoundland; review Jehier Afifi, only MB BCh, MSc, IWK Health 19 Centre, Halifax, Nova Scotia; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, 20 Sydney, Nova Scotia; Shoo K Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), 21 22 Mount Sinai Hospital, Toronto, Ontario. 23 FinMBR (Finnish Medical Birth Register): Sture Andersson, MD, Helsinki University 24 25 Hospital, Helsinki; Liisa Lehtonen, MD, Turku University Hospital, Turku; Outi Tammela, 26 MD, Tampere University Hospital, Tampere; Ulla Sankilampi, MD, Kuopio University 27 Hospital, Kuopio; Timo Saarela, MD, Oulu University Hospital, Oulu. 28 29 INN (Israel Neonatal Network): Eli Heymann, MD, Assaf Harofeh Medical Center, Tzrifin; 30 Shmuel Zangen, MD, Barzilai Medical Center, Ashkelon; Tatyana Smolkin, MD, Baruch 31 Padeh Medical Center, Poriya; Francis Mimouni, MD, Bikur Cholim Hospital, Jerusalem; 32 David Bader, MD, Bnai Zion Medical Center, Haifa; Avi Rothschild, MD, Carmel Medical 33 Center, Haifa; Zipora Strauss, Chaim Sheba Medical Center, Ramat Gan; Clari Felszer, MD, 34 Emek Medical Center, Afula; Hussam Omari, MD, French Saint Vincent de Paul Hospital, 35 36 Nazareth; Smadar Even Tov-Friedman, MD, Hadassah University Hospital-Ein Karem,

37 Jerusalem; Benjamin Bar-Oz, MD, Hadassah University Hospital-Har Hazofim, Jerusalem; http://bmjopen.bmj.com/ 38 Michael Feldman, MD, Hillel Yaffe Medical Center, Hadera; Nizar Saad, MD, Holy Family 39 (Italian) Hospital, Nazareth; Orna Flidel-Rimon, MD, Kaplan Medical Center, Rehovot; Meir 40 Weisbrod, MD, Laniado Hospital, Netanya; Daniel Lubin, MD, Mayanei Hayeshua Medical 41 Center, Bnei Brak; Ita Litmanovitz, MD, Meir Medical Center, Kfar Saba; Amir Kugelman, 42 MD, Rambam Medical Center; Eric Shinwell, MD, Rivka Ziv Medical Center, Safed; Gil 43 44 Klinger, MD, Schneider Children’s Medical Center of Israel, Rabin Medical Center

45 (Beilinson Campus), Petah Tikva; Yousif Nijim, MD, Scottish (EMMS) Hospital, Nazareth; on September 27, 2021 by guest. Protected copyright. 46 Alona Bin-Nun, MD, Shaare-Zedek Medical Center, Jerusalem; Agneta Golan, MD, Soroka 47 Medical Center, Beersheba; Dror Mandel, MD, Sourasky Medical Center, Tel Aviv; Vered 48 Fleisher-Sheffer, MD,Western Galilee Medical Center, Nahariya; David Kohelet, MD, 49 Wolfson Medical Center, Holon; Lev Bakhrakh, MD, Yoseftal Hospital, Eilat. 50 51 SEN1500 (Spanish Neonatal Network): Alejandro Avila-Alvarez, MD, and José Luis 52 Fernandez-Trisac, MD, Complexo Hospitalario Universitario De A Coruña, A Coruña; Mª 53 Luz Couce Pico, MD, and María José Fernández Seara, MD, Hospital Clínico Universitario 54 de Santiago, Santiago de Compostela; Andrés Martínez Gutiérrez, MD, Complejo 55 56 Hospitalario Albacete, Albacete; Carolina Vizcaíno , MD, Hospital General Universitario de 57 Elche, Alicante; Miriam Salvador Iglesias, MD, and Honorio Sánchez Zaplana, MD, Hospital 58 General Universitario de Alicante, Alicante; Belén Fernández Colomer, MD, and José 59 Enrique García López, MD, Hospital Universitario Central de Asturias, Oviedo, Asturias; 60 Rafael García Mozo, MD, and M. Teresa González Martínez, MD, Hospital Universitario de Cabueñes, Gijón, Asturias; Mª Dolores Muro Sebastián, MD, and Marta Balart Carbonell,

18 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 71

1 2 MD, Clínica Corachán, Barcelona, Barcelona; Joan Badia Barnusell, MD, and Mònica

3 Domingo Puiggròs, MD, Corporacio Parc Taulí, Sabadell, Barcelona; Josep Figueras Aloy, BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 MD, and Francesc Botet Mussons, MD, Hospital Clínic de Barcelona, Barcelona; Israel 5 Anquela Sanz, MD, Hospitalario De Granollers, Granollers; Gemma Ginovart Galiana, MD, 6 7 H. De La Santa Creu I Sant Pau, Barcelona; W. Coroleu, MD, Hospital Universitari Germans 8 Trias I Pujol, Badalona; Martin Iriondo, MD, Hospital Sant Joan de Déu Barcelona, 9 Esplugues de Llobregat, Barcelona; Laura Castells Vilella, MD, Hospital General de 10 Cataluña, Barcelona; Roser Porta, MD, Institute Dexeus, Barcelona; Xavier Demestre, MD, 11 and Silvia Martínez Nadal, MD, Scias-Hospital Barcelona, Barcelona; Cristina de Frutos 12 Martínez, MD, Hospital Universitario de Burgos, Burgos; María Jesús López Cuesta, MD, H. 13 14 San Pedro de Alcántara, Cáceres; Dolores Esquivel Mora, MD, and Joaquín Ortiz Tardío, 15 MD, Hospital Jerez, Cádiz; Isabel Benavente, MD, and Almudena Alonso, MD, Hospital 16 Universitario Puerta Del Mar, Cádiz; Ramón Aguilera Olmos, MD, Hospital General de 17 Castellón, Castellón; Miguel A. García Cabezas, MD, and Mª Dolores Martínez Jiménez, 18 MD, Hospital GeneralFor Universitario peer de Ciudadreview Real, Ciudad only Real; Mª Pilar Jaraba Caballero, 19 MD, and Mª Dolores Ordoñez Díaz, MD, Hospital Universitario Reina Sofía, Córdoba; 20 Alberto Trujillo Fagundo, MD, and Lluis Mayol Canals, MD, Hospital Universitari de 21 22 Girona Dr. Josep Trueta, Girona; Fermín García-Muñoz Rodrigo, MD, and Lourdes Urquía 23 Martí, MD, H.M.I. Las Palmas, Las Palmas, Gran Canaria; María Fernanda Moreno Galdo , 24 MD, and José Antonio Hurtado Suazo, MD, Hospital Universitario Virgen De Las Nieves, 25 Granada; Eduardo Narbona López, and José Uberos Fernández, MD, Hospital Universitario 26 San Cecilio, Granada; Miguel A Cortajarena Altuna, MD, and Oihana Muga Zuriarrain 27 Hospital, MD, Donostia, Gipuzkoa; David Mora Navarro, MD, Hospital Juan Ramón 28 Jiménez, Huelva, Huelva; María Teresa Domínguez, MD, Hospital Costa De La Luz, Huelva; 29 30 Mª Yolanda Ruiz del Prado, MD, and Inés Esteban Díez, MD, Hospital San Pedro, Logroño, 31 La Rioja; María Teresa Palau Benavides, MD, and Santiago Lapeña, MD, Hospital de León, 32 León, León; Teresa Prada, MD, Hospital del Bierzo, Ponferrada, León; Eduard Soler Mir, 33 MD, Hospital Arnau De Vilanova, Lleida; Araceli Corredera Sánchez, MD, Enrique Criado 34 Vega, MD, Náyade del Prado, MD, and Cristina Fernández, MD, Hospital Clínico San 35 Carlos, Madrid; Lucía Cabanillas Vilaplana, MD, and Irene Cuadrado Pérez, MD, Hospital 36

37 Universitario De Getafe, Madrid; Luisa López Gómez, MD, Hospital De La Zarzuela, http://bmjopen.bmj.com/ 38 Madrid; Laura Domingo Comeche, MD, Hospital Universitario de Fuenlabrada, Fuenlabrada, 39 Madrid; Isabel Llana Martín, MD, Hospital Madrid-Torrelodones, Madrid, Madrid; Carmen 40 González Armengod, MD, and Carmen Muñoz Labián, MD, Hospital Universitario Puerta 41 De Hierro, Majadahonda, Madrid; Mª José Santos Muñoz, MD, Hospital Severo Ochoa, 42 Leganés, Madrid; Dorotea Blanco Bravo, MD, and Vicente Pérez, MD, Hospital Gregorio 43 Marañón, Madrid; Mª Dolores Elorza Fernández, MD, Celia Díaz González, MD, and Susana 44

45 Ares Segura, MD, H.U. La Paz, Madrid; Manuela López Azorín, MD, Hospital Universitario on September 27, 2021 by guest. Protected copyright. 46 Quirónsalud Madrid, Madrid; Ana Belén Jimenez MD, Hospital Universitario Fundación 47 Jiménez Díaz, Madrid; Tomás Sánchez-Tamayo, MD, and Elías Tapia Moreno, MD, 48 Hospital Carlos Haya, Málaga; María González, MD, and José Enrique Sánchez Martínez, 49 MD, Hospital Parque San Antonio De Málaga, Málaga; José María Lloreda García, MD, 50 Hospital Universitario Santa Lucia De Cartagena, Murcia; Concepción Goñi Orayen, MD, 51 Hospital Virgen Del Camino De Pamplona, Pamplona, Navarra; Javier Vilas González, MD, 52 53 Complexo Hospitalario Pontevedra, Pontevedra; María Suárez Albo, MD, and Eva González 54 Colmenero, MD, Hospital Xeral De Vigo, Pontevedra; Elena Pilar Gutiérrez González, MD, 55 and Beatriz Vacas del Arco, MD, Hospital Universitario de Salamanca, Salamanca; Josefina 56 Márquez Fernández, MD, and Laura Acosta Gordillo, MD, Hospital Valme, Sevilla; 57 Mercedes Granero Asensio, MD, Hospital Virgen De La Macarena, Sevilla; Carmen Macías 58 Díaz, MD, Hospital Universitario Virgen Del Rocío, Sevilla; Mar Albújar, MD, Hospital 59 60 Universitari de Tarragona Joan XXIII, Tarragona; Pedro Fuster Jorge. MD, Hospital Universitario De Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife; Sabina

19 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 71 BMJ Open

1 2 Romero, MD, and Mónica Rivero Falero, MD, Hospital Universitario Nuestra Señora De

3 Candelaria, Santa Cruz de Tenerife; Ana Belén Escobar Izquierdo, Hospital Virgen De La BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Salud, Toledo; Javier Estañ Capell, MD, Hospital Clinico Universitario De Valencia, 5 Valencia; Mª Isabel Izquierdo Macián, MD, Hospital Universitari La Fe, Valencia; Mª Mar 6 7 Montejo Vicente, MD, and Raquel Izquierdo Caballero, MD, Hospital Universitario Río 8 Hortega, Valladolid; Mª Mercedes Martínez, MD, and Aintzane Euba, MD, Hospital de 9 Txagorritxu, Vitoria-Gasteiz; Amaya Rodríguez Serna, MD, and Juan María López de 10 Heredia Goya, MD, Hospital de Cruces, Baracaldo; Alberto Pérez Legorburu, MD, and Ana 11 Gutiérrez Amorós, MD, Hospital Universitario de Basurto, Bilbao; Víctor Manuel Marugán 12 Isabel, MD, and Natalio Hernández González, MD, Hospital Virgen De La Concha - 13 14 Complejo Asistencial De Zamora, Zamora; Segundo Rite Gracia, MD, Hospital Miguel 15 Servet, Zaragoza; Mª Purificación Ventura Faci, MD, and Mª Pilar Samper Villagrasa, MD, 16 Hospital Clínico Universitario Lozano Blesa, Zaragoza. 17 18 SNQ (Swedish NeonatalFor Quality peer Register): review Jiri Kofron, MD,only Södra Älvsborgs Sjukhus, 19 Borås; Katarina Strand Brodd, MD, Mälarsjukhuset, Eskilstuna; Andreas Odlind, MD, Falu 20 Lasarett, Falun; Lars Alberg, MD, Gällivare Sjukhus, Gällivare; Sofia Arwehed, MD, Gävle 21 Sjukhus, Gävle; Ola Hafström, MD, SU/Östra, Göteborg; Anna Kasemo, MD, Länssjukhuset, 22 Halmstad; Karin Nederman, MD, Helsingborgs Lasarett, Helsingborg; Lars Åhman, MD, 23 Hudiksvalls Sjukhus, Hudiksvall; Fredrik Ingemarsson, MD, Länssjukhuset Ryhov, 24 25 Jönköping; Henrik Petersson, MD, Länssjukhuset, Kalmar; Pernilla Thurn, MD, 26 Blekingesjukhuset, Karlskrona; Eva Albinsson, MD, Centralsjukhuset, Karlstad; Bo Selander, 27 MD, Centralsjukhuset, Kristianstad; Thomas Abrahamsson, MD, Universitetssjukhuset, 28 Linköping; Ingela Heimdahl, MD, Sunderby sjukhus, Luleå; Kristbjorg Sveinsdottir, MD, 29 Skånes Universitetssjukhus, Malmö/Lund; Erik Wejryd, MD, Vrinnevisjukhuset, Norrköping; 30 Anna Hedlund, MD, Skellefteå Lasarett, Skellefteå; Maria Katarina Söderberg, MD, 31 Kärnsjukhuset Skaraborg, Skövde; Boubou Hallberg, MD, Karolinska Sjukhuset, Stockholm; 32 33 Thomas Brune, MD, Södersjuhuset, Stockholm; Jens Bäckström, MD, Länssjukhuset, 34 Sundsvall; Johan Robinson, MD*, Norra Älvsborgs Länssjukhus, Trollhättan; Aijaz Farooqi, 35 MD, Norrlands Universitetssjukhus, Umeå; Erik Normann, MD, Akademiska Barnsjukhuset, 36 Uppsala; Magnus Fredriksson, MD, Visby Lasarett, Visby; Anders Palm, MD, Västerviks 37 Sjukhus, Västervik; Urban Rosenqvist, MD, Centrallasarettet, Västerås; Bengt Walde, MD, http://bmjopen.bmj.com/ 38 Centrallasarettet, Växjö; Cecilia Hagman, MD, Lasarettet, Ystad; Andreas Ohlin, MD, 39 Universitetssjukhuset, Örebro; Rein Florell, MD, Örnsköldsviks Sjukhus, Örnsköldsvik; 40 41 Agneta Smedsaas-Löfvenberg, MD, Östersunds Sjukhus, Östersund. *(To honor Dr. 42 Robinson's work, this paper is published posthumously under his name.) 43 44 SwissNeoNet (Switzerland Neonatal Network): Philipp Meyer, MD, and Claudia Anderegg,

45 MD, Cantonal Hospital, Children's Clinic, Aarau; Sven Schulzke, MD, University Children's on September 27, 2021 by guest. Protected copyright. 46 Hospital, Basel; Mathias Nelle, MD, University Hospital, Berne; Bendicht Wagner, MD, 47 University Hospital, Berne; Thomas Riedel, MD, Children's Hospital, Chur; Grégoire 48 Kaczala, MD, Cantonal Hospital, Fribourg; Riccardo E. Pfister, MD, University Hospital 49 (HUG), Geneva; Jean-François Tolsa, MD, and Matthias Roth, MD, University Hospital 50 51 (CHUV), Lausanne; Martin Stocker, MD, Children's Hospital, Lucerne; Bernhard Laubscher, 52 MD, Cantonal Hospital, Neuchatel; Andreas Malzacher, MD, Cantonal Hospital, St. Gallen; 53 John P. Micallef, MD, Children's Hospital, St. Gallen; Lukas Hegi, MD, Cantonal Hospital, 54 Winterthur; Dirk Bassler, MD, and Romaine Arlettaz, MD, University Hospital (USZ), 55 Zurich; Vera Bernet, MD, University Children's Hospital, Zurich. 56 57 Tuscan NN (TIN Toscane on-line Network, Italy): Carlo Dani, MD, Careggi University 58 Hospital, Florence, Italy; Patrizio Fiorini, MD, Anna Meyer Children’s University Hospital, 59 Florence, Italy; Paolo Ghirri, MD, University Hospital of Pisa, Pisa, Italy; Barbara Tomasini, 60 MD, University Hospital of Siena, Siena, Italy; Franca Rusconi, MD, Anna Meyer Children’s University Hospital and Regional Health Agency, Florence, Italy.

20 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 71

1 2

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 REFERENCES 5 6 7 8 1 Neu J. Necrotizing Enterocolitis: The Mystery Goes On. Neonatology 2014;106:289–95. 9 doi:10.1159/000365130 10 11 2 Battersby C, Santhalingam T, Costeloe K, et al. Incidence of neonatal necrotising 12 enterocolitis in high-income countries: a systematic review. Archives of Disease in 13 14 Childhood - Fetal and Neonatal Edition 2018;103:F182–9. doi:10.1136/archdischild- 15 2017-313880 16 17 3 Patel RM, Kandefer S, Walsh MC, et al. Causes and Timing of Death in Extremely 18 Premature InfantsFor from 2000peer through review 2011. New England only Journal of Medicine 19 2015;372:331–40. doi:10.1056/NEJMoa1403489 20 21 4 Martin CR, Dammann O, Allred EN, et al. Neurodevelopment of extremely preterm 22 infants who had necrotizing enterocolitis with or without late bacteremia. J Pediatr 23 24 2010;157:751-756.e1. doi:10.1016/j.jpeds.2010.05.042 25 26 5 Schlapbach LJ, Adams M, Proietti E, et al. Outcome at two years of age in a Swiss 27 national cohort of extremely preterm infants born between 2000 and 2008. BMC Pediatr 28 2012;12:198. doi:10.1186/1471-2431-12-198 29 30 6 Hintz SR, Kendrick DE, Stoll BJ, et al. Neurodevelopmental and Growth Outcomes of 31 Extremely Low Birth Weight Infants After Necrotizing Enterocolitis. Pediatrics 32 2005;115:696–703. doi:10.1542/peds.2004-0569 33 34 35 7 McElroy SJ. Unraveling the enigma that is neonatal necrotizing enterocolitis. J Perinatol 36 2014;34:729–30. doi:10.1038/jp.2014.155

37 http://bmjopen.bmj.com/ 38 8 Patel AL, Panagos PG, Silvestri JM. Reducing Incidence of Necrotizing Enterocolitis. 39 Clin Perinatol 2017;44:683–700. doi:10.1016/j.clp.2017.05.004 40 41 9 Jacobs SE, Tobin JM, Opie GF, et al. Probiotic Effects on Late-onset Sepsis in Very 42 Preterm Infants: A Randomized Controlled Trial. Pediatrics 2013;132:1055–62. 43 44 doi:10.1542/peds.2013-1339

45 on September 27, 2021 by guest. Protected copyright. 46 10 Costeloe K, Bowler U, Brocklehurst P, et al. A randomised controlled trial of the 47 probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising 48 enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial. NIHR Journals 49 Library 2016. 50 51 11 O’Connor DL, Gibbins S, Kiss A, et al. Effect of Supplemental Donor Human Milk 52 Compared With Preterm Formula on Neurodevelopment of Very Low-Birth-Weight 53 54 Infants at 18 Months: A Randomized Clinical Trial. JAMA 2016;316:1897–905. 55 doi:10.1001/jama.2016.16144 56 57 12 O’Connor DL, Kiss A, Tomlinson C, et al. Nutrient enrichment of human milk with 58 human and bovine milk–based fortifiers for infants born weighing <1250 g: a randomized 59 clinical trial. Am J Clin Nutr 2018;108:108–16. doi:10.1093/ajcn/nqy067 60

21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 71 BMJ Open

1 2 13 Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent

3 necrotising enterocolitis in very low birth weight infants. In: Cochrane Database of BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Systematic Reviews. John Wiley & Sons, Ltd 2017. 5 doi:10.1002/14651858.CD001241.pub7 6 7 8 14 Beltempo M, Isayama T, Vento M, et al. Respiratory Management of Extremely Preterm 9 Infants: An International Survey. NEO 2018;114:28–36. doi:10.1159/000487987 10 11 15 Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and Management of Surgical 12 Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Prospective Cohort 13 Study. Journal of the American College of Surgeons 2014;218:1148–55. 14 doi:10.1016/j.jamcollsurg.2013.11.015 15 16 17 16 Rich BS, Dolgin SE. Necrotizing Enterocolitis. Pediatrics in Review 2017;38:552–9. 18 doi:10.1542/pir.2017-0002For peer review only 19 20 17 Robinson JR, Rellinger EJ, Hatch LD, et al. Surgical necrotizing enterocolitis. Semin 21 Perinatol 2017;41:70–9. doi:10.1053/j.semperi.2016.09.020 22 23 18 Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic 24 decisions based upon clinical staging. Ann Surg 1978;187:1–7. 25 26 19 Shlomai NO, Deshpande G, Rao S, et al. Probiotics for Preterm Neonates: What Will It 27 28 Take to Change Clinical Practice? NEO 2014;105:64–70. doi:10.1159/000354891 29 30 20 Taylor RS. Probiotics to prevent necrotizing enterocolitis: Too cheap and easy? Paediatr 31 Child Health 2014;19:351–2. 32 33 21 Modi N. Probiotics and Necrotising Enterocolitis: The Devil (as Always) Is in the Detail. 34 Neonatology 2014;105:71–3. doi:10.1159/000354909 35 36 22 Neu J, Walker WA. Necrotizing Enterocolitis. N Engl J Med 2011;364:255–64. 37 doi:10.1056/NEJMra1005408 http://bmjopen.bmj.com/ 38 39 40 23 Thompson AM, Bizzarro MJ. Necrotizing enterocolitis in newborns: pathogenesis, 41 prevention and management. Drugs 2008;68:1227–38. 42 43 24 Gephart SM, McGrath JM, Effken JA, et al. Necrotizing Enterocolitis Risk. Adv Neonatal 44 Care 2012;12:77–89. doi:10.1097/ANC.0b013e31824cee94

45 on September 27, 2021 by guest. Protected copyright. 46 25 Rüegger C, Hegglin M, Adams M, et al. Population based trends in mortality, morbidity 47 and treatment for very preterm- and very low birth weight infants over 12 years. BMC 48 49 Pediatrics 2012;12:17. doi:10.1186/1471-2431-12-17 50 51 26 Horbar JD, Edwards EM, Greenberg LT, et al. Variation in Performance of Neonatal 52 Intensive Care Units in the United States. JAMA Pediatr 2017;171:e164396–e164396. 53 doi:10.1001/jamapediatrics.2016.4396 54 55 27 Ahle M, Drott P, Andersson RE. Epidemiology and Trends of Necrotizing Enterocolitis in 56 Sweden: 1987–2009. Pediatrics 2013;132:e443–51. doi:10.1542/peds.2012-3847 57 58 28 Kastenberg ZJ, Lee HC, Profit J, et al. Effect of Deregionalized Care on Mortality in Very 59 60 Low-Birth-Weight Infants With Necrotizing Enterocolitis. JAMA Pediatr 2015;169:26– 32. doi:10.1001/jamapediatrics.2014.2085

22 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 71

1 2 29 Lin PW, Stoll BJ. Necrotising enterocolitis. The Lancet 2006;368:1271–83.

3 doi:10.1016/S0140-6736(06)69525-1 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 5 30 Lin PW, Nasr TR, Stoll BJ. Necrotizing Enterocolitis: Recent Scientific Advances in 6 Pathophysiology and Prevention. Seminars in Perinatology 2008;32:70–82. 7 8 doi:10.1053/j.semperi.2008.01.004 9 10 31 Patel BK, Shah JS. Necrotizing Enterocolitis in Very Low Birth Weight Infants: A 11 Systemic Review. International Scholarly Research Notices. 2012. 12 doi:10.5402/2012/562594 13 14 32 Eaton S, Rees CM, Hall NJ. Current Research on the Epidemiology, Pathogenesis, and 15 Management of Necrotizing Enterocolitis. NEO 2017;111:423–30. 16 17 doi:10.1159/000458462 18 For peer review only 19 33 Battersby C, Longford N, Costeloe K, et al. Development of a Gestational Age–Specific 20 Case Definition for Neonatal Necrotizing Enterocolitis. JAMA Pediatr Published Online 21 First: 3 January 2017. doi:10.1001/jamapediatrics.2016.3633 22 23 34 Patel RM, Denning PW. Intestinal Microbiota and Its Relationship with Necrotizing 24 Enterocolitis. Pediatr Res 2015;78:232–8. doi:10.1038/pr.2015.97 25 26 35 Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung 27 28 maturation for women at risk of preterm birth. In: The Cochrane Library. John Wiley & 29 Sons, Ltd 2017. doi:10.1002/14651858.CD004454.pub3 30 31 36 Tanner SM, Berryhill TF, Ellenburg JL, et al. Pathogenesis of Necrotizing Enterocolitis: 32 Modeling the Innate Immune Response. The American Journal of Pathology 2015;185:4– 33 16. doi:10.1016/j.ajpath.2014.08.028 34 35 37 Yee WH, Soraisham AS, Shah VS, et al. Incidence and Timing of Presentation of 36 Necrotizing Enterocolitis in Preterm Infants. Pediatrics 2012;129:e298–304. 37 http://bmjopen.bmj.com/ 38 doi:10.1542/peds.2011-2022 39 40 38 Sawh SC, Deshpande S, Jansen S, et al. Prevention of necrotizing enterocolitis with 41 probiotics: a systematic review and meta-analysis. PeerJ 2016;4. doi:10.7717/peerj.2429 42 43 39 Kessler U, Schulte F, Cholewa D, et al. Outcome in neonates with necrotizing 44 enterocolitis and patent ductus arteriosus. World J Pediatr 2015;:1–5. 45 doi:10.1007/s12519-015-0059-6 on September 27, 2021 by guest. Protected copyright. 46 47 48 40 Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in 49 preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 50 2015;2:CD003481. doi:10.1002/14651858.CD003481.pub6 51 52 41 Gordon PV, Swanson JR, MacQueen BC, et al. A critical question for NEC researchers: 53 Can we create a consensus definition of NEC that facilitates research progress? Seminars 54 in Perinatology 2017;41:7–14. doi:10.1053/j.semperi.2016.09.013 55 56 42 Shah PS, Lui K, Sjörs G, et al. Neonatal Outcomes of Very Low Birth Weight and Very 57 58 Preterm Neonates: An International Comparison. The Journal of Pediatrics 59 2016;177:144-152.e6. doi:10.1016/j.jpeds.2016.04.083 60

23 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 71 BMJ Open

1 2 43 Berger ML, Sox H, Willke RJ, et al. Good practices for real‐world data studies of

3 treatment and/or comparative effectiveness: Recommendations from the joint BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 ISPOR‐ISPE Special Task Force on real‐world evidence in health care decision making. 5 Pharmacoepidemiol Drug Saf 2017;26:1033–9. doi:10.1002/pds.4297 6 7 8 44 Kolasa K, Borek E. Patient registries as a new quality measurement and method the 9 assessment of the treatment effectiveness. Przegl Epidemiol 2016;70:653–63. 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

24 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 71

1 2 Figure Legends

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Figure 1: Routine start of enteral feeding for extremely preterm infants 5 6 7 8 Bubble chart displaying routine start of enteral feeding for network infants < 26 weeks’ 9 gestation and 26-28 weeks’ gestation. Circle size corresponds to proportion of units per 10 11 network with routine start of enteral feeding at any given day. 12 13 Abbreviations: PD, physician dependent; GA, gestational age; ANZNN, Australian and New 14 Zealand Neonatal Network,; CNN, Canadian Neonatal Network; FinMBR, Finnish Medical 15 Birth Register; INN, Israel Neonatal Network; SEN1500, Spanish Neonatal Network; SNQ, 16 Swedish Neonatal Quality Register; SwissNeoNet, Swiss Neonatal Network; TuscanNN, 17 Tuscan Neonatal Network; 18 For peer review only 19 20 21 22 23 Figure 2: Necrotizing enterocolitis surgery prevalence rate and 95% confidence interval by 24 network for 2014 – 2015. 25 26 27 28 Abbreviations: ANZNN, Australian and New Zealand Neonatal Network,; CNN, Canadian 29 30 Neonatal Network; FinMBR, Finnish Medical Birth Register; INN, Israel Neonatal Network; 31 SEN1500, Spanish Neonatal Network; SNQ, Swedish Neonatal Quality Register; 32 SwissNeoNet, Swiss Neonatal Network; TuscanNN, Tuscan Neonatal Network; NEC, 33 necrotizing enterocolitis 34 35 36

37 http://bmjopen.bmj.com/ 38 39 Figure 3: Standardized ratios for surgically treated necrotizing enterocolitis from 2014 - 2015 40 41 42 43 Standardized ratios were adjusted for: gestational age, male sex, multiple birth and birth- 44 weight z-score.

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 Abbreviations: ANZNN, Australian and New Zealand Neonatal Network; CNN, Canadian 49 Neonatal Network; FinMBR, Finnish Medical Birth Register; INN, Israel Neonatal Network; 50 SEN1500, Spanish Neonatal Network; SNQ, Swedish Neonatal Quality Register; 51 52 SwissNeoNet, Swiss Neonatal Network; TuscanNN, Tuscan Neonatal Network; SR, 53 standardized ratio 54 55 56 57 58 59 60

25 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 27 of 71 BMJ Open

1 2 3 Tables 4 5 Table 1. Results of survey of NEC prevention practices and unit-level linked outcome analyses 6 7 8 Characteristics ANZNN CNN FinMBR INN SEN1500 SNQ SwissNeoNet TuscanNN All 9 10 Units in network, N 28 30 5 26 57 6 12 4 168 11 12 Units participating in survey, n (%) For27 (96) 29peer (97) 5 (100) review26 (100) 47 (82) only6 (100) 9 (75) 4 (100) 153 (91) 13 14 Results of unit level survey 15 Probiotic provision, n (%) 25 (93) 16 (52) 5 (100) 0 (0) 10 (21) 0 (0) 7 (78) 3 (75) 66 (43) 16 http://bmjopen.bmj.com/ 17 No 0-1 02 - 1-3 - 0 2-3 No Start of probiotics1, day 18 preference3 preference3 19 20 Probiotic species1 L / B L L - L / B - L / B L2 L / B

21 Probiotics 2 2 22 1 No No No - No - Yes No No Stop at sepsis 3 3 23 preference preference 24 < 26 weeks GA1 on September 27, 2021 by guest. Protected copyright. 25 26 Start (day) 0 0-1 02 1 0-1 02 02 1 0-1 27 28 Daily rate of advancement, ml/kg/day 15-20 10-20 15-25 20-25 10-20 15 20 10 10-20 29 1 30 26-28 weeks GA 31 Start (day) 0 0 02 0-1 0 02 02 0 0-1 32 33 Daily rate of advancement, ml/kg/day 15-20 20 25 20-25 20-25 10-25 20 20 20-25 34 Enteral feeding 35 ≤ 28 weeks GA1 36 37 Enteral feed vol. where infants ≥ 120 100-129 100-129 No 80-109 70-89 ≥ 120 80-89 No 1 3 3 38 commonly receive milk fortifier , preference preference ml/kg/day 39 40 41 42 26 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 28 of 71

1 2 3 Available, n (%) 10 (37%) 25 (81%) 5 (100%) 0 (0%) 20 (42%) 6 (100%) 5 (56%) 4 (100%) 74 (48%) 4 5 Initiation criteria1 No No No GA / - <32w / <34w <32w / <32w / No 6 preference3 preference3 BW criteria <1500g <1500g <1500g preference3 7 Stopping criteria1 No No No - No No No 1800g No 8 Donor milk preference3 preference3 preference3 preference3 preference3 preference3 preference3 9 10 11 12 Results of unit-level analyses: effect of probiotics,For feeding peerstart on day 0 and donorreview milk availability on outcome only of NEC surgery 13 0.77 - - - 0.36 NA6 0.84 14 Units providing probiotics vs not 4 15 providing probiotics , OR (95% CI) (0.48, 1.24) (0.14, 0.93) (0.61, 1.16)7 16 http://bmjopen.bmj.com/ 17 Units starting to feed on day 04 vs those 1.13 - 1.63 - - 0.12 1.16 starting after day 0 (95% CI) for <26 18 (0.70, 1.85) (0.86, 3.06) (0.02, 1.02) (0.83, 1.63)7 19 weeks’ GA NA5 NA5 20 Units starting to feed on day 04 vs those 1.78 - 1.31 - - 0.13 1.14 21 starting after day 0 (95% CI) for 26-28 7 22 weeks’ GA (0.76, 4.15) (0.69, 2.48) (0.03, 0.52) (0.74, 1.75) 23 24 Units providing donor milk4 vs. units not 0.78 - - - 0.55 - 0.86 on September 27, 2021 by guest. Protected copyright. 25 providing donor milk OR (95% CI) (0.37, 1.66) (0.21, 1.41) (0.62, 1.20)7 26 27 1Response of ≥ 50% of units. 28 29 2Unanimous response of 100% of units 30 3Units responses were distributed over entire possible range (see online supplement 2 for detailed responses). 31 32 4NEC surgery OR (95% CI) are given for networks with variability in provision of probiotics, feeding start and / or donor milk availability. Adjustment was made for GA, male sex, 33 multiple birth and birth-weight z-score. 34 5 35 OR could not be calculated for AZNN and SEN1500 as permission for linking survey and patient data was not available. 36 6OR for probiotics could not be calculated for TuscanNN as all patients were from the 3 units providing probiotics. 37 38 7OR for all includes those units in countries where all neonates either received or not received intervention. 39 40 41 42 27 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 29 of 71 BMJ Open

1 2 3 Abbreviations: ANZNN, Australian and New Zealand Neonatal Network,; CNN, Canadian Neonatal Network; FinMBR, Finnish Medical Birth 4 Register; INN, Israel Neonatal Network; SEN1500, Spanish Neonatal Network; SNQ, Swedish Neonatal Quality Register; SwissNeoNet, Swiss 5 6 Neonatal Network; TuscanNN, Tuscan Neonatal Network; N, total number in group; n,number in subgroup; L, Lactobacillus; B, Bifidobacterium; 7 NEC, necrotizing enterocolitis; OR, odds ratio; CI, confidence intervals; GA, gestational age; NA, data not available; ml, milliliter; kg, kilogram; BW, 8 birth weight; w, weeks; g, grams 9 10 11 12 For peer review only 13 14 15 16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23 24 on September 27, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 28 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 30 of 71

1 2 3 Table 2: Baseline characteristics, factors associated with NEC in literature and outcomes in neonates 240 – 286 weeks’ gestation between 2014-2015 4 (patient level data) 5 6 7 8 ANZNN CNN FinMBR INN SEN SNQ Swiss Tuscan All 9 1500 NeoNet NN 10 Eligible infants 2926 2994 317 1215 2158 849 645 185 11 289 0 6 11 (24 -28 weeks), N 12 Excluded infants, n 378 580 14 43 260 144 63 15 1497 (%) For(12.9) (19.4) peer(4.4) review(3.5) (12) (17) only(9.8) (8.1) (13.3) 13 14 Study population, N 2548 2414 303 1172 1898 705 582 170 9792 Baseline characteristics 15 Gestational age, mean (sd) 26.4 26.3 26.5 26.4 26.5 26.4 26.4 26.3 26.4 16 (1.4) (1.4) (1.3) (1.4) (1.3) (1.4) (1.4) (1.3)http://bmjopen.bmj.com/ (1.4) 17 Birth weight z-score, mean (sd) 0.03 -0.04 -0.04 -0.01 -0.11 -0.17 -0.22 0.18 -0.05 18 (0.97) (0.86) (0.93) (0.93) (0.99) (0.86) (0.85) (0.99) (0.93) 19 SGA, n (%) 264 220 32 110 243 76 69 15 1029 20 (10.4) (9.1) (10.6) (9.4) (12.8) (10.8) (11.9) (8.8) (10.5) 21 Multiple births, n (%) 691 628 88 419 568 188 171 61 2814 22 (27.1) (26.0) (29.0) (35.8) (29.9) (26.7) (29.4) (35.9) (28.7) 23 Male, n (%) 1385 1241 164 639 1000 404 320 94 5247 24 (54.4) (51.5) (54.1) (54.5) (52.7) (57.3) (55.0) (55.3) on September 27, 2021 by guest. Protected copyright. (53.6) 25 NEC associated factors 26 Antenatal steroid, n (%) 2419 2266 293 972 1761 614 546 156 9049 27 (95.7) (94.7) (97.3) (82.9) (92.9) (87.1) (93.8) (92.3) (92.6) 28 Cesarean, n (%) 1531 1444 202 829 1257 495 481 124 6363 29 (60.3) (60.0) (66.7) (70.7) (66.2) (70.7) (82.7) (72.9) (65.1) 30 PDA treated with indomethacin, n (%) NA 797 77 327 01 01 231 01 1432 31 (33.0) (25.9) (27.9) (0) (0) (39.6) (0) (19.8) 32 Sepsis, n (%) NA 506 57 297 864 165 85 54 2028 33 (21.0) (19.4) (27.5) (46.2) (23.4) (14.6) (36.5) (28.6) 34 Outcomes 35 NEC surgery, n (%) 62 74 14 42 160 18 18 9 397 36 (2.4) (3.1) (4.6) (3.6) (8.4) (2.6) (3.1) (5.3) (4.1) 37 NEC death, n (%) 50 56 6 30 62 10 14 5 233 38 (2.0) (2.3) (2.0) (2.6) (3.3) (1.4) (2.4) (2.9) (2.4) 39 All-cause Mortality, n (%) 280 259 33 254 394 68 91 37 1416 40 (11.0) (10.7) (10.9) (21.7) (20.8) (9.7) (15.6) (21.8) (14.5) 41 42 29 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 31 of 71 BMJ Open

1 2 3 4 5 ANZNN = Australian and New Zealand Neonatal Network, CNN = Canadian Neonatal Network, FinMBR = Finnish Medical Birth Register, INN = 6 Israel Neonatal Network, SEN1500 = Spanish Neonatal Network, SNQ = Swedish Neonatal Quality Register, SwissNeoNet = Swiss Neonatal 7 Network, TuscanNN = Tuscan Neonatal Network; N= total number in group, n=number in subgroup, NEC=necrotizing enterocolitis, sd=standard 8 deviation, PDA=patent ductus arteriosus. NA= data was not available. 1Spain, Sweden, and Tuscany only supplied ibuprofen or paracetamol to treat 9 PDA during the study period. 10 11 12 For peer review only 13 14 15 16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23 24 on September 27, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 30 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 32 of 71 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 Figure 1: Routine start of enteral feeding for extremely preterm infants 24 25 Bubble chart displaying routine start of enteral feeding for network infants < 26 weeks’ gestation and 26-28 26 weeks’ gestation. Circle size corresponds to proportion of units per network with routine start of enteral feeding at any given day. 27 Abbreviations: PD, physician dependent; GA, gestational age; ANZNN, Australian and New Zealand Neonatal 28 Network,; CNN, Canadian Neonatal Network; FinMBR, Finnish Medical Birth Register; INN, Israel Neonatal 29 Network; SEN1500, Spanish Neonatal Network; SNQ, Swedish Neonatal Quality Register; SwissNeoNet, 30 Swiss Neonatal Network; TuscanNN, Tuscan Neonatal Network; 31 32 199x99mm (300 x 300 DPI) 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 27, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 71 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Figure 2: Necrotizing enterocolitis surgery prevalence rate and 95% confidence interval by network for 2014 31 – 2015. 32 Abbreviations: ANZNN, Australian and New Zealand Neonatal Network,; CNN, Canadian Neonatal Network; http://bmjopen.bmj.com/ 33 FinMBR, Finnish Medical Birth Register; INN, Israel Neonatal Network; SEN1500, Spanish Neonatal Network; 34 SNQ, Swedish Neonatal Quality Register; SwissNeoNet, Swiss Neonatal Network; TuscanNN, Tuscan 35 Neonatal Network; NEC, necrotizing enterocolitis. 36 37 38 39 40 41 on September 27, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 71 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 Figure 3: Standardized ratios for surgically treated necrotizing enterocolitis from 2014 - 2015 29 30 Standardized ratios were adjusted for: gestational age, male sex, multiple birth and birth-weight z-score. 31 32 Abbreviations: ANZNN, Australian and New Zealand Neonatal Network; CNN, Canadian Neonatal Network; 33 FinMBR, Finnish Medical Birth Register; INN, Israel Neonatal Network; SEN1500, Spanish Neonatal Network; http://bmjopen.bmj.com/ SNQ, Swedish Neonatal Quality Register; SwissNeoNet, Swiss Neonatal Network; TuscanNN, Tuscan 34 Neonatal Network; SR, standardized ratio. 35 36 37 38 39 40 41 on September 27, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 71 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

1 2 The iNEO Survey (1st half) 3 4 Page 7 of 8 5 6 Feeding practices and Probiotics usage 7 8 9 33. Do you commonly provide probiotics for neonates <29 weeks GA? 10 11 (If your answer for this question is "No", please go directly to question #38) 12 13 Yes 14 No 15 16 For peer review only 17 34. Is this practice Physician dependent? 18 (Please, answer this question if you answer "Yes" for question #33) 19 Yes 20 No 21 22 35. When do you start probiotics? 23 24 (Please, answer this question if you answer "Yes" for question #33) 25 26 Start time (please count the Specify if Others 27 birth day as day 0 ) 28 Probiotics Please Select 29 30 31 36. Which probiotic do you use? (Select all that apply. If you are not sure about the species of probiotics, please select "Others") 32 (Please, answer this question if you answer "Yes" for question #33) 33 http://bmjopen.bmj.com/ 34 Lactobacillus species 35 Bifidobacterium species 36 Saccharomyces boulardii 37 38 Others (Please, specify in comments or give the name of the commercial product) 39 40 37. Do you continue or stop probiotics during episodes of sepsis? 41 (Please, answer this question if you answer "Yes" for question #33) on September 27, 2021 by guest. Protected copyright. 42 We continue it 43 We stop it 44 Physician dependent 45 46 47 38. When do you routinely start enteral feeding for preterm neonates of:

48 Is this practice 49 Please, count the Physician 50 birth day as day 0 dependent? 51 <26 weeks GA Please Select Please Select 52 53 2628 weeks GA? Please Select Please Select 54

55 56 39. What’s your usual daily rate of advancement of enteral feeds after inductions feeds are tolerated? 57 Is this practice Daily rate 58 Physician (ml/kg/day) 59 dependent? 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 71 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from for <26 weeks Please Select Please Select

1 for 2628 weeks Please Select Please Select 2

3 4 40. At what enteral feed volume do infants at <29 weeks GA most commonly receive milk fortifier? 5 6 Is this practice Comments 7 Enteral feed volume Physician 8 (optional) dependent? 9 Milk fortifier 10 Please Select Please Select 11 (ml/kg/day) 12 13 41. Do you have donormilk available (commercial or volunteer setup)? 14 15 (If your answer for this question is "No", please go directly to next page) 16 For peer review only 17 18 Yes 19 No 20 21 42. If donormilk available: 22 (Please, answer this question if you answer "Yes" for question #41) 23 24 Comments 25 GA BW 26 (optional) 27 What are the donor milk 28 initiation criteria? (less Please Select Please Select

29 than certain GA/BW) 30 When do you stop donor 31 milk?(more than certain Please Select Please Select 32 GA/BW) 33 http://bmjopen.bmj.com/ 34 35 36 37 38 Back Next 39 40 41 on September 27, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 37 of 71 BMJ Open Appendix B

1 2 Feeding practices and Probiotics usage 3 4 34. Does your NICU team commonly provide probiotics for neonates <29 weeks GA? 5 6 ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 7 Answer Options 8 # of Responses (n) 27 30 5 26 6 9 47 4 154 9 Yes 25 16 5 0 0 7 10 3 66 10 No 2 14 0 26 6 2 37 1 88 11 12 Answer Options ANZNNFor CNN peerFinMBR INNreview SNQ SNN onlySEN1500 TuscanNN Total 13 # of Responses (n) 27 30 5 26 6 9 47 4 154 14 Yes 92.59% 53.33% 100.00% 0.00% 0.00% 77.78% 21.28% 75.00% 42.86% 15 16 No 7.41% 46.67% 0.00% 100.00% 100.00% 22.22% 78.72% 25.00% 57.14% 17 18 35. Is this practice Physician dependent? http://bmjopen.bmj.com/ 19 20 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 21 # of Responses (n) 27 21 5 7 1 7 26 4 98 22 Yes 0 2 0 0 0 0 0 1 3 23 No 27 19 5 7 1 7 26 3 95 24 25 26 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN on September 27, 2021 by guest. Protected copyright. Total 27 # of Responses (n) 27 21 5 7 1 7 26 4 98 28 Yes 0.00% 9.52% 0.00% 0.00% 0.00% 0.00% 0.00% 25.00% 3.06% 29 No 100.00% 90.48% 100.00% 100.00% 100.00% 100.00% 100.00% 75.00% 96.94% 30 31 36. When does your NICU team start probiotics? 32 33 34 Start time ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 35 # of Responses (n) 25 16 5 1 0 6 10 3 66 36 0 day after birth 2 4 5 0 0 4 0 0 15 37 1 day after birth 5 5 0 0 0 1 1 0 12 38 2 days after birth 5 0 0 0 0 0 5 1 11 39 3 days after birth 1 0 0 0 0 1 1 1 4 40 4 days after birth 0 0 0 0 0 0 0 0 0 41 1 42 5 days after birth 0 0 0 0 0 0 0 1 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 1 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 38 of 71 Appendix B

1 2 6 days after birth 1 0 0 0 0 0 0 0 1 3 7 days after birth 1 0 0 0 0 0 0 0 1 4 14 days after birth 0 0 0 0 0 0 0 0 0 5 6 After infant reaches full feeds 0 2 0 0 0 0 0 0 2 7 Others 10 5 0 1 0 0 3 0 19 8 9 ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 10 Start time 11 # of Responses (n) 25 16 5 1 0 6 10 3 66 12 0 day after birth 8.00%For25.00% peer100.00% 0.00%review0.00% 66.67% only0.00% 0.00% 22.73% 13 1 day after birth 20.00% 31.25% 0.00% 0.00% 0.00% 16.67% 10.00% 0.00% 18.18% 14 2 days after birth 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 50.00% 33.33% 16.67% 15 3 days after birth 4.00% 0.00% 0.00% 0.00% 0.00% 16.67% 10.00% 33.33% 6.06% 16 4 days after birth 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 5 days after birth 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33.33% 1.52% 18 http://bmjopen.bmj.com/ 6 days after birth 4.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.52% 19 20 7 days after birth 4.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.52% 21 14 days after birth 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 22 After infant reaches full feeds 0.00% 12.50% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 3.03% 23 Others 40.00% 31.25% 0.00% 100.00% 0.00% 0.00% 30.00% 0.00% 28.79% 24 25 37. Which probiotic does your NICU team use? 26 on September 27, 2021 by guest. Protected copyright. 27 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 28 29 # of Responses (n) 28 31 5 26 6 11 50 4 161 30 Lactobacillus species 14 9 4 0 0 7 8 3 45 31 Bifidobacterium species 19 7 1 0 0 6 5 0 38 32 Saccharomyces boulardii 0 0 0 0 0 0 0 0 0 33 Others 3 8 1 0 0 0 2 0 14 34 35 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 36 # of Responses (n) 28 31 5 26 6 11 50 4 161 37 38 Lactobacillus species 50.00% 29.03% 80.00% 0.00% 0.00% 63.64% 16.00% 75.00% 27.95% 39 Bifidobacterium species 67.86% 22.58% 20.00% 0.00% 0.00% 54.55% 10.00% 0.00% 23.60% 40 Saccharomyces boulardii 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 41 Others 10.71% 25.81% 20.00% 0.00% 0.00% 0.00% 4.00% 0.00% 8.70% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 2 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 39 of 71 BMJ Open Appendix B

1 2 38. Does your NICU team continue or stop probiotics during episodes of sepsis? 3 4 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 5 # of Responses (n) 24 18 5 1 0 7 10 3 68 6 We continue it 15 5 5 0 0 3 3 3 34 7 We stop it 3 5 0 1 0 4 4 0 17 8 Physician dependent 6 8 0 0 0 0 3 0 17 9 10 11 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 12 # of Responses (n) For24 18peer5 review1 0 only7 10 3 68 13 We continue it 62.50% 27.78% 100.00% 0.00% 0.00% 42.86% 30.00% 100.00% 50.00% 14 We stop it 12.50% 27.78% 0.00% 100.00% 0.00% 57.14% 40.00% 0.00% 25.00% 15 Physician dependent 25.00% 44.44% 0.00% 0.00% 0.00% 0.00% 30.00% 0.00% 25.00% 16 17

39. When does your NICU team routinely start enteral feeding for preterm neonates of: http://bmjopen.bmj.com/ 18 19 20 <26 weeks GA ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 21 # of Responses (n) 14 14 5 9 6 9 13 1 71 22 Yes, Physician 23 12 24 Dependent 2 3 0 1 0 1 4 1 25 No, Physician 26 dependent 10 10 4 6 6 8 7 on September 27, 2021 by guest. Protected copyright. 0 51 27 Blank, Physician 28 0 day after 8 29 birth dependent 2 1 1 2 0 0 2 0 30 # of Responses (n) 8 12 0 14 0 0 23 2 59 31 Yes, Physician 32 Dependent 1 5 0 5 0 0 10 0 21 33 34 No, Physician 35 dependent 6 6 0 9 0 0 8 2 31 36 Blank, Physician 37 1 day after dependent 7 38 birth 1 1 0 0 0 0 5 0 39 # of Responses (n) 2 3 0 1 0 0 3 0 9 40 Yes, Physician 41 Dependent 1 2 0 1 0 0 2 0 6 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 3 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 40 of 71 Appendix B

1 2 No, Physician 3 dependent 1 1 0 0 0 0 0 0 2 4 5 2 days after Blank, Physician 6 birth dependent 0 0 0 0 0 0 1 0 1 7 # of Responses (n) 2 0 0 1 0 0 4 0 7 8 Yes, Physician 9 6 10 Dependent 2 0 0 1 0 0 3 0 11 No, Physician 12 dependent For0 0peer 0 review 0 0 only 0 1 0 1 13 Blank, Physician 14 3 days after 0 15 birth dependent 0 0 0 0 0 0 0 0 16 # of Responses (n) 0 0 0 0 0 0 0 1 1 17

Yes, Physician http://bmjopen.bmj.com/ 18 19 Dependent 0 0 0 0 0 0 0 0 0 20 No, Physician 21 dependent 0 0 0 0 0 0 0 0 0 22 23 4 days after Blank, Physician 24 birth dependent 0 0 0 0 0 0 0 1 1 25 # of Responses (n) 0 0 0 0 0 0 1 0 1 26 on September 27, 2021 by guest. Protected copyright. 27 Yes, Physician 28 Dependent 0 0 0 0 0 0 1 0 1 29 No, Physician 30 dependent 0 0 0 0 0 0 0 0 0 31 32 5 days after Blank, Physician 33 birth dependent 0 0 0 0 0 0 0 0 0 34 # of Responses (n) 0 0 0 1 0 0 0 0 1 35 Yes, Physician 36 Dependent 0 0 0 0 0 0 0 0 0 37 38 No, Physician 39 dependent 0 0 0 1 0 0 0 0 1 40 7 days after Blank, Physician 41 birth dependent 0 0 0 0 0 0 0 0 0 42 # of Responses (n) 1 0 0 0 0 0 1 0 2 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 4 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 41 of 71 BMJ Open Appendix B

1 2 Yes, Physician 3 Dependent 1 0 0 0 0 0 1 0 2 4 No, Physician 5 dependent 0 0 0 0 0 0 0 0 0 6 Physician Blank, Physician 7 dependent 0 8 Dependent 0 0 0 0 0 0 0 0 9 26-28 weeks GA 10 # of Responses (n) 18 19 5 12 6 9 25 2 96 11 Yes, Physician 12 Dependent For3 3peer 0 review 2 0 only 1 7 1 17 13 No, Physician 14 66 15 dependent 13 15 4 8 6 8 11 1 16 0 day after Blank, Physician 17 birth dependent 2 1 1 2 0 0 7 0 13 http://bmjopen.bmj.com/ 18 # of Responses (n) 7 10 0 12 0 0 20 1 50 19 Yes, Physician 20 21 21 Dependent 2 3 0 5 0 0 11 0 22 No, Physician 23 dependent 4 6 0 6 0 0 7 1 24 24 1 day after Blank, Physician 25 birth dependent 1 1 0 1 0 0 2 0 5 on September 27, 2021 by guest. Protected copyright. 26 # of Responses (n) 2 0 0 1 0 0 3 1 7 27 28 Yes, Physician 29 Dependent 2 0 0 1 0 0 2 0 5 30 No, Physician 31 dependent 0 0 0 0 0 0 1 0 1 32 2 days after Blank, Physician 33 birth dependent 0 0 0 0 0 0 0 1 1 34 # of Responses (n) 0 0 0 0 0 0 0 0 0 35 Yes, Physician 36 37 Dependent 0 0 0 0 0 0 0 0 0 38 No, Physician 39 dependent 0 0 0 0 0 0 0 0 0 40 3 days after Blank, Physician 41 birth dependent 0 0 0 0 0 0 0 0 0 42 # of Responses (n) 0 0 0 1 0 0 0 0 1 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 5 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 42 of 71 Appendix B

1 2 Yes, Physician 3 Dependent 0 0 0 0 0 0 0 0 0 4 5 No, Physician 6 dependent 0 0 0 1 0 0 0 0 1 7 4 days after Blank, Physician 8 birth dependent 0 0 0 0 0 0 0 0 0 9 # of Responses (n) 0 0 0 0 0 0 0 0 0 10 Yes, Physician 11 0 12 Dependent 0 0 0 0 0 0 0 0 No, Physician For peer review only 13 14 dependent 0 0 0 0 0 0 0 0 0 15 5 days after Blank, Physician 16 birth dependent 0 0 0 0 0 0 0 0 0 17 # of Responses (n) 0 0 0 0 0 0 0 0 0 18 http://bmjopen.bmj.com/ 19 Yes, Physician 20 Dependent 0 0 0 0 0 0 0 0 0 21 No, Physician 22 dependent 0 0 0 0 0 0 0 0 0 23 Blank, Physician 24 7 days after dependent 0 25 birth 0 0 0 0 0 0 0 0 26 # of Responses (n) 0 0 0 0 0 0 0 on September 27, 2021 by guest. Protected copyright. 0 0 27 Yes, Physician 28 Dependent 0 0 0 0 0 0 0 0 0 29 No, Physician 30 31 dependent 0 0 0 0 0 0 0 0 0 32 Physician Blank, Physician 33 Dependent dependent 0 0 0 0 0 0 0 0 0 34 35 <26 weeks GA ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 36 37 Total # of Responses (n) 27 29 5 26 6 9 45 4 151 38 Yes, Physician 39 Dependent 7.41% 10.34% 0.00% 3.85% 0.00% 11.11% 8.89% 25.00% 7.95% 40 No, Physician 41 dependent 37.04% 34.48% 80.00% 23.08% 100.00% 88.89% 15.56% 0.00% 33.77% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 6 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 43 of 71 BMJ Open Appendix B

1 2 0 day after Blank, Physician 3 birth dependent 7.41% 3.45% 20.00% 7.69% 0.00% 0.00% 4.44% 0.00% 5.30% 4 Yes, Physician 5 Dependent 3.70% 17.24% 0.00% 19.23% 0.00% 0.00% 22.22% 0.00% 13.91% 6 7 No, Physician 8 dependent 22.22% 20.69% 0.00% 34.62% 0.00% 0.00% 17.78% 50.00% 20.53% 9 1 day after Blank, Physician 10 birth dependent 3.70% 3.45% 0.00% 0.00% 0.00% 0.00% 11.11% 0.00% 4.64% 11 Yes, Physician 12 Dependent 3.70%For 6.90% peer 0.00% 3.85%review 0.00% 0.00% only 4.44% 0.00% 3.97% 13 14 No, Physician 15 dependent 3.70% 3.45% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.32% 16 2 days after Blank, Physician 17 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.22% 0.00% 0.66% 18 http://bmjopen.bmj.com/ 19 Yes, Physician 20 Dependent 7.41% 0.00% 0.00% 3.85% 0.00% 0.00% 6.67% 0.00% 3.97% 21 No, Physician 22 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.22% 0.00% 0.66% 23 3 days after Blank, Physician 24 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 26 Yes, Physician on September 27, 2021 by guest. Protected copyright. 27 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 No, Physician 29 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 Blank, Physician 31 4 days after dependent 32 birth 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25.00% 0.66% 33 Yes, Physician 34 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.22% 0.00% 0.66% 35 No, Physician 36 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 37 Blank, Physician 38 5 days after 39 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 40 Yes, Physician 41 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 7 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 44 of 71 Appendix B

1 2 No, Physician 3 dependent 0.00% 0.00% 0.00% 3.85% 0.00% 0.00% 0.00% 0.00% 0.66% 4 7 days after Blank, Physician 5 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 6 7 Yes, Physician 8 Dependent 3.70% 0.00% 0.00% 0.00% 0.00% 0.00% 2.22% 0.00% 1.32% 9 No, Physician 10 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 11 Physician Blank, Physician 12 Dependent dependent 0.00%For 0.00% peer 0.00% 0.00%review 0.00% 0.00% only 0.00% 0.00% 0.00% 13 14 26-28 weeks GA 15 Total # of Responses (n) 27 29 5 26 6 9 48 4 154 16 Yes, Physician 17 Dependent 11.11% 10.34% 0.00% 7.69% 0.00% 11.11% 14.58% 25.00% 11.04% http://bmjopen.bmj.com/ 18 No, Physician 19 dependent 48.15% 51.72% 80.00% 30.77% 100.00% 88.89% 22.92% 25.00% 42.86% 20 21 0 day after Blank, Physician 22 birth dependent 7.41% 3.45% 20.00% 7.69% 0.00% 0.00% 14.58% 0.00% 8.44% 23 Yes, Physician 24 Dependent 7.41% 10.34% 0.00% 19.23% 0.00% 0.00% 22.92% 0.00% 13.64% 25 No, Physician on September 27, 2021 by guest. Protected copyright. 26 dependent 14.81% 20.69% 0.00% 23.08% 0.00% 0.00% 14.58% 25.00% 15.58% 27 28 29 1 day after Blank, Physician 30 birth dependent 3.70% 3.45% 0.00% 3.85% 0.00% 0.00% 4.17% 0.00% 3.25% 31 32 Yes, Physician 33 Dependent 7.41% 0.00% 0.00% 3.85% 0.00% 0.00% 4.17% 0.00% 3.25% 34 No, Physician 35 36 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 0.65% 37 38 2 days after Blank, Physician 39 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25.00% 0.65% 40 Yes, Physician 41 42 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 8 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 45 of 71 BMJ Open Appendix B

1 2 3 No, Physician 4 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 3 days after Blank, Physician 6 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 Yes, Physician 8 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 10 No, Physician 11 dependent 0.00% 0.00% 0.00% 3.85% 0.00% 0.00% 0.00% 0.00% 0.65% 12 4 days after Blank, Physician For peer review only 13 dependent 14 birth 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 15 Yes, Physician 16 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 No, Physician 18 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00%http://bmjopen.bmj.com/ 0.00% 19 5 days after Blank, Physician 20 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 21 birth 22 Yes, Physician 23 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 24 No, Physician 25 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 26 7 days after Blank, Physician on September 27, 2021 by guest. Protected copyright. 27 birth dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 Yes, Physician 29 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 31 No, Physician 32 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 Physician Blank, Physician 34 Dependent dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 35 36 40. What is the usual daily rate of advancement of enteral feeds after inductions feeds are tolerated in your NICU? 37 38 for <26 weeks ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 39 40 # of Responses (n) 2 1 1 2 0 0 4 0 10 41 Yes, Physician 42 Dependent 1 1 0 1 0 0 3 0 6 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 9 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 46 of 71 Appendix B

1 2 No, Physician 3 dependent 1 0 0 0 0 0 0 0 1 4 5 Blank, Physician 6 5 ml/kg/day dependent 0 0 1 1 0 0 1 0 3 7 34 8 # of Responses (n) 4 12 0 2 2 2 10 2 9 Yes, Physician 10 Dependent 2 4 0 0 2 1 5 1 15 11 No, Physician 12 dependent For1 7peer 0 review 2 0 only 1 4 0 15 13 Blank, Physician 14 10 dependent 4 15 ml/kg/day 1 1 0 0 0 0 1 1 16 # of Responses (n) 8 5 1 3 3 2 4 1 27 17 Yes, Physician 18 Dependent 6 0 1 2 1 0 1 http://bmjopen.bmj.com/ 0 11 19 No, Physician 20 dependent 2 3 0 1 2 2 1 1 12 21 22 15 Blank, Physician 23 ml/kg/day dependent 0 2 0 0 0 0 2 0 4 24 # of Responses (n) 10 8 1 12 0 5 22 0 58 25 Yes, Physician 26 Dependent 3 1 0 3 0 0 5 on September 27, 2021 by guest. Protected copyright. 0 12 27 No, Physician 28 29 dependent 6 7 1 7 0 4 16 0 41 30 20 Blank, Physician 31 ml/kg/day dependent 1 0 0 2 0 1 1 0 5 32 # of Responses (n) 2 2 2 5 0 0 4 0 15 33 Yes, Physician 34 Dependent 0 1 1 3 0 0 1 0 6 35 No, Physician 36 9 37 dependent 2 1 1 2 0 0 3 0 38 25 Blank, Physician 39 ml/kg/day dependent 0 0 0 0 0 0 0 0 0 40 # of Responses (n) 1 3 0 2 1 0 1 1 9 41 Yes, Physician 42 Dependent 0 1 0 1 0 0 1 0 3 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 10 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 47 of 71 BMJ Open Appendix B

1 2 No, Physician 3 dependent 1 0 0 1 1 0 0 1 4 4 Blank, Physician 5 No standard dependent 0 2 0 0 0 0 0 0 2 6 for 26-28 weeks 0 7 # of Responses (n) 0 0 0 2 0 0 1 0 3 8 9 Yes, Physician 10 Dependent 0 0 0 2 0 0 0 0 2 11 No, Physician 12 dependent For0 0peer 0 review 0 0 only 0 0 0 0 13 Blank, Physician 14 1 15 5 ml/kg/day dependent 0 0 0 0 0 0 1 0 16 # of Responses (n) 3 3 1 2 1 0 8 1 19 17 Yes, Physician 18 Dependent 2 1 0 0 1 0 5 http://bmjopen.bmj.com/ 1 10 19 No, Physician 20 dependent 1 2 0 1 0 0 3 0 7 21 22 10 Blank, Physician 23 ml/kg/day dependent 0 0 1 1 0 0 0 0 2 24 # of Responses (n) 8 5 0 1 1 2 4 0 21 25 Yes, Physician 26 Dependent 5 1 0 0 0 1 1 on September 27, 2021 by guest. Protected copyright. 0 8 27 28 No, Physician 29 dependent 2 2 0 1 0 1 2 0 8 30 15 Blank, Physician 31 ml/kg/day dependent 1 2 0 0 1 0 1 0 5 32 # of Responses (n) 9 19 1 14 2 7 19 2 73 33 34 Yes, Physician 35 Dependent 4 4 1 2 1 1 6 0 19 36 No, Physician 37 dependent 4 14 0 10 1 5 10 1 45 38 20 Blank, Physician 39 ml/kg/day dependent 1 1 0 2 0 1 3 1 9 40 # of Responses (n) 6 2 3 6 1 0 15 0 33 41 Yes, Physician 42 Dependent 1 1 2 4 1 0 3 0 12 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 11 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 48 of 71 Appendix B

1 2 No, Physician 3 dependent 5 1 1 2 0 0 11 0 20 4 25 Blank, Physician 5 ml/kg/day dependent 0 0 0 0 0 0 1 0 1 6 # of Responses (n) 1 2 0 1 1 0 1 1 7 7 8 Yes, Physician 9 Dependent 0 0 0 0 0 0 1 0 1 10 No, Physician 11 dependent 1 0 0 1 1 0 0 1 4 12 Blank, Physician For peer review only 13 No standard dependent 0 2 0 0 0 0 0 0 2 14 15 16 for <26 weeks ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 17 Total # of Responses (n) 27 31 5 26 6 9 45 4 153 18 Yes, Physician http://bmjopen.bmj.com/ 19 Dependent 3.70% 3.23% 0.00% 3.85% 0.00% 0.00% 6.67% 0.00% 3.92% 20 No, Physician 21 dependent 3.70% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.65% 22 Blank, Physician 23 24 5 ml/kg/day dependent 0.00% 0.00% 20.00% 3.85% 0.00% 0.00% 2.22% 0.00% 1.96% 25 Yes, Physician 26 Dependent 7.41% 12.90% 0.00% 0.00% 33.33% 11.11% 11.11% 25.00% on September 27, 2021 by guest. Protected copyright. 9.80% 27 No, Physician 28 dependent 3.70% 22.58% 0.00% 7.69% 0.00% 11.11% 8.89% 0.00% 9.80% 29 10 Blank, Physician 30 dependent 3.70% 3.23% 0.00% 0.00% 0.00% 0.00% 2.22% 25.00% 2.61% 31 ml/kg/day 32 Yes, Physician 33 Dependent 22.22% 0.00% 20.00% 7.69% 16.67% 0.00% 2.22% 0.00% 7.19% 34 No, Physician 35 dependent 7.41% 9.68% 0.00% 3.85% 33.33% 22.22% 2.22% 25.00% 7.84% 36 15 Blank, Physician 37 dependent 38 ml/kg/day 0.00% 6.45% 0.00% 0.00% 0.00% 0.00% 4.44% 0.00% 2.61% 39 Yes, Physician 40 Dependent 11.11% 3.23% 0.00% 11.54% 0.00% 0.00% 11.11% 0.00% 7.84% 41 No, Physician 42 dependent 22.22% 22.58% 20.00% 26.92% 0.00% 44.44% 35.56% 0.00% 26.80% 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 12 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 49 of 71 BMJ Open Appendix B

1 2 20 Blank, Physician 3 ml/kg/day dependent 3.70% 0.00% 0.00% 7.69% 0.00% 11.11% 2.22% 0.00% 3.27% 4 Yes, Physician 5 Dependent 0.00% 3.23% 20.00% 11.54% 0.00% 0.00% 2.22% 0.00% 3.92% 6 7 No, Physician 8 dependent 7.41% 3.23% 20.00% 7.69% 0.00% 0.00% 6.67% 0.00% 5.88% 9 25 Blank, Physician 10 ml/kg/day dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 11 Yes, Physician 12 Dependent 0.00%For 3.23% peer 0.00% 3.85%review 0.00% 0.00% only 2.22% 0.00% 1.96% 13 14 No, Physician 15 dependent 3.70% 0.00% 0.00% 3.85% 16.67% 0.00% 0.00% 25.00% 2.61% 16 Blank, Physician 17 No standard dependent 0.00% 6.45% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.31% 18 http://bmjopen.bmj.com/ for 26-28 weeks 19 20 Total # of Responses (n) 27 31 5 26 6 9 48 4 156 21 Yes, Physician 22 Dependent 0.00% 0.00% 0.00% 7.69% 0.00% 0.00% 0.00% 0.00% 1.28% 23 No, Physician 24 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 26 Blank, Physician on September 27, 2021 by guest. Protected copyright. 27 5 ml/kg/day dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 0.64% 28 Yes, Physician 29 Dependent 7.41% 3.23% 0.00% 0.00% 16.67% 0.00% 10.42% 25.00% 6.41% 30 No, Physician 31 dependent 3.70% 6.45% 0.00% 3.85% 0.00% 0.00% 6.25% 0.00% 4.49% 32 33 10 Blank, Physician 34 ml/kg/day dependent 0.00% 0.00% 20.00% 3.85% 0.00% 0.00% 0.00% 0.00% 1.28% 35 Yes, Physician 36 Dependent 18.52% 3.23% 0.00% 0.00% 0.00% 11.11% 2.08% 0.00% 5.13% 37 No, Physician 38 dependent 7.41% 6.45% 0.00% 3.85% 0.00% 11.11% 4.17% 0.00% 5.13% 39 40 15 Blank, Physician 41 ml/kg/day dependent 3.70% 6.45% 0.00% 0.00% 16.67% 0.00% 2.08% 0.00% 3.21% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 13 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 50 of 71 Appendix B

1 2 Yes, Physician 3 Dependent 14.81% 12.90% 20.00% 7.69% 16.67% 11.11% 12.50% 0.00% 12.18% 4 No, Physician 5 dependent 14.81% 45.16% 0.00% 38.46% 16.67% 55.56% 20.83% 25.00% 28.85% 6 Blank, Physician 7 20 8 ml/kg/day dependent 3.70% 3.23% 0.00% 7.69% 0.00% 11.11% 6.25% 25.00% 5.77% 9 Yes, Physician 10 Dependent 3.70% 3.23% 40.00% 15.38% 16.67% 0.00% 6.25% 0.00% 7.69% 11 No, Physician 12 dependent 18.52%For 3.23% peer 20.00% 7.69%review 0.00% 0.00% only 22.92% 0.00% 12.82% 13 25 Blank, Physician 14 dependent 15 ml/kg/day 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 0.64% 16 Yes, Physician 17 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 0.64% http://bmjopen.bmj.com/ 18 No, Physician 19 dependent 3.70% 0.00% 0.00% 3.85% 16.67% 0.00% 0.00% 25.00% 2.56% 20 21 Blank, Physician 22 No standard dependent 0.00% 6.45% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.28% 23 24 41. At what enteral feed volume do infants at <29 weeks GA most commonly receive milk fortifier? 25 26 on September 27, 2021 by guest. Protected copyright. 27 28 Enteral Feed Volume of Milk 29 Fortifier (ml/kg/day) ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 30 # of Responses (n) 1 1 0 6 0 0 0 0 8 31 Yes, Physician 32 33 Dependent 0 0 0 1 0 0 0 0 1 34 No, Physician 35 dependent 1 1 0 3 0 0 0 0 5 36 37 Blank, Physician 38 2 39 <60 dependent 0 0 0 2 0 0 0 0 40 # of Responses (n) 0 1 0 1 0 0 1 0 3 41 Yes, Physician 42 Dependent 0 1 0 1 0 0 1 0 3 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 14 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 51 of 71 BMJ Open Appendix B

1 2 No, Physician 3 dependent 0 0 0 0 0 0 0 0 0 4 Blank, Physician 5 dependent 0 6 60-69 0 0 0 0 0 0 0 0 7 # of Responses (n) 0 1 0 1 2 0 1 0 5 8 Yes, Physician 9 Dependent 0 0 0 0 1 0 0 0 1 10 No, Physician 11 dependent 0 1 0 1 1 0 1 0 4 12 For peer review only 13 Blank, Physician 14 70-79 dependent 0 0 0 0 0 0 0 0 0 15 # of Responses (n) 0 1 0 3 1 0 10 2 17 16 Yes, Physician 17 Dependent 0 0 0 0 0 0 2 0 2 18 http://bmjopen.bmj.com/ 19 No, Physician 20 dependent 0 0 0 3 1 0 8 2 14 21 Blank, Physician 22 80-89 dependent 0 1 0 0 0 0 0 0 1 23 # of Responses (n) 2 2 0 4 0 0 4 0 12 24 Yes, Physician 25

Dependent 1 0 0 2 0 0 3 on September 27, 2021 by guest. Protected copyright. 0 6 26 27 No, Physician 28 dependent 0 1 0 2 0 0 0 0 3 29 Blank, Physician 30 90-99 dependent 1 1 0 0 0 0 1 0 3 31 # of Responses (n) 2 13 1 7 0 4 18 0 45 32 33 Yes, Physician 34 Dependent 1 5 0 0 0 0 4 0 10 35 No, Physician 36 dependent 1 8 1 7 0 4 13 0 34 37 Blank, Physician 38 dependent 0 0 0 0 0 0 1 0 1 39 100-109 40 # of Responses (n) 0 1 1 1 0 0 2 0 5 41 Yes, Physician 42 Dependent 0 0 1 0 0 0 0 0 1 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 15 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 52 of 71 Appendix B

1 2 No, Physician 3 dependent 0 1 0 1 0 0 2 0 4 4 Blank, Physician 5 dependent 0 6 110-119 0 0 0 0 0 0 0 0 7 # of Responses (n) 6 7 2 0 1 2 3 0 21 8 Yes, Physician 9 Dependent 2 2 1 0 1 0 1 0 7 10 11 No, Physician 12 dependent For3 5peer 1 review 0 0 only 2 2 0 13 13 14 Blank, Physician 15 120-129 dependent 1 0 0 0 0 0 0 0 1 16 # of Responses (n) 12 3 1 1 0 3 4 0 24 17 Yes, Physician 18 http://bmjopen.bmj.com/ Dependent 4 1 0 0 0 0 2 0 7 19 20 No, Physician 21 dependent 7 1 1 1 0 3 2 0 15 22 Blank, Physician 23 >=130 dependent 1 1 0 0 0 0 0 0 2 24 # of Responses (n) 1 0 0 0 0 0 1 0 2 25 26 Yes, Physician on September 27, 2021 by guest. Protected copyright. 27 Dependent 1 0 0 0 0 0 0 0 1 28 No, Physician 29 dependent 0 0 0 0 0 0 1 0 1 30 Fortifier is Blank, Physician 31 not used dependent 0 0 0 0 0 0 0 0 0 32 # of Responses (n) 3 1 0 1 2 0 4 2 13 33 34 35 Yes, Physician 36 Dependent 2 0 0 0 0 0 3 1 6 37 No, Physician 38 dependent 0 1 0 1 1 0 0 1 4 39 Not based 40 on enteral Blank, Physician 41 feed volume dependent 1 0 0 0 1 0 1 0 3 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 16 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 53 of 71 BMJ Open Appendix B

1 2 Enteral Feed Volume of Milk 3 Fortifier (ml/kg/day) ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 4 Total # of Responses (n) 27 31 5 25 6 9 48 4 155 5 6 Yes, Physician 7 Dependent 0.00% 0.00% 0.00% 4.00% 0.00% 0.00% 0.00% 0.00% 0.65% 8 No, Physician 9 dependent 3.70% 3.23% 0.00% 12.00% 0.00% 0.00% 0.00% 0.00% 3.23% 10 Blank, Physician 11 dependent 12 <60 0.00% 0.00% 0.00% 8.00% 0.00% 0.00% 0.00% 0.00% 1.29% Yes, Physician For peer review only 13 14 Dependent 0.00% 3.23% 0.00% 4.00% 0.00% 0.00% 2.08% 0.00% 1.94% 15 No, Physician 16 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 Blank, Physician 18 http://bmjopen.bmj.com/ dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 60-69 20 Yes, Physician 21 Dependent 0.00% 0.00% 0.00% 0.00% 16.67% 0.00% 0.00% 0.00% 0.65% 22 No, Physician 23 dependent 0.00% 3.23% 0.00% 4.00% 16.67% 0.00% 2.08% 0.00% 2.58% 24 Blank, Physician 25

dependent on September 27, 2021 by guest. Protected copyright. 26 70-79 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 27 Yes, Physician 28 Dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4.17% 0.00% 1.29% 29 No, Physician 30 31 dependent 0.00% 0.00% 0.00% 12.00% 16.67% 0.00% 16.67% 50.00% 9.03% 32 Blank, Physician 33 80-89 dependent 0.00% 3.23% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.65% 34 Yes, Physician 35 36 Dependent 3.70% 0.00% 0.00% 8.00% 0.00% 0.00% 6.25% 0.00% 3.87% 37 No, Physician 38 dependent 0.00% 3.23% 0.00% 8.00% 0.00% 0.00% 0.00% 0.00% 1.94% 39 40 Blank, Physician 41 90-99 dependent 3.70% 3.23% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 1.94% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 17 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 54 of 71 Appendix B

1 2 Yes, Physician 3 Dependent 3.70% 16.13% 0.00% 0.00% 0.00% 0.00% 8.33% 0.00% 6.45% 4 No, Physician 5 dependent 3.70% 25.81% 20.00% 28.00% 0.00% 44.44% 27.08% 0.00% 21.94% 6 7 Blank, Physician 8 100-109 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 0.65% 9 10 Yes, Physician 11 Dependent 0.00% 0.00% 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.65% 12 No, Physician For peer review only 13 dependent 0.00% 3.23% 0.00% 4.00% 0.00% 0.00% 4.17% 0.00% 2.58% 14 15 Blank, Physician 16 110-119 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 Yes, Physician 18 http://bmjopen.bmj.com/ Dependent 7.41% 6.45% 20.00% 0.00% 16.67% 0.00% 2.08% 0.00% 4.52% 19 20 No, Physician 21 dependent 11.11% 16.13% 20.00% 0.00% 0.00% 22.22% 4.17% 0.00% 8.39% 22 Blank, Physician 23 24 120-129 dependent 3.70% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.65% 25 Yes, Physician 26 Dependent 14.81% 3.23% 0.00% 0.00% 0.00% 0.00% 4.17% 0.00% on September 27, 2021 by guest. Protected copyright. 4.52% 27 No, Physician 28 29 dependent 25.93% 3.23% 20.00% 4.00% 0.00% 33.33% 4.17% 0.00% 9.68% 30 Blank, Physician 31 >=130 dependent 3.70% 3.23% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.29% 32 Yes, Physician 33 Dependent 3.70% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.65% 34 No, Physician 35 36 dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.08% 0.00% 0.65% 37 Fortifier is Blank, Physician 38 not used dependent 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 39 Yes, Physician 40 Dependent 7.41% 0.00% 0.00% 0.00% 0.00% 0.00% 6.25% 25.00% 3.87% 41 No, Physician 42 dependent 0.00% 3.23% 0.00% 4.00% 16.67% 0.00% 0.00% 25.00% 2.58% 43 Not based 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 18 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 55 of 71 BMJ Open Appendix B

1 Not based 2 on enteral Blank, Physician 3 feed volume dependent 3.70% 0.00% 0.00% 0.00% 16.67% 0.00% 2.08% 0.00% 1.94% 4 5 42. Does your NICU have donor-milk available (commercial or volunteer setup)? 6 7 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 8 9 # of Responses (n) 27 31 4 26 6 9 48 4 155 10 Yes 10 25 4 0 6 5 20 4 74 11 No 17 6 0 26 0 4 28 0 81 12 For peer review only 13 Answer Options ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 14 # of Responses (n) 27 31 4 26 6 9 48 4 155 15 Yes 37.04% 80.65% 100.00% 0.00% 100.00% 55.56% 41.67% 100.00% 47.74% 16 17 No 62.96% 19.35% 0.00% 100.00% 0.00% 44.44% 58.33% 0.00% 52.26% 18 http://bmjopen.bmj.com/ 19 43. If donor-milk available: 20 21 22 Donor milk Initiation Criteria ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 23 # of Responses (n) 3 0 0 0 0 0 1 0 4 24 600 grams 0 0 0 0 0 0 0 0 0 25 0 700 grams 0 0 0 0 0 0 0 on September 27, 2021 by guest. Protected copyright. 0 26 0 27 800 grams 0 0 0 0 0 0 0 0 28 900 grams 0 0 0 0 0 0 0 0 0 29 1000 grams 2 0 0 0 0 0 1 0 3 30 1200 grams 0 0 0 0 0 0 0 0 0 31 28 weeks 1300 grams 0 0 0 0 0 0 0 0 0 32 1500 grams 1 0 0 0 0 0 0 0 1 33 1600 grams 0 0 0 0 0 0 0 0 0 34 1800 grams 0 0 0 0 0 0 0 0 0 35 2000 grams 0 0 0 0 0 0 0 0 0 36 BW not criteria 0 0 0 0 0 0 0 0 0 37 0 38 Others 0 0 0 0 0 0 0 0 39 # of Responses (n) 0 1 0 0 0 0 0 0 1 40 600 grams 0 0 0 0 0 0 0 0 0 41 700 grams 0 0 0 0 0 0 0 0 0 42 800 grams 0 0 0 0 0 0 0 0 0 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 19 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 56 of 71 Appendix B

1 2 900 grams 0 0 0 0 0 0 0 0 0 3 1000 grams 0 0 0 0 0 0 0 0 0 4 1200 grams 0 1 0 0 0 0 0 0 1 5 29 weeks 1300 grams 0 0 0 0 0 0 0 0 0 6 1500 grams 0 0 0 0 0 0 0 0 0 7 1600 grams 0 0 0 0 0 0 0 0 0 8 1800 grams 0 0 0 0 0 0 0 0 0 9 2000 grams 0 0 0 0 0 0 0 0 0 10 BW not criteria 0 0 0 0 0 0 0 0 0 11 0 12 Others 0 0 0 0 0 0 0 0 For1 3peer0 review0 0 only0 2 0 6 13 # of Responses (n) 14 600 grams 0 0 0 0 0 0 0 0 0 15 700 grams 0 0 0 0 0 0 0 0 0 16 800 grams 0 0 0 0 0 0 0 0 0 17 900 grams 0 0 0 0 0 0 0 0 0 http://bmjopen.bmj.com/ 18 1000 grams 0 0 0 0 0 0 1 0 1 19 1200 grams 0 0 0 0 0 0 0 0 0 20 30 weeks 1300 grams 0 1 0 0 0 0 0 0 1 21 2 22 1500 grams 1 1 0 0 0 0 0 0 23 1600 grams 0 0 0 0 0 0 0 0 0 24 1800 grams 0 0 0 0 0 0 0 0 0 25 2000 grams 0 0 0 0 0 0 0 0 0 26 BW not criteria 0 1 0 0 0 0 1 on September 27, 2021 by guest. Protected copyright. 0 2 27 Others 0 0 0 0 0 0 0 0 0 28 # of Responses (n) 3 5 1 0 0 3 15 2 29 29 600 grams 0 0 0 0 0 0 0 0 0 30 700 grams 0 0 0 0 0 0 0 0 0 31 0 32 800 grams 0 0 0 0 0 0 0 0 33 900 grams 0 0 0 0 0 0 0 0 0 34 1000 grams 0 0 0 0 0 0 0 0 0 35 1200 grams 0 0 0 0 0 0 0 0 0 36 32 weeks 1300 grams 0 0 0 0 0 0 0 0 0 37 1500 grams 2 3 0 0 0 3 15 2 25 38 1600 grams 0 0 0 0 0 0 0 0 0 39 1800 grams 0 0 1 0 0 0 0 0 1 40 2000 grams 0 0 0 0 0 0 0 0 0 41 BW not criteria 1 2 0 0 0 0 0 0 3 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 20 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 57 of 71 BMJ Open Appendix B

1 2 Others 0 0 0 0 0 0 0 0 0 3 # of Responses (n) 0 0 0 0 1 0 0 1 2 4 600 grams 0 0 0 0 0 0 0 0 0 5 700 grams 0 0 0 0 0 0 0 0 0 6 800 grams 0 0 0 0 0 0 0 0 0 7 900 grams 0 0 0 0 0 0 0 0 0 8 1000 grams 0 0 0 0 0 0 0 0 0 9 1200 grams 0 0 0 0 0 0 0 0 0 10 33 weeks 0 11 1300 grams 0 0 0 0 0 0 0 0 12 1500 grams 0 0 0 0 0 0 0 0 0 For peer review only 1 13 1600 grams 0 0 0 0 0 0 0 1 14 1800 grams 0 0 0 0 0 0 0 0 0 15 2000 grams 0 0 0 0 1 0 0 0 1 16 BW not criteria 0 0 0 0 0 0 0 0 0 17 Others 0 0 0 0 0 0 0 0 0 http://bmjopen.bmj.com/ 18 # of Responses (n) 1 7 0 0 3 0 0 0 11 19 600 grams 0 0 0 0 0 0 0 0 0 20 0 21 700 grams 0 0 0 0 0 0 0 0 22 800 grams 0 0 0 0 0 0 0 0 0 23 900 grams 0 0 0 0 0 0 0 0 0 24 1000 grams 0 0 0 0 0 0 0 0 0 25 1200 grams 1 0 0 0 0 0 0 0 1 26 34 weeks 1300 grams 0 0 0 0 0 0 0 on September 27, 2021 by guest. Protected copyright. 0 0 27 1500 grams 0 3 0 0 0 0 0 0 3 28 1600 grams 0 0 0 0 0 0 0 0 0 29 1800 grams 0 1 0 0 0 0 0 0 1 30 2000 grams 0 1 0 0 0 0 0 0 1 31 4 32 BW not criteria 0 2 0 0 2 0 0 0 33 Others 0 0 0 0 0 0 0 0 0 34 BW blank 0 0 0 0 1 0 0 0 1 35 # of Responses (n) 0 0 0 0 2 0 0 0 2 36 600 grams 0 0 0 0 0 0 0 0 0 37 700 grams 0 0 0 0 0 0 0 0 0 38 800 grams 0 0 0 0 0 0 0 0 0 39 900 grams 0 0 0 0 0 0 0 0 0 40 1000 grams 0 0 0 0 0 0 0 0 0 41 1200 grams 0 0 0 0 0 0 0 0 0 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 21 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 58 of 71 Appendix B

1 2 35 weeks 1300 grams 0 0 0 0 0 0 0 0 0 3 1500 grams 0 0 0 0 0 0 0 0 0 4 1600 grams 0 0 0 0 0 0 0 0 0 5 1800 grams 0 0 0 0 0 0 0 0 0 6 2000 grams 0 0 0 0 0 0 0 0 0 7 BW not criteria 0 0 0 0 0 0 0 0 0 8 Others 0 0 0 0 0 0 0 0 0 9 BW blank 0 0 0 0 2 0 0 0 2 10 0 2 0 0 0 0 0 0 2 11 # of Responses (n) 12 600 grams 0 0 0 0 0 0 0 0 0 For peer review only 0 13 700 grams 0 0 0 0 0 0 0 0 14 800 grams 0 0 0 0 0 0 0 0 0 15 900 grams 0 0 0 0 0 0 0 0 0 16 1000 grams 0 0 0 0 0 0 0 0 0 17 1200 grams 0 0 0 0 0 0 0 0 0 http://bmjopen.bmj.com/ 18 37 weeks 1300 grams 0 0 0 0 0 0 0 0 0 19 1500 grams 0 0 0 0 0 0 0 0 0 20 1600 grams 0 0 0 0 0 0 0 0 0 21 0 22 1800 grams 0 0 0 0 0 0 0 0 23 2000 grams 0 0 0 0 0 0 0 0 0 24 BW not criteria 0 2 0 0 0 0 0 0 2 25 Others 0 0 0 0 0 0 0 0 0 26 # of Responses (n) 1 5 4 0 0 2 2 on September 27, 2021 by guest. Protected copyright. 1 15 27 600 grams 0 0 0 0 0 0 0 0 0 28 700 grams 0 0 0 0 0 0 0 0 0 29 800 grams 0 0 0 0 0 0 0 0 0 30 900 grams 0 0 0 0 0 0 0 0 0 31 0 32 1000 grams 0 0 0 0 0 0 0 0 33 1200 grams 0 2 0 0 0 0 0 0 2 34 GA not 35 criteria 1300 grams 0 0 0 0 0 0 0 0 0 36 1500 grams 0 2 1 0 0 1 1 0 5 37 1600 grams 0 0 0 0 0 0 0 0 0 38 1800 grams 0 1 0 0 0 0 1 0 2 39 2000 grams 0 0 0 0 0 0 0 0 0 40 BW not criteria 1 0 3 0 0 0 0 1 5 41 Others 0 0 0 0 0 1 0 0 1 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 22 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 59 of 71 BMJ Open Appendix B

1 2 # of Responses (n) 1 0 0 0 0 0 0 0 1 3 600 grams 0 0 0 0 0 0 0 0 0 4 700 grams 0 0 0 0 0 0 0 0 0 5 800 grams 0 0 0 0 0 0 0 0 0 6 900 grams 0 0 0 0 0 0 0 0 0 7 1000 grams 0 0 0 0 0 0 0 0 0 8 1200 grams 0 0 0 0 0 0 0 0 0 9 Other 1300 grams 0 0 0 0 0 0 0 0 0 10 1500 grams 0 0 0 0 0 0 0 0 0 11 12 1600 grams 0 0 0 0 0 0 0 0 0 1800 grams For0 0peer0 review0 0 only0 0 0 0 13 14 2000 grams 0 0 0 0 0 0 0 0 0 15 BW not criteria 0 0 0 0 0 0 0 0 0 16 Others 1 0 0 0 0 0 0 0 1 17 Donor milk Stopped ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total http://bmjopen.bmj.com/ 18 # of Responses (n) 0 0 0 0 0 0 0 0 0 19 1000 grams 0 0 0 0 0 0 0 0 0 20 1300 grams 0 0 0 0 0 0 0 0 0 21 0 22 1500 grams 0 0 0 0 0 0 0 0 23 1700 grams 0 0 0 0 0 0 0 0 0 24 28 weeks 1800 grams 0 0 0 0 0 0 0 0 0 25 1900 grams 0 0 0 0 0 0 0 0 0 26 2000 grams 0 0 0 0 0 0 0 on September 27, 2021 by guest. Protected copyright. 0 0 27 BW not criteria 0 0 0 0 0 0 0 0 0 28 Others 0 0 0 0 0 0 0 0 0 29 # of Responses (n) 0 0 0 0 0 0 0 0 0 30 1000 grams 0 0 0 0 0 0 0 0 0 31 0 32 1300 grams 0 0 0 0 0 0 0 0 33 1500 grams 0 0 0 0 0 0 0 0 0 34 1700 grams 0 0 0 0 0 0 0 0 0 35 30 weeks 1800 grams 0 0 0 0 0 0 0 0 0 36 1900 grams 0 0 0 0 0 0 0 0 0 37 2000 grams 0 0 0 0 0 0 0 0 0 38 BW not criteria 0 0 0 0 0 0 0 0 0 39 Others 0 0 0 0 0 0 0 0 0 40 # of Responses (n) 0 0 0 0 0 0 0 0 0 41 1000 grams 0 0 0 0 0 0 0 0 0 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 23 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 60 of 71 Appendix B

1 2 1300 grams 0 0 0 0 0 0 0 0 0 3 1500 grams 0 0 0 0 0 0 0 0 0 4 1700 grams 0 0 0 0 0 0 0 0 0 5 31 weeks 1800 grams 0 0 0 0 0 0 0 0 0 6 1900 grams 0 0 0 0 0 0 0 0 0 7 2000 grams 0 0 0 0 0 0 0 0 0 8 BW not criteria 0 0 0 0 0 0 0 0 0 9 Others 0 0 0 0 0 0 0 0 0 10 3 3 1 0 1 0 5 0 13 11 # of Responses (n) 12 1000 grams 0 0 0 0 0 0 0 0 0 For peer review only 1 13 1300 grams 0 0 0 0 0 0 1 0 14 1500 grams 1 0 0 0 0 0 4 0 5 15 1700 grams 1 0 0 0 0 0 0 0 1 16 32 weeks 1800 grams 0 0 1 0 0 0 0 0 1 17 1900 grams 0 0 0 0 0 0 0 0 0 http://bmjopen.bmj.com/ 18 2000 grams 0 0 0 0 0 0 0 0 0 19 BW not criteria 1 3 0 0 0 0 0 0 4 20 Others 0 0 0 0 0 0 0 0 0 21 1 22 BW blank 0 0 0 0 1 0 0 0 23 # of Responses (n) 0 0 0 0 1 0 1 1 3 24 1000 grams 0 0 0 0 0 0 0 0 0 25 1300 grams 0 0 0 0 0 0 0 0 0 26 1500 grams 0 0 0 0 0 0 1 on September 27, 2021 by guest. Protected copyright. 1 2 27 1700 grams 0 0 0 0 0 0 0 0 0 28 33 weeks 1800 grams 0 0 0 0 0 0 0 0 0 29 1900 grams 0 0 0 0 0 0 0 0 0 30 2000 grams 0 0 0 0 1 0 0 0 1 31 0 32 BW not criteria 0 0 0 0 0 0 0 0 0 33 Others 0 0 0 0 0 0 0 0 34 # of Responses (n) 3 10 0 0 2 2 6 1 24 35 1000 grams 0 0 0 0 0 0 0 0 0 36 1300 grams 0 0 0 0 0 0 0 0 0 37 1500 grams 1 0 0 0 0 0 2 0 3 38 1700 grams 0 0 0 0 0 0 0 0 0 39 34 weeks 1800 grams 1 0 0 0 0 1 2 1 5 40 1900 grams 0 0 0 0 0 0 0 0 0 41 2000 grams 0 1 0 0 0 1 0 0 2 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 24 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 61 of 71 BMJ Open Appendix B

1 2 BW not criteria 1 7 0 0 2 0 2 0 12 3 Others 0 1 0 0 0 0 0 0 1 4 BW blank 0 1 0 0 0 0 0 0 1 5 # of Responses (n) 0 0 0 0 2 1 0 0 3 6 1000 grams 0 0 0 0 0 0 0 0 0 7 1300 grams 0 0 0 0 0 0 0 0 0 8 1500 grams 0 0 0 0 0 0 0 0 0 9 1700 grams 0 0 0 0 0 0 0 0 0 10 35 weeks 0 11 1800 grams 0 0 0 0 0 0 0 0 12 1900 grams 0 0 0 0 0 0 0 0 0 For peer review only 0 13 2000 grams 0 0 0 0 0 0 0 0 14 BW not criteria 0 0 0 0 0 1 0 0 1 15 Others 0 0 0 0 0 0 0 0 0 16 BW blank 0 0 0 0 2 0 0 0 2 17 # of Responses (n) 2 1 0 0 0 0 0 0 3 http://bmjopen.bmj.com/ 18 1000 grams 0 0 0 0 0 0 0 0 0 19 1300 grams 0 0 0 0 0 0 0 0 0 20 0 21 1500 grams 0 0 0 0 0 0 0 0 22 1700 grams 0 0 0 0 0 0 0 0 0 23 36 weeks 1800 grams 0 0 0 0 0 0 0 0 0 24 1900 grams 0 0 0 0 0 0 0 0 0 25 2000 grams 0 0 0 0 0 0 0 0 0 26 BW not criteria 2 0 0 0 0 0 0 on September 27, 2021 by guest. Protected copyright. 0 2 27 Others 0 0 0 0 0 0 0 0 0 28 BW blank 0 1 0 0 0 0 0 0 1 29 # of Responses (n) 0 1 0 0 0 0 0 0 1 30 1000 grams 0 0 0 0 0 0 0 0 0 31 32 1300 grams 0 0 0 0 0 0 0 0 0 33 1500 grams 0 0 0 0 0 0 0 0 0 34 1700 grams 0 0 0 0 0 0 0 0 0 35 37 weeks 1800 grams 0 0 0 0 0 0 0 0 0 36 1900 grams 0 0 0 0 0 0 0 0 0 37 2000 grams 0 0 0 0 0 0 0 0 0 38 BW not criteria 0 1 0 0 0 0 0 0 1 39 Others 0 0 0 0 0 0 0 0 0 40 # of Responses (n) 0 1 0 0 0 0 0 0 1 41 0 42 1000 grams 0 0 0 0 0 0 0 0 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 25 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 62 of 71 Appendix B

1 2 1300 grams 0 0 0 0 0 0 0 0 0 3 1500 grams 0 0 0 0 0 0 0 0 0 4 1700 grams 0 0 0 0 0 0 0 0 0 5 38 weeks 1800 grams 0 0 0 0 0 0 0 0 0 6 1900 grams 0 0 0 0 0 0 0 0 0 7 2000 grams 0 0 0 0 0 0 0 0 0 8 BW not criteria 0 1 0 0 0 0 0 0 1 9 Others 0 0 0 0 0 0 0 0 0 10 0 1 4 0 0 1 5 2 13 11 # of Responses (n) 12 1000 grams 0 0 0 0 0 0 0 0 0 For peer review only 0 13 1300 grams 0 0 0 0 0 0 0 0 14 1500 grams 0 0 0 0 0 0 1 0 1 15 1700 grams 0 0 1 0 0 0 0 0 1 16 GA not 17 criteria 1800 grams 0 0 0 0 0 0 1 1 2 http://bmjopen.bmj.com/ 18 1900 grams 0 0 0 0 0 0 0 0 0 19 2000 grams 0 0 0 0 0 0 0 0 0 20 BW not criteria 0 1 2 0 0 0 3 1 7 21 2 22 Others 0 0 1 0 0 1 0 0 23 # of Responses (n) 2 6 0 0 0 1 2 0 11 24 1000 grams 0 0 0 0 0 0 0 0 0 25 1300 grams 0 0 0 0 0 0 0 0 0 26 1500 grams 0 0 0 0 0 0 0 on September 27, 2021 by guest. Protected copyright. 0 0 27 1700 grams 0 0 0 0 0 0 0 0 0 28 Other 1800 grams 0 0 0 0 0 0 0 0 0 29 1900 grams 0 0 0 0 0 0 0 0 0 30 2000 grams 0 0 0 0 0 1 0 0 1 31 1 32 BW not criteria 0 1 0 0 0 0 0 0 33 Others 2 4 0 0 0 0 2 0 8 34 BW blank 0 1 0 0 0 0 0 0 1 35 36 Donor milk Initiation Criteria ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 37 Total # of Responses (n) 10 23 5 0 6 5 20 4 73 38 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 39 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 40 41 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 42 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 26 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 63 of 71 BMJ Open Appendix B

1 2 1000 grams 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.00% 0.00% 4.11% 3 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4 28 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 1500 grams 10.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 6 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 8 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 10 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 11 12 600 grams 0.00%For0.00% peer0.00% 0.00%review0.00% 0.00% only0.00% 0.00% 0.00% 13 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 14 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 15 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 16 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 1200 grams 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% http://bmjopen.bmj.com/ 18 29 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 21 22 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 23 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 24 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 26 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% on September 27, 2021 by guest. Protected copyright. 0.00% 27 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 29 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.00% 0.00% 1.37% 31 32 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 30 weeks 1300 grams 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 34 1500 grams 10.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.74% 35 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 36 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 37 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 38 BW not criteria 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 5.00% 0.00% 2.74% 39 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 40 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 41 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 27 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 64 of 71 Appendix B

1 2 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 3 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 6 32 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 1500 grams 20.00% 13.04% 0.00% 0.00% 0.00% 60.00% 75.00% 50.00% 34.25% 8 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 1800 grams 0.00% 0.00% 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 10 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 11 12 BW not criteria 10.00% 8.70% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4.11% Others 0.00%For0.00% peer0.00% 0.00%review0.00% 0.00% only0.00% 0.00% 0.00% 13 14 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 15 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 16 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% http://bmjopen.bmj.com/ 18 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 33 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 21 22 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 23 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25.00% 1.37% 24 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 2000 grams 0.00% 0.00% 0.00% 0.00% 16.67% 0.00% 0.00% 0.00% 1.37% 26 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% on September 27, 2021 by guest. Protected copyright. 0.00% 27 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 29 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 31 32 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 34 1200 grams 10.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 35 34 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 36 1500 grams 0.00% 13.04% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4.11% 37 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 38 1800 grams 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 39 2000 grams 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 40 BW not criteria 0.00% 8.70% 0.00% 0.00% 33.33% 0.00% 0.00% 0.00% 5.48% 41 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 28 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 65 of 71 BMJ Open Appendix B

1 2 BW blank 0.00% 0.00% 0.00% 0.00% 16.67% 0.00% 0.00% 0.00% 1.37% 3 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 6 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 8 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 35 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 10 11 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 12 1600 grams 0.00%For0.00% peer0.00% 0.00%review0.00% 0.00% only0.00% 0.00% 0.00% 13 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 14 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 15 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 16 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 BW blank 0.00% 0.00% 0.00% 0.00% 33.33% 0.00% 0.00% 0.00% 2.74% http://bmjopen.bmj.com/ 18 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 21 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 22 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 23 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 24 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 37 weeks 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 26 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% on September 27, 2021 by guest. Protected copyright. 0.00% 27 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 29 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 BW not criteria 0.00% 8.70% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.74% 31 32 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 34 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 35 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 36 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 37 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 38 1200 grams 0.00% 8.70% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.74% 39 GA not 40 criteria 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 41 1500 grams 0.00% 8.70% 20.00% 0.00% 0.00% 20.00% 5.00% 0.00% 6.85% 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 29 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 66 of 71 Appendix B

1 2 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 3 1800 grams 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 5.00% 0.00% 2.74% 4 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 BW not criteria 10.00% 0.00% 60.00% 0.00% 0.00% 0.00% 0.00% 25.00% 6.85% 6 Others 0.00% 0.00% 0.00% 0.00% 0.00% 20.00% 0.00% 0.00% 1.37% 7 600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 8 700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 10 11 900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 12 1000 grams 0.00%For0.00% peer0.00% 0.00%review0.00% 0.00% only0.00% 0.00% 0.00% 13 1200 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 14 Other 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 15 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 16 1600 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% http://bmjopen.bmj.com/ 18 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 Others 10.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.37% 21 ANZNN CNN FinMBR INN SNQ SNN SEN1500 TuscanNN Total 22 Donor milk Stopped 23 Total # of Responses (n) 10 23 5 0 6 5 19 4 72 24 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 26 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% on September 27, 2021 by guest. Protected copyright. 0.00% 27 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 28 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 29 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 31 32 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 34 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 35 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 36 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 37 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 38 30 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 39 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 40 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 41 42 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 30 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 67 of 71 BMJ Open Appendix B

1 2 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 3 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 4 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 6 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 31 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 8 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 10 11 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 12 Others 0.00%For0.00% peer0.00% 0.00%review0.00% 0.00% only0.00% 0.00% 0.00% 13 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 14 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.26% 0.00% 1.39% 15 1500 grams 10.00% 0.00% 0.00% 0.00% 0.00% 0.00% 21.05% 0.00% 6.94% 16 1700 grams 10.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 17 32 weeks 1800 grams 0.00% 0.00% 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% http://bmjopen.bmj.com/ 18 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 21 BW not criteria 10.00% 13.04% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.56% 22 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 23 BW blank 0.00% 0.00% 0.00% 0.00% 16.67% 0.00% 0.00% 0.00% 1.39% 24 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 26 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.26% 25.00% on September 27, 2021 by guest. Protected copyright. 2.78% 27 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 33 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 29 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 2000 grams 0.00% 0.00% 0.00% 0.00% 16.67% 0.00% 0.00% 0.00% 1.39% 31 32 BW not criteria 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 34 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 35 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 36 1500 grams 10.00% 0.00% 0.00% 0.00% 0.00% 0.00% 10.53% 0.00% 4.17% 37 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 38 34 weeks 1800 grams 10.00% 0.00% 0.00% 0.00% 0.00% 20.00% 10.53% 25.00% 6.94% 39 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 40 2000 grams 0.00% 4.35% 0.00% 0.00% 0.00% 20.00% 0.00% 0.00% 2.78% 41 42 BW not criteria 10.00% 30.43% 0.00% 0.00% 33.33% 0.00% 10.53% 0.00% 16.67% 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 31 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

BMJ Open Page 68 of 71 Appendix B

1 2 Others 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 3 BW blank 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 4 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 6 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 8 35 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 9 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 10 11 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 12 BW not criteria 0.00%For0.00% peer0.00% 0.00%review0.00% 20.00% only0.00% 0.00% 1.39% 13 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 14 BW blank 0.00% 0.00% 0.00% 0.00% 33.33% 0.00% 0.00% 0.00% 2.78% 15 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 16 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% http://bmjopen.bmj.com/ 18 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 36 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 21 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 22 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 23 BW not criteria 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 2.78% 24 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 25 BW blank 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 26 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% on September 27, 2021 by guest. Protected copyright. 0.00% 27 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 28 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 29 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 30 37 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 31 32 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 33 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 34 BW not criteria 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 35 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 36 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 37 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 38 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 39 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 40 38 weeks 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 41 42 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 32 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Page 69 of 71 BMJ Open Appendix B

1 2 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 3 BW not criteria 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 4 Others 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 6 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 7 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.26% 0.00% 1.39% 8 1700 grams 0.00% 0.00% 20.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 9 GA not 10 criteria 11 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 5.26% 25.00% 2.78% 12 1900 grams 0.00%For0.00% peer0.00% 0.00%review0.00% 0.00% only0.00% 0.00% 0.00% 13 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 14 BW not criteria 0.00% 4.35% 40.00% 0.00% 0.00% 0.00% 15.79% 25.00% 9.72% 15 Others 0.00% 0.00% 20.00% 0.00% 0.00% 20.00% 0.00% 0.00% 2.78% 16 1000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 17 1300 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% http://bmjopen.bmj.com/ 18 1500 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 19 1700 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 20 Other 21 1800 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 22 1900 grams 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 23 2000 grams 0.00% 0.00% 0.00% 0.00% 0.00% 20.00% 0.00% 0.00% 1.39% 24 BW not criteria 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 1.39% 25 Others 20.00% 17.39% 0.00% 0.00% 0.00% 0.00% 10.53% 0.00% 11.11% 26 BW blank 0.00% 4.35% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% on September 27, 2021 by guest. Protected copyright. 1.39% 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 iNEO Survey NEC prevention For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 33 / 33 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 70 of 71

1 STROBE Statement—Checklist of items that should be included in reports of cohort studies 2 Item

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 No Recommendation 5 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 6 - mentioned in the abstract (design), p. 2 7 (b) Provide in the abstract an informative and balanced summary of what was done 8 9 and what was found 10 - done, p. 2 11 Introduction 12 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 14 - done (see introduction), p. 4 15 Objectives 3 State specific objectives, including any prespecified hypotheses 16 - done (see introduction), p. 4 17 18 Methods For peer review only 19 Study design 4 Present key elements of study design early in the paper 20 - done (see article summary, introduction, methods ), pp. 2, 4ff. 21 22 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 23 exposure, follow-up, and data collection 24 - done (see methods), pp. 5-8 25 26 Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of 27 participants. Describe methods of follow-up 28 - done (see methods – study population), p. 5 29 (b) For matched studies, give matching criteria and number of exposed and 30 31 unexposed 32 - NA 33 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 34 modifiers. Give diagnostic criteria, if applicable 35 36 - done (see methods), pp. 5-8

37 Data sources/ 8* For each variable of interest, give sources of data and details of methods of http://bmjopen.bmj.com/ 38 measurement assessment (measurement). Describe comparability of assessment methods if there is 39 more than one group 40 41 - done (see methods), pp. 5-8 42 Bias 9 Describe any efforts to address potential sources of bias 43 - done (see methods – outcome and measures / statistical analysis), pp. 6-8 44 Study size 10 Explain how the study size was arrived at 45 on September 27, 2021 by guest. Protected copyright. 46 - done (see methods – study population), p. 5 47 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 48 describe which groupings were chosen and why 49 50 - done (see methods – outcome and measures / statistical analysis), pp. 6-8 51 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 52 - done (see methods – statistical analysis) p. 7-8 53 (b) Describe any methods used to examine subgroups and interactions 54 55 - done (see methods – statistical analysis), p. 7-8 56 (c) Explain how missing data were addressed 57 - done (see methods – statistical analysis), p. 7-8 58 (d) If applicable, explain how loss to follow-up was addressed 59 60 - NA (e) Describe any sensitivity analyses - NA 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 71 of 71 BMJ Open

1 Results 2 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 eligible, examined for eligibility, confirmed eligible, included in the study, 5 completing follow-up, and analysed 6 - done (see results), pp. 9-11 7 8 (b) Give reasons for non-participation at each stage 9 - done (results – statistical analysis / study population), p. 5-11 10 (c) Consider use of a flow diagram 11 - NA 12 13 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and 14 information on exposures and potential confounders 15 - done (see methods and results), pp. 5-11 16 (b) Indicate number of participants with missing data for each variable of interest 17 18 For- donepeer (see results), review p. 9-11 only 19 (c) Summarise follow-up time (eg, average and total amount) 20 - NA 21 22 Outcome data 15* Report numbers of outcome events or summary measures over time 23 - done (see results), p. 9 – 11 24 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and 25 their precision (eg, 95% confidence interval). Make clear which confounders were 26 27 adjusted for and why they were included 28 - done (see methods and results), pp. 5 – 11 29 (b) Report category boundaries when continuous variables were categorized 30 - done (see results), p. 9-11 31 32 (c) If relevant, consider translating estimates of relative risk into absolute risk for a 33 meaningful time period 34 - NA: cohort study setting required calculation of odds ratios. 35 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and 36

37 sensitivity analyses http://bmjopen.bmj.com/ 38 - done (see results and discussion) pp. 9-15 39 40 Discussion 41 Key results 18 Summarise key results with reference to study objectives 42 - done (see discussion paragraph 1), p. 11f 43 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or 44

45 imprecision. Discuss both direction and magnitude of any potential bias on September 27, 2021 by guest. Protected copyright. 46 - done (see article summary), p. 2 f., (see discussion), p. 14 47 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 48 multiplicity of analyses, results from similar studies, and other relevant evidence 49 50 - done (see discussion / conclusion), p. 14f. 51 Generalisability 21 Discuss the generalisability (external validity) of the study results 52 - done (see discussion), pp. 11-15 53 54 Other information 55 Funding 22 Give the source of funding and the role of the funders for the present study and, if 56 applicable, for the original study on which the present article is based 57 - done (see declarations – competing interests), p. 1f. 58 59 60 *Give information separately for exposed and unexposed groups.

2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 72 of 71

1 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 2 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 5 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 6 available at http://www.strobe-statement.org. 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

Preventive strategies and factors associated with surgically treated necrotizing enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-031086.R1

Article Type: Original research

Date Submitted by the 16-Jul-2019 Author:

Complete List of Authors: Adams, Mark; Universitätsspital Zürich, Department of Neonatology; University Zurich, Epidemiology, Biostatistics and Prevention Institute Bassler, Dirk; University Hospital Zurich, Department of Neonatology Darlow, Brian; University of Otago Lui, Kei; Royal Hospital for Women, Department of Newborn Care; University of New South Wales Reichman, Brian; Sheba Medical Centre, Gertner Institute for Epidemiology and Health Policy Research Hakansson, Stellan; Umeå University Hospital, Department of Clinical Sciences/Pediatrics Norman, Mikael; Department of Clinical Science, Intervention and Technology, Karolinska Institute, Department of Clinical Science, http://bmjopen.bmj.com/ Intervention and Technology Lee, Shoo; Mount Sinai Hospital and University of Toronto, Department of Paediatrics Helenius, Kjell; Turku University Hospital, Department of Pediatrics Lehtonen, Liisa; University of Turku Finland, Department of Pediatrics San Feliciano, Laura; University Hospital Salamanca, Division of Neonatology Vento, Maximo; University of Valencia, Division of Neonatology and

Health Research Institute La Fe on September 27, 2021 by guest. Protected copyright. Moroni, Marco; Anna Meyer Children’s University Hospital, Neonatal Intensive Care Unit Beltempo, Marc; Montreal Children’s Hospital, McGill University, Department of Pediatrics Yang, Junmin; Mount Sinai Hospital and University of Toronto, Department of Paediatrics Shah, Prakesh; Mount Sinai Hospital and University of Toronto, Department of Paediatrics

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Gastroenterology and hepatology

NEONATOLOGY, Paediatric gastroenterology < PAEDIATRICS, Keywords: PERINATOLOGY, PAEDIATRICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 71 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from

1 2 Preventive strategies and factors associated with surgically treated necrotizing

3 enterocolitis in extremely preterm infants: an international unit survey linked with BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 retrospective cohort data analysis 5 6 1 1 2 3 7 Mark Adams, PhD , Dirk Bassler, MD, MSc , Brian A Darlow, MD , Kei Lui, MD , Brian 4 5 6 8 Reichman, MBChB , Stellan Håkansson, MD , Mikael Norman, MD , Shoo K Lee, MBBS, 9 PhD7,8, Kjell K Helenius, MD9, Liisa Lehtonen, MD9, Laura San Feliciano, MD10, Maximo 10 Vento, MD, PhD11, Marco Moroni, MD12, Marc Beltempo, MD13, Junmin Yang, PhD7, 11 Prakesh S Shah, MD, MSc7,8; on behalf of the International Network for Evaluating 12 Outcomes (iNeo) of Neonatesǂ 13 ǂ 14 Group Information: Investigators of the International Network for Evaluating Outcomes 15 (iNeo) of Neonates are provided in the Acknowledgements 16 17 Affiliations: 18 1Department of Neonatology,For peer University reviewHospital Zurich, Universityonly of Zurich, Switzerland; 19 Department of Paediatrics, University of Otago, Christchurch, New Zealand; 3Royal Hospital 20 for Women, National Perinatal Epidemiology and Statistic Unit, University of New South 21 4 22 Wales, Randwick, Australia; Gertner Institute for Epidemiology and Health Policy Research, 5 23 Sheba Medical Centre, Israel; Department of Clinical Sciences/Pediatrics, Umeå University 24 Hospital, Umeå, Sweden; 6Department of Neonatal Medicine, Karolinska University Hospital 25 and Karolinska Institutet, Stockholm, Sweden; 7Department of Paediatrics, Mount Sinai 26 Hospital and University of Toronto, Toronto, Canada; 8Maternal-Infant Care Research 27 Centre, Mount Sinai Hospital, Toronto, Canada; 9Department of Pediatrics, Turku University 28 Hospital and University of Turku, Turku, Finland; 10Division of Neonatology, University 29 11 30 Hospital Salamanca, Salamanca, Spain; Division of Neonatology and Health Research 12 31 Institute La Fe, University of Valencia, Valencia, Spain; Neonatal Intensive Care Unit, 32 Anna Meyer Children’s University Hospital, Florence, Italy; 13Department of Pediatrics, 33 Montreal Children’s Hospital, McGill University, Montreal, QC, Canada. 34 35 Address correspondence to: Mark Adams, Department of Neonatology, University Hospital 36

37 Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland; Tel. +4143 253 3034; http://bmjopen.bmj.com/ 38 E-mail: [email protected]. 39 40 Short title: NEC prevention practices and their impact on outcome 41 42 Financial Disclosure Statement 43 Mark Adams receives a salary as network coordinator for the Swiss Neonatal Network. The 44

45 remaining authors have indicated they have no financial relationships relevant to this article to on September 27, 2021 by guest. Protected copyright. 46 disclose. 47 48 Funding Sources: Funding for iNeo has been provided by a Canadian Institutes of Health 49 Research Chair in Reproductive and Child Health Services and Policy Research (APR- 50 126340) held by PSS. The Australian and New Zealand Neonatal Network is predominantly 51 funded by membership contributions from participating centres. The Canadian Neonatal 52 53 Network is supported by a team grant from the Canadian Institutes of Health Research (CTP 54 87518), the Ontario Ministry of Health, and individual participating centres. The Finnish 55 Medical Birth Register is governmentally funded and kept by the National Institute for Health 56 and Welfare (THL). The Israel Neonatal Network very low birth weight infant database is 57 partially funded by the Israel Center for Disease Control and the Ministry of Health. The 58 Neonatal Research Network of Japan is partly funded by a Health Labour Sciences Research 59 60 Grant from the Ministry of Health, Labour and Welfare of Japan. SEN1500 is supported by funds from the Spanish Neonatal Society (SENeo). The Swedish Neonatal Quality Register is

1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 71 BMJ Open

1 2 funded by the Swedish Government (Ministry of Health and Social Affairs) and the body of

3 regional health care providers (County Councils). SwissNeoNet is partially funded by BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 participating units in the form of membership fees. Tuscany Neonatal Network is funded by 5 the Tuscany Region. The United Kingdom Neonatal Collaborative receives no core funding. 6 7 8 Role of the Funders/Sponsors: The funding bodies played no role in the design and conduct 9 of the study; collection, management, analysis, and interpretation of the data; preparation, 10 review, or approval of the manuscript; and decision to submit the manuscript for publication. 11 12 13 Conflict of Interest Statement: Mark Adams receives a salary as network coordinator for the 14 Swiss Neonatal Network. The remaining authors have indicated they have no potential 15 conflicts of interest relevant to this article to disclose 16 17 List of abbreviations 18 For peer review only 19 ANZNN: Australia/New Zealand Neonatal Network; CNN: Canadian Neonatal Network; 20 FINMBR: Finish Medical Birth Register; GA: gestational age; INN: Israel Neonatal Network; 21 NEC: Necrotizing enterocolitis; NICU: neonatal intensive care unit; OR: odds ratio; PDA: 22 patent ductus arteriosus; SEN1500 Spanish Neonatal Network; SNQ: Swedish Neonatal 23 Quality Register; SR: standardized ratio; SwissNeoNet: Swiss Neonatal Network; TuscanNN: 24 Tuscany Neonatal Network in Italy. 25 26 27 28 ABSTRACT 29 30 Objectives: To compare necrotizing enterocolitis (NEC) prevention practices and NEC 31 associated factors between units from eight countries of the International Network for 32 Evaluation of Outcomes of Neonates (iNeo), and to assess their association with surgical NEC 33 rates. 34 Design: Prospective unit-level survey combined with retrospective cohort study. 35 Setting: Neonatal intensive care units (NICUs) in Australia/New Zealand, Canada, Finland, 36

37 Israel, Spain, Sweden, Switzerland and Tuscany (Italy). http://bmjopen.bmj.com/ 0 6 38 Patients: Extremely preterm infants born between 24 to 28 weeks’ gestation, with birth 39 weights <1500 g, and admitted between 2014-2015. 40 Exposures: NEC prevention practices (probiotics, feeding, donor milk) using responses of an 41 on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in 42 literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and 43 sepsis) using cohort data. 44

45 Outcome measures: Surgical NEC rates and death following NEC using cohort data. on September 27, 2021 by guest. Protected copyright. 46 Results: The survey response rate was 91% (153 units). Both probiotic provision and donor 47 milk availability varied between 0-100% among networks whereas feeding initiation and 48 advancement rates were practically similar in most networks. The 9792 infants included in the 49 cohort study to link survey results and cohort outcomes, revealed similar baseline 50 characteristics but considerable differences in factors associated with NEC between networks. 51 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4-8.4% between networks. 52 53 Standardized ratios for surgical NEC were lower for Australia/ New Zealand, higher for 54 Spain, and comparable for the remaining six networks. 55 Conclusions: The variation in implementation of NEC prevention practices and in factors 56 associated with NEC in literature could not be associated with the variation in surgical NEC 57 incidence. This corroborates the current lack of consensus surrounding the use of preventive 58 strategies for NEC and emphasizes the need for research. 59 60

2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 71

1 2

3 ARTICLE SUMMARY BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 Strengths and limitations of this study 5 6 7  We report on a large, multinational patient database and high survey response rate, 8 enabling a snapshot of contemporary necrotizing enterocolitis outcome and practices. 9  Survey was completed by a single representative at each site rather than all 10 practitioners, whereas responses were based on NICU policies rather than personal 11 opinion. 12 13  As individual patient data for NEC prevention were not available, we applied a 14 pragmatic approach linking unit level survey data on prevention with patient level 15 cohort data on outcome and risk factors to report on a possible association between 16 NEC prevention and outcome. 17  When linking survey with cohort study data we have assumed that all neonates within 18 a unit were treatedFor equally, peer which review is an assumption onlyand needs confirmation but is 19 20 acceptable for generating a hypothesis. 21 22 Keywords 23 Very preterm infants, necrotising enterocolitis, surgery, prevention, risk factors 24 25 Word count 26 3375 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 71 BMJ Open

1 2 INTRODUCTION

4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 71

1 2 METHODS

5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 71 BMJ Open

1 2 collaborating countries. Infants with major congenital anomalies and those born outside any

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 of the participating hospitals and admitted after 1 week of age were excluded, as these infants 5 6 7 may not have received all described preventive measures. 8 9 10 All networks have obtained ethical/regulatory approval or its equivalent from their local 11 12 granting agencies to allow for de-identified data to be collated and sent to the iNeo 13 14 Coordinating Centre. Overall coordination of the project is also approved by the Research 15 16 Ethics Board at the Mount Sinai Hospital, Toronto, Ontario Canada for the development, 17 18 For peer review only 19 compilation, hosting and management of the iNeo dataset at the MiCare Research Centre (12- 20 21 0336-E). Privacy and confidentiality of patient data is of prime importance to the iNeo 22 23 collaboration and data handling is in accordance with the Privacy Commissioner’s guidelines. 24 25 26 Covariate Definitions 27 28 29 Gestational age (GA) was determined by the best estimate based on early prenatal ultrasound, 30 31 32 last menstrual period, or physical examination of infants at birth, in that order. Birth weight z 33 34 scores were calculated relative to population- and sex-specific birth weight for gestational age 35 36 references selected by each network as most appropriate for the comparison. Antenatal steroid 37 http://bmjopen.bmj.com/ 38 39 use was defined as any administration before birth, regardless of the time interval, PDA by 40 41 clinical or echocardiographic diagnosis, and sepsis by clear clinical evidence of infection as 42 43 well as at least 1 relevant positive result from blood or cerebral fluid cultures. 44

45 on September 27, 2021 by guest. Protected copyright. 46 Outcomes and Measures 47 48 A lack of consensus on defining NEC among the 8 participating countries led us to use 49 50 51 surgical NEC as primary outcome. Surgical NEC was defined as laparotomy, laparoscopy, 52 53 bowel resection, or intraperitoneal drain placement for NEC or suspected NEC. Indication to 54 55 operate was pneumoperitoneum or clinical deterioration despite maximal medical 56 57 58 therapy.[15–17]. Using surgical NEC as primary outcome also allows exclusion of potential 59 60 cases of spontaneous intestinal perforations as they can be identified reliably only at surgery.

6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 71

1 2 Mortality following NEC was defined as death after receiving a diagnosis of NEC stage 2 or

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 above, according to Bell’s criteria[18], and was analyzed to ensure that the comparison of 5 6 7 surgical NEC among countries was not biased by a high proportion of potential surgical NEC 8 9 cases missing due to higher NEC death rates. As Sweden does not collect NEC data according 10 11 to Bell's criteria, its mortality following NEC may be somewhat lower than reported. 12 13 14 15 Statistical analysis 16 17 18 Unit level analyses:For Unit level peer survey responses review were reported only using descriptive statistics and 19 20 reported as percentages or displayed graphically. 21 22 Mixed level analyses: Unit level data for preventative approaches of probiotic usage, early 23 24 25 feeding and donor milk availability were analyzed for their association with patient level data 26 27 of surgical NEC. A multi-level logistic regression model was developed with surgical NEC as 28 29 dependent variable, and unit-level practices (probiotics, early feeding and donor milk use) and 30 31 individual patient level data (GA, male sex, multiple births, and birth-weight z-score) as 32 33 34 independent variables. Adjusted odds ratios (ORs) and 95% confidence interval (CI) were 35 36 calculated. This analysis was not possible for Australia/New Zealand and Spain, as

37 http://bmjopen.bmj.com/ 38 permission for linking survey information and patient data were not available. No model 39 40 41 could be developed for networks where all units provided any of the prophylactic approach to 42 43 all or to none of their patients. Generalized estimation equation was used to account for auto- 44 45 correlation within units. on September 27, 2021 by guest. Protected copyright. 46 47 48 Patient level analyses: Patient level data were used to calculate variations in baseline 49 50 characteristics, factors associated with NEC in literature, surgical NEC rates and mortality 51 52 following NEC for participating networks. Standardized ratios (SRs) for participating 53 54 networks were calculated as the observed number of infants who received NEC surgery 55 56 57 divided by the number of infants expected to receive NEC surgery, based on the sum of 58 59 predicted probabilities from a multivariable adjusted logistic regression model using data 60 from all other countries in the study. Adjustment was made for the same parameters as for the

7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 71 BMJ Open

1 2 odds ratios. SR estimates were graphically displayed. As the SR estimate are calculated in

3 BMJ Open: first published as 10.1136/bmjopen-2019-031086 on 14 October 2019. Downloaded from 4 relation to all other countries combined, it is not directly comparable between contributors. 5 6 7 Data management and statistical analyses were performed at the iNeo Coordinating Centre in 8 9 Toronto, Canada using SAS version 9.2 (SAS Institute Inc., Cary, NC). 10 11 12 13 14 Patient and public involvement 15 16 17 This study used de-identified data. Patients or public were not involved in the development of 18 For peer review only 19 the research question, the outcome measures or the study design. The results of this study 20 21 22 will be disseminated to the public via the iNeo-website (www.ineonetwork.org) and to the 23 24 parent groups of the individual networks. 25 26 27 28 29 30 31 32 33 34 35 36