spiral.imperial.ac.uk · Web viewTITLE PAGE . Title: I. ncidence of . neonatal . Necrotising. Enterocolitis . in . high-income . countries: a. s. ystematic . r. eview. Battersby

TITLE PAGE

Title: Incidence of neonatal Necrotising Enterocolitis in high-income countries:

a systematic review

Battersby C1, Santhalingam T 2, Costeloe K3, Modi N1

Affiliations

1Neonatal Data Analysis Unit, Section of Neonatal Medicine, Department of

Medicine, Chelsea and Westminster campus, Imperial College London, UK

2King’s College London

3Barts and the London School of Medicine and Dentistry

Corresponding author

Dr Cheryl Battersby

Room G.4.2 4th Floor, Lift Bank D,

Department of Medicine, Section of Neonatal Medicine, Imperial College London

Chelsea and Westminster campus, 369 Fulham Road, London, SW10 9NH, UK

Email: [email protected]

Tel: +44 (020) 3315 3396 Fax: +44 (020) 3315 8050

Co-authors

Tharsika Santhalingam, King’s College, London.

Kate Costeloe, Barts and the London School of Medicine and Dentistry, London.

Neena Modi, Neonatal Data Analysis Unit, Department of Medicine, Section of

Neonatal Medicine, Imperial College London, Chelsea and Westminster Hospital,

London.

1

Key words: necrotising enterocolitis; incidence; high-income; preterm; babies

Word count: 2497

ABSTRACT

Objective

To conduct a systematic review of neonatal necrotising enterocolitis (NEC) rates in

high income countries published in peer-reviewed journals.

Methods

We searched MEDLINE, EMBASE and PUBMED databases for observational

studies published in peer-reviewed journals. We selected studies reporting national,

regional or multi-centre rates of NEC in 34 Organisation for Economic Co-operation

and Development (OECD) countries. Two investigators independently screened

studies against pre-determined criteria. For included studies, we extracted country,

year of publication in peer-reviewed journal, study time period, study population

inclusion and exclusion criteria, case definition, gestation or birth-weight specific

NEC and mortality rates. PROSPERO registration no. CRD42015030046.

Results

Of the 1888 references identified, 120 full manuscripts were reviewed; 33 studies

met inclusion criteria; 14 studies with the most recent data from 12 countries were

included in the final analysis. We identified an almost four-fold difference, from 2% to

7%, in the rate of NEC among babies born <32 weeks gestation and an almost five-

fold difference, from 5% to 22%, among those with a birth weight <1000g but few

studies covered the entire at-risk population. The most commonly applied definition

was Bell’s stage ≥2, used in seven studies. Other definitions included Bell’s stage 1-

2

3, definitions from the Centre of Disease, Control and Prevention (CDC),

International Classification for Diseases (ICD), and combinations of clinical and

radiological signs as specified by study authors.

Conclusion

The reasons for international variation in NEC incidence are an important area for

future research. Reliable inferences require clarity in defining population coverage

and consistency in the case definition applied.

INTRODUCTION

The early survival of preterm babies has increased in high resource settings and as

a consequence, the number at risk of serious complications that commonly occur in

the neonatal period, such as necrotising enterocolitis (NEC) is increasing. NEC is

now one of the leading causes of mortality and morbidity in neonatal intensive care

(1, 2). The poor understanding of its aetiology and pathophysiology (3) and absence

of a non-invasive diagnostic test have resulted in a lack of clarity of what constitutes

‘NEC’. Recent reports from the United States describe a fall in NEC incidence

despite a rising preterm term birth rate (4). Understanding variation between different

populations and over time in the incidence of this serious gastrointestinal disease is

important in identifying determinants, designing preventive trials, and implementing

quality improvement programmes. Little is known of international variation in disease

burden. The aim of this study was to review systematically and summarise published

data that most closely describe the national incidence of NEC in high income

countries.

3

METHODS

Scope

We included countries in the Organisation for Economic Co-operation and

Development (OECD) as these have broadly comparable resources, rates of survival

of very preterm babies, and the necessary infrastructure to capture and report

national-level data.

Data sources and search strategy

The systematic review was registered prospectively on PROSPERO (registration no

CRD42015030046) (5). Methods were developed according to recommendations

from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (6).

Two review authors independently performed the search. The first systematic search

was performed by CB using MEDLINE, between 1946 and 2015 December 5th,

EMBASE, between 1974 and 2015 December 15th and PUBMED between 1979 and

2016 April 28th respectively using “Necrotising Enterocolitis” (MesH) and “Country”.

TS repeated the search between 30th April and 3rd May 2016. We restricted the

search to the 34 countries in the OECD (7) and did not apply language restrictions.

These countries comprised Australia, Austria, Belgium, Canada, Chile, Czech

Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,

Ireland, Israel, Italy, Japan, Korea, Luxembourg, Mexico, Netherlands, New Zealand,

Norway, Poland, Portugal, Slovak Republic, Slovenia, Spain, Sweden, Switzerland,

Turkey, United Kingdom and the United States.

4

Study selection

CB and TS independently reviewed all abstracts. Reference lists were further hand-

searched for relevant studies omitted in the initial electronic searches. We excluded

reviews, viewpoints, editorials and assessments of interventions including

randomised controlled trials. Full manuscripts for observational studies reporting the

incidence of NEC in the country of interest were retrieved. Following review of the

final manuscript, exclusion criteria were single centre, missing numerators and

denominators, not generalisable e.g. study population included only small for

gestational age (GA) babies or singleton-births. A study was eligible for inclusion if

the rate of NEC was provided at national, regional or multi-centre level. Of the

eligible studies, those most representative of the population were included (in order

of preference; national, regional, multi-centre). In order to minimise risk of double

counting babies when multiple studies from the same country overlapped in time,

only the most recent was included unless the studies presented the data differently

in more detail (e.g. birth-weight categories) or relevant ways (e.g. one by gestational

age and the other by birth-weight) in which case both were used. Any

disagreements between TS and CB over article inclusion, exclusion and/or data

extraction were resolved through consensus.

Data extraction and synthesis

Extracted data were stored in Microsoft Excel file format. The following information

was extracted from each study: country, year of publication, study time period, study

population inclusion and exclusion criteria, case definition, gestation or birth-weight

specific NEC rates (with or without laparotomy), mortality if available (with or without

laparotomy). Where raw numbers were available we present specific NEC rates;

5

where only graphs were available in the published report, we sought raw numbers

from the authors.

We further present country rates of NEC by the case definition applied, and by

widely used GA and birth-weight categories (<28w, 28-31w and <32w GA; birth-

weight <1000g, 1001-1499g, <1500g).

Study-quality assessment

We assessed the risk of bias of each study using a modified version of the Hoy 2012

tool including eight of the ten appropriate parameters addressing internal and

external validity (8) (Supplementary Table 2). We omitted the two parameters non-

response bias and whether data were obtained directly from the subjects as these

were not applicable to our study population. Each parameter was assessed as

having either low or high risk of bias. Unclear or data unavailable to make a

judgement were regarded as having a high risk of bias. The overall risk of bias was

then scored according to the number of high risk of bias parameters per study: low

(≤2), moderate (3-4), and high (≥5).

RESULTS

Studies identified

The PRISMA flowchart of search results is shown in Figure 1. We identified 1888

publications; 1633 studies remained after removing duplicates. After screening titles

and abstracts, 1513 articles were excluded because they did not report NEC in any

population; we reviewed the full manuscripts of the 120 remaining articles. 33 articles

were eligible for inclusion and 14 studies presented the most recent data (Table 1).

6

Table 1 Results of search by OECD country

Country Studies including duplicates

(n)

Studies excluding duplicates

(n)

Included studies for full

manuscript review (n)

Eligible for

inclusion studies

Final included

most recent studies

Australia and New Zealand

174 152 6 4 1

Austria 16 13 1 0 0Belgium 8 8 0 0 0Canada 112 91 18 9 2Chile 5 3 1 0 0Czech Republic 4 3 1† 0 0Denmark 23 17 2 0 0Estonia 1 1 0 0 0Finland 10 7 2 1 1France 47 36 5 0 0Germany 103 96 7 2 1Greece 8 6 0 0 0Hungary 4 3 0 0 0Iceland 2 2 0 0 0Ireland 83 78 1 0 0Israel 42 31 4 0 0Italy 74 61 2 2 1Japan 74 62 9 3 1Korea 14 10 2 1 1Luxembourg 0 0 0 0 0Mexico 26 16 1 0 0Netherlands 48 42 1 0 0Norway 11 7 0 0 0Poland 20 17 3 1 1Portugal 3 2 0 0 0Slovak Republic 0 0 0 0 0Slovenia 2 2 0 0 0Spain 38 31 3 1 1Sweden 30 25 5 1 1Switzerland 46 43 8 2 1Turkey 53 42 0 0 0United Kingdom 212 203 4 0 0United States 588 516 34 6 2Grey literature 7 7 0 0 0Total 1888 1633 120 33 14

† Full manuscript unavailable

Characteristics of included studies

The country, time period, study inclusion and exclusion criteria, design, case

definition applied and rates of NEC by GA and/or birth-weight categories of the

included studies are shown in Table 2. Eligible but excluded studies are reported in

7

Supplementary Table S1. The 14 included studies represented data from 12 of the

34 OECD countries across Europe, Asia and the United States (Table 2). One study

included data from both Australia and New Zealand (9). We included two studies

from Canada: one provided the most recent data from 2008-2012 for babies born

less than 29 weeks (10); the other included the most recent data from 2003-2011 for

babies born 29-32w GA (11). We included two studies from United States with

overlapping time periods; one from 511 US Vermont Oxford Network Centres 2005-

2006 across birth-weight categories ≤1500g (12) and a regional study with more

recent data from California 2005-2011 by GA categories (13). We included one study

from each of the following countries: Finland, Germany, Italy, Japan, Korea, Poland,

Spain, Sweden and Switzerland. Four studies were multi-centre (14-17), two studies

were regional (13, 18) and eight studies were national (9-12, 19-22). Most study

populations comprised babies admitted to a neonatal unit; two studies included live

births obtained from birth registry data, as the denominator (13, 19). Inclusion criteria

were based on birth-weight in seven studies; GA in four studies; GA and birth-weight

in two studies; and no GA or birth-weight restriction in one national linkage study.

Some studies restricted the population to babies that survived beyond 12 to 72 hours

after birth, and excluded babies with congenital anomalies (11, 21). With exception

of the study from Finland conducted in 1996 (19), all studies included data from the

last 15 years. The study from Sweden covered the longest period (1987-2009) using

data linkage between national registers.

8

Table 2 Characteristics of studies reporting country-level NEC incidence in OECD countries (in alphabetical order of country)

Country (Reference) Time period

Population inclusion and exclusion criteria, total number of infants

National/regional/multi-centre Case-

definition

Rate of NEC (by GA weeks (w) or birth-weight) as reported

Mortality (% of babies with NEC) if reported

Australia and New Zealand (9)

2005-2007

<32w

Admitted to tertiary neonatal unit

n=9995

National, retrospective

29 tertiary units in Australia and New Zealand Neonatal network (ANZNN)

Bell’s stage ≥2

<32w 3.5%

<25w 14.3%

25-26w 7.8%

27-28w 4.2%

29-31w 1.0%

Not reported

Canada (10) 2008-2012

<29w

Admitted to tertiary units

n=6026


25 of 30 tertiary units in Canadian Neonatal Network (CNN)

Bell’s stage ≥2

<29w 8.7%

22 to <26w 10%-14%

26 to <29w 6%-8%

Not reported

Canada (11) 2003-2011

<33w

Admitted to tertiary units

Excluded major congenital anomalies

29-32w n=17,589


Represents 95% of infants admitted to tertiary units in Canada. 75% of VLBW babies were admitted to tertiary units in CNN

Bell’s stage ≥2

29-32w 2.7% Not reported

Finland (19) 1996-1997

<1000g and ≥22w stillborn and live born in maternity hospitals

n=283

National, prospective

All 44 maternity hospitals in Finland

Bell’s all stages 1-3

<1000g 22% Not reported

9




definition



Germany, NEO-KISS database (14)

2007-11

<1500g

Admitted to neonatal units

n=33,048

Multi-centre, prospective

228 units

Represents 78% of VLBW babies (<1500g) born in Germany over their 5 year study period.

At least one radiological and two clinical findingsa

<1500g 2.9% Not reported

Italy (18) 1999-2002

<1500g and 23-37w

Admitted to neonatal unit

n=2035

Regional, prospective

14 tertiary units in Lombardy North of Italy

Bell’s stage ≥2

<1500g 3.1%

23w 6.5%

24w 13.1%

25-26w 8.4%

27-29w 2.6%

30-31w 1.0%

<1500g NEC

surgically treated 1.1%

Not reported

10




definition



Japan, (21) 2006-2008

<1500g, admitted to neonatal unit; admission defined as a stay for >24 hours, excluded congenital anomalies

n=9812

National; retrospective; comparison with Canada

Neonatal Research Network of Japan (NRNJ) represents 45% of VLBW (<1500g) babies born in Japan because many tertiary units were not endorsed by the Japanese government

70 of the 75 tertiary units designated by the Japanese government

Bell’s stage ≥2

NRNJ 153/9812 <1500g 1.6%

<25w 5.7%

25-26w 2.7%

27-28w 1.3%

29-32w 0.2%

>32w 1/1118 0.1%

Not reported

Korea (South)

(15)2013- 2014

All VLBW <1500g babies born in or transferred to neonatal unit within 28 days of birth

n=2326

Multi-centre, prospective One or more clinical and one or more radiological signsb

<1500g 6.8% 72(52%) had surgery

57(38%) medical

38(26.2%) of the NEC group died directly caused by NEC

Poland, Polish Neonatology Surveillance Network (PNSN) (16)

2009 <1500g


n=910


Six tertiary academic centres

Represents 19.1% of all VLBW babies born in Poland in 2009

At least two of a list of clinical and radiological signsc

<1500g 8.7% Not reported

11




definition



Spain, Spanish Society of Neonatology for VLBW babies (SEN1500) (17)

2002-2005

400-1500g,


n=8,836


Represents ˃95% of those born in tertiary hospitals of the Spanish public hospital network (SEN 1500) and 38.1-46.3% of all ELBW and VLBW babies born in the country

48/59 hospitals

Bell’s stage ≥2

400-1500g 6.9%

≤1000g 10.9%

1001-1500g 4.7%

NEC surgery 2.8% of <1500g

38% all NEC mortality

Sweden, National Patient Register, Swedish Medical Birth Register National Cause of Death (20)

1987-2009

All children born in Sweden n=2,381,318


Linkage of data with national registries

ICD-9 coded

All 0.03%

<28w 4.6%

28-31w 1.5%

32-36w 0.1%

Not reported

Switzerland, Swiss Neonatal Network

(22)

2000-2012 (2000-2004,

2005-2008,

2009-2012)

<32w GA

Epoch 2009-2012

n=2896


Represents of all VLBW <1500g

Represented 95% of the population as compared to birth registry of the Swiss Federal Statistical office

Nine level 3, six level 2 units

Bell’s stage ≥2

Years 2009-2012

<32w 2.6%

23w 11.1%

24w 5.5%

25w 3.6%

26w 3.2%

27w 3.7%

28w 2.2%

29w 1.6%

30w 1.1%

31w 0.7%

Not reported

12




definition



United States (12) 2005-2006

501-1500g,

n=71,808


511 US VON centres, approximately two-thirds of babies born VLBW in United States

At least one clinical and one radiological findinge

501-1500g 6.9%

501-750g 12.0%

751-1000g 9.2%

1001-1250g 5.7%

1251-1500g 3.3%

Mortality

501-750g 42%

751-1000g 29.4%

1001-1250g 21.3%

1251-1500g 15.9%

United States (13) 2005-2011

All live births <1500g born into CPQCC or co-located facilities.

<1500g n=30,566

<32w n=26,452

Regional, retrospective

Represents more than 90% of all perinatal facilities in California.

California Perinatal Quality Care Collaborative (CPQCC)

At least one clinical and one radiological findingf

<1500g 6.1%

<32w 6.8%

<24 7.8%

24-27 9.8%

28-31 4.4%

32-36 2.1%

Approximately 800 cases of “surgical NEC”

21.9% all NEC mortality

VLBW Very low birth-weight; VON Vermont Oxford Network; CDC Centre of disease control and prevention; ICD International Classification of Diseases

a CDC; Histopathological evidence of NEC OR at least one characteristic radiographic abnormality of pneumoperitoneum/pneumatosis intestinalis/unchanged ‘rigid’ loops of small bowel PLUS at least two of the following without other explanation: vomiting, abdominal distension, pre-feeding residuals, persistent microscopic or gross blood in stools.

b one or more of the following clinical signs: bilious gastric aspirator emesis, abdominal distension or occult or gross blood in stool AND one or more of the following radiographic findings: pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum.

c At least two of the following signs: vomiting, abdominal distension, pre-feeding residuals, redness of flanks, persistent microscopic or gross blood in stools, at least one of the following criteria, pneumoperitoneum, pneumatosis intestinalis, unchanging ‘rigid’ loops of small bowel or histological evidence of NEC, proven histologically

13

d ICD-9 code for NEC (777.5) in discharge record were selected, non-specific NEC

e VON definition: NEC was diagnosed at surgery, at post-mortem exam or by using key clinical and radiographic criteria. Specifically at least one clinical finding (bilious aspirate or emesis, abdominal distension, or occult or gross blood in the stool in the absence of anal fissures) and at least one radiographic finding (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum) required to secure diagnosis. Any babies with an operative diagnosis of spontaneous intestinal perforation (SIP) were excluded

f Defined as NEC diagnosed at operation or at post-mortem , or if NEC was diagnosed: one or more clinical signs from bilious gastric aspirate or emesis, abdominal distension, or occult or gross blood in the stool in the absence of an anal fissure, and 1 more radiographic findings including pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum

14

Case definitions for NEC

The most commonly applied definition was Bell’s stage ≥2, used in seven studies (9-

11, 17, 18, 21, 22). Other definitions included Bell’s stage 1-3 (19), the definition

from the Centre of Disease, Control and Prevention (CDC) (14) and the International

Classification for Diseases (ICD) which consisted of a code rather than a definition

(20). The remaining four studies used a combination of clinical and radiological signs

as specified by study authors (12, 13, 15, 16).

Risk of bias

Assessments using the modified risk of bias tool (8) showed that of the 14 included

studies, the overall risk of bias was low for one, moderate for eleven and high for two

studies (Table 3). We were unable to find any validation studies for the data sources

used. Eight studies were prospectively and six were retrospectively designed.

15

Table 3 Modified risk of bias assessment of the 14 included studies using a modified* version of the Hoy 2012 tool (8)

Excluded the assessment of “non-response bias” and “data collection from subjects” as not applicable

Study Country (Reference)

Representation

Sampling Random Selection

Case definition

Reliability of tool/ database validated

Method of data collection *

Prevalence period

Numerators and denominators

Overall risk of bias

Australia and New Zealand (9)

High High Low Low High Low Low Low Moderate

Canada (11) High Low Low Low High High Low Low Moderate

Canada (10) High High Low Low High Low Low Low Moderate

Finland (19) Low Low Low Low High Low Low Low Low

Germany (14) High High Low Low High High High High High

Italy (18) High High Low Low High Low Low High Moderate

Korea (15) High High Low Low High High Low Low Moderate

Japan (11) High High Low Low High Low Low Low Moderate

Poland (16) High High Low Low High Low Low Low Moderate

16

Spain (17) High High Low Low High Low Low High Moderate

Sweden (20) Low Low Low High High High Low Low Moderate

Switzerland (22) High High Low Low High Low Low Low Moderate

United States (12) High High Low Low High Low Low Low Moderate

United States (13) High High Low Low High High High Low High

*retrospective studies were included in high risk

17

Origins of data

With the exception of Finland (19), Sweden (20), Italy (18), data were extracted from

established networks that have maintained registers or databases, restricted to very

low birth-weight (VLBW) (<1500g) or very preterm (<32w GA) babies. Population

coverage differed, even among national studies, with some only including tertiary

neonatal units e.g. Canadian Neonatal Network which includes 75% of VLBW babies

in Canada and the Swiss Neonatal Network which includes level 2 and 3 neonatal

units, representing 90% of all VLBW babies born in Switzerland (22).

Comparison of rate of NEC by case definition, GA and birth-weight categories

We present the rate of NEC by case definition, GA and birth-weight categories

(Table 4). Comparing by GA, the rate of NEC was highest among the most preterm,

but higher among babies born at 24w compared to 23w GA (18, 19). For studies

using Bell’s staging 2, the rate of NEC was lowest in Japan across all GA

categories. The rate of NEC among preterm babies born <28w GA ranged from 2%

in Japan (21), 4% in Switzerland (22), to 7-9% in Australia, Canada, and Italy (9, 11,

18). Among babies born 28-31w, the rate of NEC ranged from 0.2% in Japan to 2-

3% in the other countries. Overall, the rate of NEC for all babies <32w GA ranged

from 2% in Japan to 3-4% in the other countries. In studies using other definitions,

the rate of NEC among <28w ranged from 5% in Sweden (20), to 10% in United

States (13). Studies using the VON definition, requiring one clinical sign and one

radiological finding reported higher incidences of NEC; around 7% for babies <32w

GA, compared to 2-4% in other studies.

Among babies <1500g, studies using Bell’s staging ≥2 reported an NEC rate

ranging from 2% in Japan, to 3% in Italy (18), to 6-7% in Korea and Spain (15, 17).

18

Studies using other definitions, reported an NEC rate ranging from 3% in Sweden

and Germany (14, 20), to 6-7% in the United States, to 9% in Poland (16). The

rate among babies born <1000g was highest in Finland (22.0 %) which used Bell’s

stage 1-3 as the case definition (19).

19

Table 4 Comparison of NEC rates as reported in the published literature by case definitions, gestational age and birth weight

Country, reference Definitions Gestational age (weeks) Birth-weight (g)

<28 28-31 <32 <1000 1000 to 1499 <1500

incidence (95% CI)Australia and New Zealand (9)

Bell’s stage ≥2 6.9 a (6.1, 7.6) 1.0 b (0.7, 1.2) 3.5 (3.2,3.9)

Canada (10, 11) 8.7 a (8.0, 9.4) 2.7 b (2.5, 2.9) 4.2 c (4.0, 4.5)Italy (18) 7.5 (5.2, 9.7) 1.7 (0.9, 2.4) 3.5 (2.6, 4.4) 3.0 (2.3, 3.8)Japan (21) 2.0 a (1.8, 2.2) 0.2 b (0.07,

0.4)1.6 c (1.5, 1.8) 1.6 (1.3, 1.8)

Korea (15) 6.4 (5.4, 7.4)Spain (17) 10.9f (9.8, 11.9) 4.8g (4.2,

5.3)6.9 d (6.4, 7.5)

Switzerland (22) 4.0e (3.2, 4.8) 1.9 (1.5, 2.2) 2.5 (2.2, 2.9)Finland (19) Bell’s stage 1-3 22.0 (17.1, 26.7)

Germany (14) At least one radiological and two clinical findings

2.9 (2.7, 3.1)

Poland (16) At least two of a list of clinical and radiological signs

8.7 (6.9, 10.5)

Sweden (20) ICD-9 code 4.6 (4.1, 5.1) 1.5 (1.3, 1.7) 2.4 (2.2, 2.7) 4.6 (4.1, 5.2) 1.5 (1.3, 1.7) 2.7 (2.4, 2.9)

United States (12) Vermont Oxford Network definition

10.4f (10.1, 10.8)

4.4g (4.2,4.6) 6.9d (6.7, 7.1)

United States California (13)

Vermont Oxford Network definition

9.6 (9.1, 10.1) 4.4 (4.0, 4.7) 6.8 (6.5, 7.1) 9.4 (8.9, 9.9) 3.9 (3.7, 4.2) 6.1 (5.9, 6.4)

a≤28w b29-31w c ≤32w d23-34w e≤26w d ≤1500g; e Years 2000-2012 f ≤1000g g1001 to 1500g; grey shaded areas indicate unavailable data

20

Laparotomy and mortality for NEC

Only four of the studies reported mortality of babies with NEC; for all NEC mortality

this ranged from 21.9% to 38% (12, 15, 17, 23).

DISCUSSION

We identified an almost four-fold difference, from 2% to 7%, in the rate of NEC

among babies born <32 weeks gestation in reports from twelve high income

countries. We also identified an almost five-fold difference from 5% to 22% in the

rate of NEC among those born <1000g. However, caution is warranted in interpreting

this variation. Studies varied in NEC case definition, quality, risk of bias, and

population coverage. Bell’s stage 2-3, was most commonly used to ascertain cases,

but growing recognition of the need for a more suitable case definition has led to

investigators applying different combinations of radiological and clinical signs. The

inconsistencies in definitions used make it difficult to make international

comparisons. A further important observation is that population data are necessary

for accurate estimation of burden of disease but there was variable coverage among

the national studies reported with very few studies truly covering the entire at-risk

population. Some studies described as population based were in fact limited to

tertiary centres, introducing selection bias as babies that might have died in lower

level units prior to transfer were excluded; for example the Neonatal Research

Network of Japan represented only 45% of VLBW babies and the VON centres only

two-thirds at the time of the study. Differences in inclusion criteria also limit

comparability, with some studies including all neonatal unit admissions and others

including only babies that survived a certain length of time. These limitations detract

from ability to make meaningful comparisons and argue for establishing standard

21

reporting criteria for NEC studies such as have been produced in other disease

areas (24).

Variation among studies with similar NEC definitions and inclusion criteria may

indicate differences in clinical practices, such as criteria for offering intensive care to

babies at the limits of viability (25, 26). Countries with a more active approach may

have higher NEC rates because of the higher survival of the extreme preterm babies

most at risk of developing NEC. Variations in feeding practices may also influence

the risk of NEC. Japan has the lowest reported rate, attributed to early and

“aggressive” enteral feeding and high use of unpasteurized Human Donor Milk

(HDM), though these practices have not been investigated with rigour.

Since undertaking this systematic review we have completed a two-year, prospective

whole population study of NEC in England (27) using the Neonatal Dataset extracted

from the National Neonatal Research Database (NNRD), a repository containing

data from admissions to all neonatal units in England. Since this study, the NNRD

now also includes all admissions from Scotland and Wales. We found that the

incidence of severe NEC, defined as that confirmed at laparotomy/post-mortem, or

resulting in death, was 3% in babies born <32 weeks GA.

The strengths of our study are the broad search criteria aimed at maximising the

likelihood that all relevant studies worldwide with data from more than one centre

would be identified. We also acknowledge limitations. By restricting the scope of this

review to NEC rates published in peer-review journals, we excluded annual data

published by some networks on their websites e.g. ANZNN reports (28).

Furthermore, due to the large volume of literature on NEC, we accept that despite

the broad criteria we may still have missed relevant and more recent publications.

22

Although we set pre-defined inclusion and exclusion criteria, these were difficult to

apply because of the heterogeneity of the studies. We justified the exclusion of

studies published by research groups such as National Institute of Child Health and

Development (NICHD) (2, 29-38) based on the restriction to academic units,

representing 5% of the population of VLBW born in the United States (2). For some

countries with multiple studies, selecting the most recent and nationally

representative data was not straightforward. For example, for Italy, we excluded a

study which had a greater number of neonatal units and geographical spread (39),

but was older, presenting data for the period 1995-6, which may explain their lower

NEC incidence despite applying a more liberal NEC definition when compared to the

more recent study presenting data for the period 1999-2002 (18). For Australia and

New Zealand, we excluded studies conducted over 15 years ago from the NSW and

Australian Capital Territory (40, 41). For Canada, we included two studies which

contained most recent data, although their primary focus was not NEC. One included

data for babies born up to 29w, and the other for babies born ≥29w (10, 11).

The wide range of definitions used for case ascertainment reflect the disparate

purposes for which studies were conducted, some primarily for research, others for

benchmarking and quality improvement exercises, but they limit the extent to which

the data can reliably be compared and pooled nationally and internationally. Bell’s

criteria were compiled to assist in management after the diagnosis of NEC was

made, and not as a case definition, yet are widely used for this latter purpose.

Additionally, different components of Bell’s staging are commonly selected by

authors to define NEC. Studies mandated different numbers of clinical and

radiological signs for NEC case ascertainment. Germany and Poland requires the

presence of one radiological sign and at least two clinical signs, making it a more

23

stringent criterion than the Vermont Oxford Network (VON) definition, which requires

one radiological and one clinical sign. The Swedish study used ICD codes to identify

NEC cases and included all cases without further specification, including ‘suspected

NEC’ (20). ICD codes are not a definition but are assigned after the diagnosis has

been made. We have recently published evidence-based gestation-specific criteria

for NEC case ascertainment that include abdominal x-ray findings and clinical signs

(42).

In conclusion, in this review, we highlight the limited information on population

incidence of NEC internationally, and the challenges in achieving complete

population coverage, and applying a consistent case definition. A number of

preventive and therapeutic approaches to reduce the incidence and impact of NEC

are under current and planned investigation. We recommend that to improve

comparisons and generalisability of conclusions, international consensus is sought

for the case definition for NEC, and criteria for reporting on the population covered.

Figure 1 PRISMA flow diagram of included studies

Contributors’ statements

Cheryl Battersby: Dr Battersby conceptualised and designed the study and data

collection forms, performed the initial searches, extracted the data, drafted the initial

manuscript, and approved the final manuscript as submitted

Tharsika Santhalingam: Dr Santhalingam carried out the initial searches and

extracted the data independently, reviewed and revised the manuscript, and

approved the final manuscript as submitted.

24

Kate Costeloe: Professor Costeloe critically reviewed the manuscript, contributed to

each draft, and approved the final manuscript as submitted.

Neena Modi: Professor Modi critically reviewed the manuscript and approved the

final manuscript as submitted.

Funding Source: This paper represents independent research funded by the

National Institute for Health Research (NIHR) under its Programme Grants for

Applied Research Programme (Grant Reference Number RP-PG-0707-10010). The

views expressed are those of the authors and not necessarily those of the NHS, the

NIHR or the Department of Health.

Financial Disclosure: The authors have no financial relationships relevant to this

article to disclose.

Potential Conflicts of Interest: The authors have no conflicts of interest relevant to

this article to disclose.

What is already known on this topic?

The number of babies at risk of developing neonatal necrotising enterocolitis

(NEC) in high resource settings is increasing with improving survival of

preterm babies.

Little is known of international variation in disease burden and no study has

systematically reviewed the published literature for NEC rates in high income

countries.

25

What this study adds?

Internationally there is a four to five-fold reported difference in rates of

necrotising enterocolitis between high income countries.

A standardised approach to reporting population coverage, study inclusion

criteria and NEC definition would enable more accurate international

comparisons

Acknowledgements

We wish to thank Luigi Galiardi, Riccardo Pfister and Fei Chen for providing the raw

numbers corresponding to the graphs in their publications.

REFERENCES

1. Berrington JE, Hearn RI, Bythell M, et al. Deaths in Preterm Infants: Changing Pathology Over 2 Decades. The journal of pediatrics. 2012;160:49-53.e1 doi: http://dx.doi.org/10.1016/j.jpeds.2011.06.046 [published Online.

2. Stoll BJ, Hansen NI, Bell EF, et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015;314:1039-51 Online.

3. Neu J. Necrotizing Enterocolitis: The Mystery Goes On. Neonatology. 2014;106:289-95 Online.

4. Horbar JD, Edwards EM, Greenberg LT, et al. Variation in Performance of Neonatal Intensive Care Units in the United States. JAMA Pediatr. 2017;171:6 Online.

5. PROSPERO. International prospective register of systematic reviews.

6. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:2046-4053 Online.

7. OECD. List of OECD Member countries 2014:http://www.oecd.org.

26

http://www.oecd.org/

http://dx.doi.org/10.1016/j.jpeds.2011.06.046

8. Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol. 2012;65:934-9 Online.

9. Hossain S, Shah PS, Ye XY, et al. Outcome comparison of very preterm infants cared for in the neonatal intensive care units in Australia and New Zealand and in Canada. Journal of Paediatrics and Child Health. 2015;51:881-8 doi: 10.1111/jpc.12863 [published Online.

10.Lee SK, Shah PS, Singhal N, et al. Association of a quality improvement program with neonatal outcomes in extremely preterm infants: a prospective cohort study. Canadian Medical Association Journal. 2014;186:E485-E94 doi: 10.1503/cmaj.140399 [published Online.

11. Isayama T, Shah PS, Ye XY, et al. Adverse Impact of Maternal Cigarette Smoking on Preterm Infants: A Population-Based Cohort Study. Am J Perinatol. 2015;32:1105-11 Online.

12.Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg. 2009;44:1072-5 Online.

13.Kastenberg ZJ, Lee HC, Profit J, et al. Effect of deregionalized care on mortality in very low-birth-weight infants with necrotizing enterocolitis. Jama, Pediatr. 2015;169:26-32 doi: 10.1001/jamapediatrics.2014.2085 [published Online.

14.Leistner R, Piening B, Gastmeier P, et al. Nosocomial infections in very low birthweight infants in Germany: current data from the National Surveillance System NEO-KISS. Klin Padiatr. 2013;225:75-80 Online.

15.Youn YA, Kim E-K, Kim SY. Necrotizing Enterocolitis among Very-Low-Birth-Weight Infants in Korea. Journal of Korean Medical Science. 2015;30:S75-S80 doi: 10.3346/jkms.2015.30.S1.S75 [published Online.

16.Wojkowska-Mach J, Rozanska A, Borszewska-Kornacka M, et al. Necrotising enterocolitis in preterm infants: epidemiology and antibiotic consumption in the Polish neonatology network neonatal intensive care units in 2009. PLoS One. 2014;9 Online.

17.Moro M, Perez-Rodriguez J, Figueras-Aloy J, et al. Predischarge morbidities in extremely and very low-birth-weight infants in Spanish neonatal units. Am J Perinatol. 2009;26:335-43 doi: 10.1055/s-0028-1110083 [published Online First: 2008/12/19].

18.Gagliardi L, Bellu R, Cardilli V, et al. Necrotising enterocolitis in very low birth weight infants in Italy: incidence and non-nutritional risk factors. J Pediatr Gastroenterol Nutr. 2008;47:206-10 doi: 10.1097/MPG.0b013e318174e855 [published Online First: 2008/07/31].

19.Tommiska V, Heinonen K, Ikonen S, et al. A National Short-Term Follow-Up Study of Extremely Low Birth Weight Infants Born in Finland in 1996–1997. Pediatrics. 2001;107:e2 doi: 10.1542/peds.107.1.e2 [published Online.

20.Ahle M, Drott P, Andersson RE. Epidemiology and trends of necrotizing enterocolitis in Sweden: 1987-2009. Pediatrics. 2013;132:2012-3847 Online.

27

21. Isayama T, Lee SK, Mori R, et al. Comparison of Mortality and Morbidity of Very Low Birth Weight Infants Between Canada and Japan. Pediatrics. 2012;130:e957-e65 doi: 10.1542/peds.2012-0336 [published Online.

22.Chen F, Bajwa NM, Rimensberger PC, et al. Thirteen-year mortality and morbidity in preterm infants in Switzerland. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2016; doi: 10.1136/archdischild-2015-308579 [published Online.

23.Kastenberg ZJ, Lee HC, Gould JB, et al. Level of Neonatal Intensive Care and Mortality in Infants with Necrotizing Enterocolitis. J Surg Res. 2014;186:572-3 doi: http://dx.doi.org/10.1016/j.jss.2013.11.499 [published Online.

24.Fitchett EJA, Seale AC, Vergnano S, et al. Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE-NI): an extension of the STROBE statement for neonatal infection research. Lancet Infect Dis. 2016;16:e202-e13 Online.

25.Draper ES, Zeitlin J, Fenton AC, et al. Investigating the variations in survival rates for very preterm infants in 10 European regions: the MOSAIC birth cohort. Arch Dis Child Fetal Neonatal Ed. 2009;94:19 Online.

26.Cuttini M, Nadai M, Kaminski M, et al. End-of-life decisions in neonatal intensive care: physicians' self-reported practices in seven European countries. EURONIC Study Group. Lancet. 2000;355:2112-8 Online.

27.Battersby C, Longford N, Mandalia S, et al. Incidence and enteral feed antecedents of severe neonatal necrotising enterocolitis across neonatal networks in England, 2012-3: a whole-population surveillance study. The Lancet Gastroenterology & Hepatology. 2017;2:43-51 doi: 10.1016/s2468-1253(16)30117-0 [published Online.

28.Australia and New Zealand neonatal network. Annual reports 2014.

29.Shah TA, Meinzen-Derr J, Gratton T, et al. Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation. J Perinatol. 2012;32:552-8 Online.

30.Hack M, Horbar JD, Malloy MH, et al. Very Low Birth Weight Outcomes of the National Institute of Child Health and Human Development Neonatal Network. Pediatrics. 1991;87:587-97 Online.

31.Hack M, Wright LL, Shankaran S, et al. Very-low-birth-weight outcomes of the National Institute of Child Health and Human Development Neonatal Network, November 1989 to October 1990. American Journal of Obstetrics and Gynecology. 1995;172:457-64 doi: http://dx.doi.org/10.1016/0002-9378(95)90557-X [published Online.

32.Fanaroff AA, Wright LL, Stevenson DK, et al. Very-low-birth-weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, May 1991 through December 1992. American Journal of Obstetrics and Gynecology. 1995;173:1423-31 doi: http://dx.doi.org/10.1016/0002-9378(95)90628-2 [published Online.

33.Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research

28

http://dx.doi.org/10.1016/0002-9378(95)90628-2

http://dx.doi.org/10.1016/0002-9378(95)90557-X

http://dx.doi.org/10.1016/0002-9378(95)90557-X

http://dx.doi.org/10.1016/j.jss.2013.11.499

network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics. 2001;107:E1 Online First: 2001/01/03].

34.Hintz SR, Kendrick DE, Stoll BJ, et al. Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants After Necrotizing Enterocolitis. Pediatrics. 2005;115:696-703 doi: 10.1542/peds.2004-0569 [published Online.

35.Fanaroff AA, Hack M, Walsh MC. The NICHD neonatal research network: changes in practice and outcomes during the first 15 years. Semin Perinatol. 2003;27:281-7 Online First: 2003/09/27].

36.Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. American Journal of Obstetrics and Gynecology. 2007;196:147.e1-.e8 doi: http://dx.doi.org/10.1016/j.ajog.2006.09.014 [published Online.

37.Guillet R, Stoll BJ, Cotten CM, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2006;117:e137-42 doi: 10.1542/peds.2005-1543 [published Online First: 2006/01/05].

38.Stoll BJ, Hansen NI, Bell EF, et al. Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network. Pediatrics. 2010;126:443-56 doi: 10.1542/peds.2009-2959 [published Online.

39.Rubaltelli FF, Dani C, Reali MF, et al. Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology. Acta Paediatr. 1998;87:1261-8 Online.

40.Luig M, Lui K. Epidemiology of necrotizing enterocolitis--Part I: Changing regional trends in extremely preterm infants over 14 years. J Paediatr Child Health. 2005;41:169-73 doi: 10.1111/j.1440-1754.2005.00582.x [published Online First: 2005/04/09].

41.Cust AE, Darlow BA, Donoghue DA. Outcomes for high risk New Zealand newborn infants in 1998-1999: a population based, national study. Arch Dis Child Fetal Neonatal Ed. 2003;88:F15-22 Online.

42.Battersby C, Longford N, Costeloe K, et al. Development of a gestational age–specific case definition for neonatal necrotizing enterocolitis. JAMA, Pediatr. 2017;171:256-63 doi: 10.1001/jamapediatrics.2016.3633 [published Online.

29

http://dx.doi.org/10.1016/j.ajog.2006.09.014

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