Enteral feeding practices in very preterm infants: an international ...

Original article
▶ An additional appendices
is published online only.
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1Department of Paediatrics,
University Hospital of North
Norway, Tromsø, Norway
2Neonatal Services, Royal
Women’s Hospital, Melbourne,
Australia
3Institute of Clinical Medicine,
University of Tromsø, Tromsø,
Norway
4Newcastle Hospitals NHS
Foundation Trust, Newcastle
upon Tyne, UK
Correspondence to
Claus Klingenberg,
Department of Paediatrics,
University Hospital of North
Norway, N-9038 Tromsø,
Norway;
claus.klingenberg@unn.no
Accepted 6 February 2011
Published Online First
18 August 2011
F56
Enteral feeding practices in very preterm infants: an
international survey
Claus Klingenberg, 1–3 Nicholas D Embleton, 4 Sue E Jacobs, 2 Liam A F O’Connell, 2
Carl A Kuschel 2
ABSTRACT
Objective To evaluate enteral feeding practices in
neonatal units in different countries and on different
continents.
Design A web-based survey of 127 tertiary neonatal
intensive care units in Australia, Canada, Denmark,
Ireland, New Zealand, Norway, Sweden and the UK.
Results 124 units (98%) responded. 59 units (48%)
had a breast milk bank or access to donor human milk
(Australia/New Zealand 2/27, Canada 6/29, Scandinavia
20/20 and UK/Ireland 31/48). The proportion of units
initiating enteral feeding within the fi rst 24 h of life
was: 43/124 (35%) if gestational age (GA)

Norway (9), Sweden (8), Ireland (8) and to 42 in the UK. The
questionnaire, consisting of multiple-choice and open-ended
questions, requested information about the demographics of
the unit, presence of a milk bank or access to DHM, human
milk analysis, initiation and advancement of enteral feeds,
indications for and use of human milk fortifi er (HMF), supplementation
with oral vitamins and postdischarge feeding (see
online supplementary appendix). Follow-up for non-responders
was by email and telephone. A second consultant in the
unit was approached if necessary.
Data analysis
Data were analysed using SPSS (v 16.0) statistical software.
Descriptive results are expressed as numbers and proportions
(%). When comparing feeding practices between the four different
regions, a one-way analysis of variance was used with
Bonferroni post hoc comparison. A p value 10 intensive care cots) were:
Canada 23/29 (79%), Australia/New Zealand 18/27 (67%),
UK/Ireland 22/48 (46%) and Scandinavia 7/20 (35%). All
units in Scandinavia and approximately two thirds of units
in UK/Ireland had access to DHM, which was less common
Table 1 Enteral nutrition strategies for very preterm infants in four geographical regions
Total
(N=124)
UK/Ireland
(N=48)
Original article
in Canada and Australia/New Zealand (table 1). All Swedish
units routinely analysed the protein and fat content in human
milk, but outside Sweden only one unit in Denmark and one in
Australia routinely used a human milk analyser.
Table 1 describes when enteral feeding is started, advanced
and mode of feeding (bolus vs continuous), with marked differences
between the four regions. In general, Scandinavia
introduced enteral feeds the earliest, followed by UK/Ireland
(fi gure 1). There were also marked differences in clinical indications
for delaying the introduction of enteral feeds (table 2).
Continuous feeding was routinely used for infants below 28
weeks’ gestation in almost half of the Scandinavian units
and in approximately one sixth of units in UK/Ireland, but
rarely in Australia/New Zealand and Canada. In contrast,
minimal enteral feeding was common in Canada but rare in
Scandinavia. Target enteral feeding volume in ‘stable’ preterm
infants was 140–160 ml/kg/day in most Canadian units and
161–180 ml/kg/day or higher in the other regions (table 1).
Differences in the use of HMF were not as large as with
feeding strategies (table 3). Fifteen of 48 UK/Ireland units
only added HMF to human milk when the infant ‘needed it’,
for instance because of poor weight gain or low urea values.
However, there was a large variation in the required enteral
volume tolerated (ml/kg/day) before adding HMF (fi gure 2).
In Canada approximately two thirds of the units added HMF
when an enteral volume of 80–140 ml/kg/day was tolerated.
In UK/Ireland approximately four fi fths of the units added
Canada
(N=29)
Australia/New Zealand
(N=27)
Scandinavia
(N=20) p Value
Access to donor human milk
From own milk bank 30 (24) 9 2 2 17 0.001
From external milk bank 29 (23) 22 4 0 3
No access to donor milk
Feeds commenced at 0–24 h of life
65 (53) 17 23 25 0
GA

Original article
Figure 1 (A–C) Timing of start of enteral feeding depending on gestational age (GA)/birth weight (BW).
HMF only when an enteral volume ≥150 ml/kg/day was tolerated.
In contrast, in UK/Ireland approximately two thirds of
the units started with full strength HMF, whereas in Canada
approximately two thirds of units commenced half strength
HMF or less. Approximately two thirds of the units routinely
using HMF provided additional vitamin supplementation even
F58
though most multi-component HMF products contain supplemental
vitamins.
Most units did not recommend protein or fat supplements
after discharge to infants who were receiving breast milk
exclusively at discharge (table 4). In Canada and UK/Ireland,
specifi c postdischarge formulas were frequently recommended
Arch Dis Child Fetal Neonatal Ed 2012;97:F56−F61. doi:10.1136/adc.2010.204123

Table 2 Specifi c clinical situations where units would usually delay onset of enteral feeding
UK/Ireland
(N=48)
in infants who were not breast fed at discharge. ‘Standard’
term infant formula was more commonly used in Australia/
New Zealand and Scandinavia.
DISCUSSION
This survey demonstrates large differences in feeding practices
for preterm infants in four separate geographical regions.
Access to DHM may be an important factor. Differences
in feeding intervals, target volumes, vitamin supplementation
and the use of HMF seem to refl ect the lack of clear
evidence.
Many mothers of preterm infants struggle to initiate
lactation. 19 Most units with access to DHM commenced
enteral feeding on the fi rst day of life, even in the most immature
infants, and advanced more rapidly than units without
access to DHM. Units without access to DHM frequently
delayed the introduction of enteral feeds until mother’s own
milk was available. Our survey shows a low use of DHM for
Canada
(N=29)
Australia/New Zealand
(N=27)
No human breast milk available* 35 (73) 16 (55) 24 (89) 0 (0)
Growth restricted infant/reversed or absent end
diastolic fl ow in the umbilical artery
27 (56) 13 (45) 20 (74) 3 (15)
Infant with signifi cant perinatal asphyxia (lactic
acidosis, multiorgan involvement)
41 (85) 27 (93) 25 (93) 12 (60)
Not yet passed meconium 1 (2) 2 (7) 0 (0) 0 (0)
Indwelling umbilical artery 3 (6) 1 (3.5) 2 (7) 0 (0)
Results expressed as number (%).
*Human breast milk here includes both mother’s own milk and donor human milk.
Table 3 Human milk fortifi cation (HMF) practices in preterm infants
UK/Ireland
(N=48)
Canada
(N=29)
Australia/New Zealand
(N=27)
Use of HMF
Only in selected cases 15 0 3 1
Routinely used in defi ned population
Eligibility criteria for HMF
33 29 24 19
Birth weight* 21 23 22 18
Gestational age
Criteria for commencing HMF
21 20 17 10
Certain enteral volume tolerated/day† 29 23 23 12
Postnatal age
Criteria for ceasing HMF
9 11 6 8
Reached a certain weight 6 16 19 10
Reached a certain GA 6 7 7 4
When fully breast feeding
When adding HMF
28 20 13 14
Start full strength 21 8 12 1
Start half strength (1–7 days) 9 15 10 9
Start less than half strength
Preparation of HMF
2 4 1 8
Bedside for each (1–2) feed 15 17 14 0
In milk kitchen for each 1–2 feeds 11 2 5 7
In milk kitchen, refrigerated for 12–24 h
Added vitamins when infant is on full strength HMF
6 8 4 11
No extra vitamins given 15 4 9 7
Extra multivitamins/vitamin D 17 23 14 11
Results expressed as number, as not all neonatal units responded to all survey questions.
*Birthweight cut-off as criterion for using HMF: 2 units

Original article
Differences in feeding mode may refl ect Scandinavian studies
that suggested possible benefi ts from continuous feeding.
25 26 In contrast, a systematic review suggested that infants
fed by continuous feeding took longer to reach full feeds. 27
However, all studies comparing feeding mode are small and
evidence of benefi t for a particular feeding mode is limited.
Rapidly growing preterm infants have high protein and
energy requirements. Recent European guidelines recommend
enteral protein intakes of 4.0–4.5 g/kg/day for infants
less than 1000 g and 3.5–4.0 g/kg/day for infants from 1000
to 1800 g. 6 After the fi rst 3–4 weeks, the protein content of
expressed breast milk is ~1.1–1.3 g/100 ml. Commercial HMF
increases protein content by 0.8–1.0 g/100 ml, 28 meaning that
an enteral volume of 180 (160–200) ml/kg/day is required to
approach a protein intake of 4.0 g/kg/day. 29 Most units in
this survey aimed for similar target volumes, although some
Canadian units had lower target volumes. While fortifi cation
can be individualised to improve protein intake and growth
when volumes are 150–160 ml/kg/day, 30 increasing the daily
enteral volume to 180 ml/kg/day 29 31 may be a simpler way to
achieve the same goal.
Adding HMF to human milk increases its osmolality and
may delay gastric emptying. 32 Some clinicians believe that
HMF increases feed intolerance, which may explain why
some units delay its introduction. However, feed intolerance
is a poorly defi ned symptom in preterm infants 2 and has no
clear relationship with NEC. Clinically, signifi cant gastrointestinal
adverse effects are not more common in preterm
infants receiving HMF. 33 A recent study reported that human
Figure 2 Enteral volume tolerated before adding human milk fortifier (HMF)
to human breast milk.
Table 4 Postdischarge enteral nutrition practices
F60
UK/Ireland
(N=48)
milk-based HMF reduced the risk of NEC. 14 Caution is needed
when interpreting this study, as the incidence of NEC was
very high (15%) in the control group and the incidence of NEC
in the human-milk based HMF group was similar to reports
from units using cow’s-milk based HMF. 20–22
Optimal nutritional management of preterm infants after
discharge is a dilemma. Poor growth is associated with worse
cognitive outcome, 34 but feeding breast milk after discharge
has benefi cial effects on cognition and longer term health. 35
Postdischarge formula was widely used in Canada and UK/
Ireland, despite no evidence of benefi t. 36
Our survey asked specifi cally for the ‘policy of the unit’.
However, as a single neonatologist responded, personal bias
cannot be excluded. Our survey does not describe actual enteral
nutrition received, so some caution is needed when comparing
our results with studies that have reported specifi c intakes.
The strength of this study is the high response rate from four
distinct geographical regions. We believe the responses refl ect
true differences in enteral feeding strategies and that this survey
gives an updated overview of the breadth of enteral nutrition
practices in developed countries in 2010.
CONCLUSION
This study highlights enormous variability in neonatal feeding
practice in four different geographical regions refl ecting
both lack of evidence and strong local traditions. There is a
need for evidence-based enteral feeding strategies that optimise
enteral nutrition (both in hospital and after discharge)
while minimising the risk of NEC. Future multicentre trials
comparing different feeding practices should be suffi ciently
powered to examine important long term (growth and development)
as well as more immediate outcomes (eg, death, NEC
and nosocomial infection).
Acknowledgements The authors thank the neonatal units in the following
hospitals and centres for providing data for this survey.
In Australia: Royal Darwin Hospital, Darwin; The Townsville Hospital, Townsville;
Mater Mothers’ Hospital, Brisbane; Royal Brisbane and Women’s Hospital,
Brisbane; John Hunter Children’s Hospital, Newcastle; Royal Prince Alfred Hospital,
Sydney; Liverpool Hospital, Liverpool; Nepean Hospital, Sydney; Royal Hospital
for Women, Sydney; Royal North Shore Hospital, Sydney; Westmead Hospital,
Sydney; The Children’s Hospital at Westmead, Sydney; The Canberra Hospital,
Canberra; Mercy Hospital for Women, Melbourne; Monash Medical Centre,
Melbourne; The Royal Women’s Hospital, Melbourne; Royal Children’s Hospital,
Melbourne; Royal Hobart Hospital, Hobart; Flinders Medical Centre, Adelaide;
Women’s and Children’s Hospital, Adelaide; King Edward Memorial Hospital for
Women and Princess Margaret Hospital for Children, Perth.
In Canada: Children’s Hospital of Eastern Ontario, Ottawa; The Ottawa Hospital,
Ottawa; IWK Health Centre, Halifax; Children’s Women’s Health Centre of BC,
Vancouver; BC Children’s Hospital, Vancouver; Foothills Medical Centre, Calgary;
Royal Alexandra Hospital, Edmonton; Janeway Children’s Health & Rehabilitation
Centre, St. John’s; Kingston General Hospital, Kingston; McMaster Children’s
Hospital, Hamilton; Royal Columbian Hospital, New Westminster; St. Boniface
General Hospital, Winnipeg; St. Joseph’s Health Care, London; Sunnybrook &
Canada
(N=29)
Australia/New Zealand
(N=27)
Exclusive breast milk feeding
No routine nutritional supplements unless baby is not growing well* 48 24 26 15
Extra protein routinely recommended
Not exclusive breast feeding
0 3 0 4
Specially designed postdischarge formula 43 21 5 7
’Normal’ (term) formula 5 5 21 9
Term formula, increased strength (10–20%) 0 1 0 3
Results expressed as number, as not all neonatal units responded to all survey questions.
*Nutritional supplements defi ned as extra protein or fat, and do not include extra vitamins.
Scandinavia
(N=20) p Value
Arch Dis Child Fetal Neonatal Ed 2012;97:F56−F61. doi:10.1136/adc.2010.204123

Women’s College Health Sciences Centre, Toronto; The Moncton Hospital,
Moncton; University of Manitoba Health Sciences Centre, Winnipeg; Victoria
General Hospital, Victoria; Hospital for Sick Children, Toronto; Mount Sinai
Hospital, Toronto; Universite de Montreal Hospital Sainte-Justine, Montreal;
Centre Hospitalier Universitaire de Quebec, Quebec City; Jewish General Hospital,
Montreal; Royal Victoria Hospital, McGill University Health Centre, Montreal;
Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke; Royal University
Hospital, Saskatoon; Regina General Hospital, Regina; Dr. Everett Chalmers
Regional Hospital, Fredericton; Cape Breton Regional Hospital, Sydney; Surrey
Memorial Hospital (Level 2), Surrey.
In Denmark: Odense University Hospital, Odense; Rigshospitalet, Copenhagen;
Århus University Hospital, Århus.
In New Zealand: National Women’s Health, Auckland; Middlemore Hospital,
Auckland; Waikato Hospital, Hamilton; Wellington Regional Hospital, Wellington;
Christchurch Women’s Hospital, Christchurch; Dunedin Hospital, Dunedin.
In Ireland: The Rotunda Hospital, Dublin; National Maternity Hospital, Dublin;
Coombe Women’s Hospital, Dublin; Cork University Maternity Hospital, Cork; Our
Lady of Lourdes Hospital, Drogheda; St. Munchin’s Regional Maternity Hospital,
Limerick; University College Hospital, Galway.
In Norway: Oslo University Hospital-Rikshospitalet, Oslo; Oslo University Hospital-
Ullevål, Oslo; Akershus University Hospital, Lørenskog; Stavanger University
Hospital, Stavanger; Haukeland University Hospital, Bergen; Health Sunnmøre
Trust, Ålesund; St. Olav University Hospital, Trondheim; Nordland Central Hospital,
Bodø; University Hospital of North Norway, Tromsø.
In Sweden: Örebro University Hospital, Örebro; Karolinska University Hospital-
Astrid Lindgren Solna, Stockholm; Karolinska University Hospital-Huddinge,
Stockholm; Sahlgrenska University Hospital, Gothenburg; Linköping University
Hospital, Linköping; Norrland University Hospital, Umeå; Uppsala University
Hospital, Uppsala; Lund University Hospital, Lund.
In the UK: Aberdeen Maternity Hospital, Aberdeen; Royal Infi rmary of Edinburgh,
Edinburgh; Royal Hospital for Sick Children, Glasgow; Royal Victoria Infi rmary,
Newcastle upon Tyne; Leeds General Infi rmary, Leeds; Addenbrooke’s Hospital,
Cambridge; Birmingham Heartlands Hospital, Birmingham; Birmingham Women’s
Hospital, Birmingham; Chelsea & Westminster Hospital, London; Derriford Hospital,
Plymouth; University College London Hospital, London; Homerton University
Hospital, London; James Cook University Hospital, Middlesbrough; Southampton
General Hospital, Southampton; John Radcliffe Hospital, Oxford; Leicester Royal
Infi rmary, Leicester; Norfolk and Norwich University Hospital, Norwich; Queen’s
Medical Centre, Nottingham; Nottingham City Hospital, Nottingham; Peterborough
District Hospital, Peterborough; Queen Alexandra Hospital, Portsmouth; Royal
Hallamshire Hospital, Sheffi eld; Royal Shrewsbury Hospital, Shrewsbury;
Southmead Hospital, Bristol; St George’s Hospital, London; St Mary’s Hospital,
Manchester; St Michael’s Hospital, Bristol; Bradford Royal Infi rmary, Bradford;
Women and Children’s Hospital, Hull; Liverpool Women’s Hospital, Liverpool; Royal
Preston Hospital, Preston; University Hospital of North Tees, Stockton; William
Harvey Hospital, Kent; York Hospital, York; Forth Park Hospital, Kirkcaldy; Royal
Maternity Hospital, Belfast; City Hospitals Sunderland, Sunderland; King’s College
Hospital, London; St Peter’s Hospital, Chertsey; Queen Charlottes and Chelsea
Hospital, London; Royal London Hospital, London.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1. King C. What’s new in enterally feeding the preterm infant? Arch Dis Child Fetal
Neonatal Ed 2010;95:F304–8.
2. Patole S. Strategies for prevention of feed intolerance in preterm neonates: a
systematic review. J Matern Fetal Neonatal Med 2005;18:67–76.
3. Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence
of neonatal necrotising enterocolitis: a systematic review and meta-analysis of
observational studies. Arch Dis Child Fetal Neonatal Ed 2005;90:F147–51.
4. Flidel-Rimon O, Branski D, Shinwell ES. The fear of necrotizing enterocolitis
versus achieving optimal growth in preterm infants–an opinion. Acta Paediatr
2006;95:1341–4.
5. Menon G, Boyle EM, Embleton ND, et al. Introduction of enteral feeds in preterm
infants. Pediatrics 2004;114:327–8.
6. Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm
infants: commentary from the European Society of Paediatric Gastroenterology,
Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr
2010;50:85–91.
7. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation:
an inevitable consequence of current recommendations in preterm infants?
Pediatrics 2001;107:270–3.
Original article
8. Gartner LM, Morton J, Lawrence RA, et al. Breastfeeding and the use of human
milk. Pediatrics 2005;115:496–506.
9. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely
low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol
2009;29:57–62.
10. Bombell S, McGuire W. Delayed introduction of progressive enteral feeds to
prevent necrotising enterocolitis in very low birth weight infants. Cochrane
Database Syst Rev 2008;2:CD001970.
11. McGuire W, Bombell S. Slow advancement of enteral feed volumes to prevent
necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst
Rev 2008;2:CD001241.
12. Bombell S, McGuire W. Early trophic feeding for very low birth weight infants.
Cochrane Database Syst Rev 2009;3:CD000504.
13. Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in
life decreases the incidence of necrotizing enterocolitis in very low birth weight
infants. Pediatrics 2003;111:529–34.
14. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is
associated with a lower rate of necrotizing enterocolitis than a diet of human milk
and bovine milk-based products. J Pediatr 2010;156:562–7.e1.
15. Mosqueda E, Sapiegiene L, Glynn L, et al. The early use of minimal enteral
nutrition in extremely low birth weight newborns. J Perinatol 2008;28:264–9.
16. Patole S, Muller R. Enteral feeding of preterm neonates: a survey of Australian
neonatologists. J Matern Fetal Neonatal Med 2004;16:309–14.
17. Hans DM, Pylipow M, Long JD, et al. Nutritional practices in the neonatal
intensive care unit: analysis of a 2006 neonatal nutrition survey. Pediatrics
2009;123:51–7.
18. Tuthill DP. A survey of neonatal nutrition policies and practices in the UK and
Eire. Matern Child Nutr 2007;3:120–8.
19. Schanler RJ, Lau C, Hurst NM, et al. Randomized trial of donor human milk
versus preterm formula as substitutes for mothers’ own milk in the feeding of
extremely premature infants. Pediatrics 2005;116:400–6.
20. Markestad T, Kaaresen PI, Rønnestad A, et al. Early death, morbidity, and need
of treatment among extremely premature infants. Pediatrics 2005;115:1289–98.
21. Fellman V, Hellström-Westas L, Norman M, et al. One-year survival of extremely
preterm infants after active perinatal care in Sweden. JAMA 2009;301:2225–33.
22. Luoto R, Matomäki J, Isolauri E, et al. Incidence of necrotizing enterocolitis in
very-low-birth-weight infants related to the use of Lactobacillus GG. Acta Paediatr
2010;99:1135–8.
23. Rønnestad A, Abrahamsen TG, Medbø S, et al. Late-onset septicemia in a
Norwegian national cohort of extremely premature infants receiving very early full
human milk feeding. Pediatrics 2005;115:e269–76.
24. Flidel-Rimon O, Friedman S, Lev E, et al. Early enteral feeding and nosocomial
sepsis in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed
2004;89:F289–92.
25. Dsilna A, Christensson K, Alfredsson L, et al. Continuous feeding promotes
gastrointestinal tolerance and growth in very low birth weight infants. J Pediatr
2005;147:43–9.
26. Dsilna A, Christensson K, Gustafsson AS, et al. Behavioral stress is affected
by the mode of tube feeding in very low birth weight infants. Clin J Pain
2008;24:447–55.
27. Premji S, Chessell L. Continuous nasogastric milk feeding versus intermittent
bolus milk feeding for premature infants less than 1500 grams. Cochrane
Database Syst Rev 2003;1:CD001819.
28. Kempley ST, Sinha AK, Thomas MR. Which milk for the sick preterm infant? Curr
Paediatr 2005;15:390–9.
29. Schanler RJ, Hurst NM, Lau C. The use of human milk and breastfeeding in
premature infants. Clin Perinatol 1999;26:379–98, vii.
30. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortifi cation of human milk fed to
preterm infants: does it make a difference? J Perinatol 2006;26:614–21.
31. Kuschel CA, Evans N, Askie L, et al. A randomized trial of enteral feeding
volumes in infants born before 30 weeks’ gestation. J Paediatr Child Health
2000;36:581–6.
32. Ewer AK, Yu VY. Gastric emptying in pre-term infants: the effect of breast milk
fortifi er. Acta Paediatr 1996;85:1112–15.
33. Kuschel CA, Harding JE. Multicomponent fortifi ed human milk for promoting
growth in preterm infants. Cochrane Database Syst Rev 2004;2:CD000343.
34. Cooke RW, Foulder-Hughes L. Growth impairment in the very preterm and
cognitive and motor performance at 7 years. Arch Dis Child 2003;88:482–7.
35. Vohr BR, Poindexter BB, Dusick AM, et al. Persistent benefi cial effects of breast
milk ingested in the neonatal intensive care unit on outcomes of extremely low
birth weight infants at 30 months of age. Pediatrics 2007;120:e953–9.
36. Henderson G, Fahey T, McGuire W. Multicomponent fortifi cation of human
breast milk for preterm infants following hospital discharge. Cochrane Database
Syst Rev 2007;7:CD004866.
Arch Dis Child Fetal Neonatal Ed 2012;97:F56−F61. doi:10.1136/adc.2010.204123 F61