2. Position of equipoise on ‘when to start’ IUGR babies with AREDFV on antenatal Dopplers do have an increased risk of NEC BUT…no evidence that delaying feeds is of benefit AND…delaying feeds may increase;- –sepsis, cholestasis, chronic lung disease, duration of intensive care and length of hospital stay

3. Should one delay feeds? The ‘evidence’ Cochrane review ‘early’ < 4 days 2 small studies included 72 preterm infants only No differences seen for –days feedings held, weight gain, conjugated jaundice, necrotizing enterocolitis and death. Kennedy KA, Tyson JE. Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants

4. Where does current practice come from?

5. Historical comparison in late 70s Switch from aggressive to conservative management Brown and Sweet (Mount Sinai N.Y) Proven NEC in –14 / 1,745 LBW infants 1970 – 1974 –1 / 932 LBW infants 1974 - 1978

6. Started feeds at 5-7 days in ‘at risk’ infants (not defined) 3 hourly feeds of water, then diluted formula Increased volume and conc n over 16 days No statistics in the paper! Previous approach not described

7. ‘early’ ‘late’ 0-24 hours (day 1) Nil by mouth 24-48 hours (day 2) Start milk feeds according to tables 1 & 2 Nil by mouth 48-119 hours (day 3-5) Progress with feeding according to tables 1 & 2 Nil by mouth 120-143 hours (day 6) Progress with feeding according to tables 1 & 2 Start milk feeds according to tables 1 & 2 144 hours onwards (day 7+) Progress with feeding according to tables 1 & 2 ADEPT Trial feeding regimes

8. ‘early’ ‘late’ 0-24 hours (day 1) Nil by mouth 24-48 hours (day 2) Start milk feeds according to tables 1 & 2 Nil by mouth 48-119 hours (day 3-5) Progress with feeding according to tables 1 & 2 Nil by mouth 120-143 hours (day 6) Progress with feeding according to tables 1 & 2 Start milk feeds according to tables 1 & 2 144 hours onwards (day 7+) Progress with feeding according to tables 1 & 2 ADEPT Trial feeding regimes

9. ‘early’ ‘late’ 0-24 hours (day 1) Nil by mouth 24-48 hours (day 2) Start milk feeds according to tables 1 & 2 Nil by mouth 48-119 hours (day 3-5) Progress with feeding according to tables 1 & 2 Nil by mouth 120-143 hours (day 6) Progress with feeding according to tables 1 & 2 Start milk feeds according to tables 1 & 2 144 hours onwards (day 7+) Progress with feeding according to tables 1 & 2 ADEPT Trial feeding regimes

10. ‘early’ ‘late’ 0-24 hours (day 1) Nil by mouth 24-48 hours (day 2) Start milk feeds according to tables 1 & 2 Nil by mouth 48-119 hours (day 3-5) Progress with feeding according to tables 1 & 2 Nil by mouth 120-143 hours (day 6) Progress with feeding according to tables 1 & 2 Start milk feeds according to tables 1 & 2 144 hours onwards (day 7+) Progress with feeding according to tables 1 & 2 ADEPT Trial feeding regimes

11. ‘early’ ‘late’ 0-24 hours (day 1) Nil by mouth 24-48 hours (day 2) Start milk feeds according to tables 1 & 2 Nil by mouth 48-119 hours (day 3-5) Progress with feeding according to tables 1 & 2 Nil by mouth 120-143 hours (day 6) Progress with feeding according to tables 1 & 2 Start milk feeds according to tables 1 & 2 144 hours onwards (day 7+) Progress with feeding according to tables 1 & 2 ADEPT Trial feeding regimes

12. Day of initial milk feeding Dorling & McClure 1999 East Anglian SURVEY

13. Day of feeding Volume of milk according to birth weight (ml/kg/HOUR) <600g600-749g750-999g1000- 1249g  1250g 10.5 1.0 20.5 1.01.5 30.51.0 1.52.0 41.01.5 2.02.5 51.52.0 2.53.0 62.02.5 3.03.5 72.53.0 3.54.0 - 4.5 83.03.5 4.0 - 4.55.0 - 5.5 93.54.04.0 - 4.55.0 - 5.56.0 - 6.25 104.04.5 - 5.05.0 - 5.56.0 - 6.25 114.5 - 5.05.5 - 6.06.0 - 6.25 125.5 - 6.06.25 136.25 14Increase as required South West Neonatal Forum

14. Day of feeding Volume of milk according to birth weight (ml/kg/DAY) <600g600-749g750-999g1000- 1249g  1250g 112 24 212 2436 31224 3648 42436 4860 53648 6072 64860 7284 76072 8496 - 108 87284 96 - 108120-132 9849696-108120-132144-150 1096108-120120-132144-150 11108-120132-144144-150 12132-144150 13150 14Increase as required South West Neonatal Forum

15. Why not increase faster? Schedules developed from Southwest practice mid point of a ‘reasonable’ approach ‘too fast’ might lead to accusation of raised NEC not representative of UK experience

16. Milk types Choice of milk –Mother’s own breast milk, –Donated breast milk –Infant formula (preterm / term) Advise infants with gestation <34 weeks to be fed preterm formula within one week of starting milk. BMF if additional nutrition required once baby tolerating > 150ml/kg/day.

17. Exclusions and Deviations Withholding feeds or deviating from feeding schedule for feed intolerance or clinical deterioration At local clinician’s discretion.At local clinician’s discretion.

18. Exclusions and Deviations Gastric residuals common. Providing the infant is well and has no abnormal abdominal signs it is usually Safe to continue with enteral feeds when gastric aspirate is 2-3 ml or less (2 ml if <750 grams birth weight) –Mihatsch et al. J Pediatr Gastroenterol Nutr 2002;35:144-8.

19. Restarting after exclusion or Deviation Either –restart from day 1 of schedule or –re-start at the volume previously tolerated then increase as schedule or –hold for one or more days at a certain volume and then increase as schedule

20. Not Not reasons for deviation type of milk available ventilation status presence of an UAC / UVC

21. Milk feeding and ventilation 2 13

22. UAC presence: the ‘evidence’ 1 Small trial only 29 infants: unable to exclude effect on NEC! Cohort papers significant confounding data (sick infants need a UAC) Davey, J Pediatr 1994. Feeding premature infants while low umbilical artery catheters are in place: a prospective, randomized trial.

23. Milk feeding and UAC 2 13

24. Breast milk better than formula (n=343) McGuire, Anthony Arch Dis Child Fetal Neonatal Ed 2003. Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review. of NEC

25. A Breast Feeding Friendly Trial Please encourage EBM as much as possible!

26. Thank you for your attention Any Questions?

28. Speed of advance Kennedy & Tyson. Rapid versus slow rate of advancement of feedings for promoting growth and preventing necrotizing enterocolitis in parenterally fed low-birth-weight infants (Cochrane Review). 369 babies from three trials > 20 v < 20 cc/kg/day increase

29. Speed of advance faster increase in feed volumes –reduction in days to full enteral feeding –less days to regain birth weight –NO effect on NEC RR = 0.90 95% CI 0.46 - 1.77

30. Trophic feeds / MEF etc Stimulate endocrine and motor gut function 10- 20 ml/kg/day for > 48 hours Cochrane study of 6 trials Tyson JE, Kennedy KA. Minimal enteral nutrition for promoting feeding tolerance and preventing morbidity in parenterally fed infants.

31. MEF Cochrane review Outcomes significantly affected by MEF –length of stay: WMD 15.6 days less stay in MEF group (95% CI 8.5 to 22.8) –days to full feeding: WMD 2.7 days less in MEF group (95% CI 0.98 to 4.4). No difference in NEC or death rates last updated in 1997: 3 studies since

32. Further studies on MEN Schanler –n=171, NEC 13 in MEF, 10 controls McClure –n= 100, NEC 1 in MEF, 2 controls Van Elberg –IUGR infants, n=42, NEC 0 in MEF, 1 control Added to previous meta-analysis: NEC 10.5% in MEF, 9.4% controls (RR 1.07, 95%CI 0.84-1.36)

33. ADEPT - exclusions Major congenital abnormality Twin-twin transfusion Intra-uterine or exchange transfusion Rhesus haemolysis Multi-organ failure prior to randomisation Inotrope support prior to randomisation Already received enteral feed

34. ADEPT outcomes Primary outcomes –Time to reach full enteral feeds (for 72 hours) –NEC Secondary outcomes –Death –Duration of level 1 and level 2 IC –Growth: wt and OFC z-scores at 36w & d/c –Sepsis, cholestasis, bowel perforation, CLD

35. ADEPT sample size Time to reach full feeds –data taken from East Anglia –380 babies needed to show difference of 3 days with 90% power NEC –Incidence approx 15% –400 babies needed to show reduction to 7.5% with 60% power

36. Thank you for your attention Any Questions?