Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH

1
Feeding the preterm IUGR infant

• Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH
• Centre for Neonatal Research and Education
• KEM Hospital for Women, University of Western
  Australia Perth

2
Feeding preterm IUGR infants

• Experimental studies show that hypoxia reduces
  intestinal blood flow and oxygen delivery through
  adrenergic vasoconstriction.
• Nowicki et al 1988
• ? Oxygen extraction can compensate for a 30
  reduction in gut blood flow, but enteral feeding
  reduces the ability of oxygen extraction to
  compensate for the effects of hypoxia.
• Bulkley et al 1985, Szabo et al 1987
• Metabolic demands of enteral feeds increase O2
  consumption by the intestine.
• Nowicki et al 1983

3
Feeding preterm IUGR infants

• SMA and Coeliac axis flow is significantly
  reduced on D1 and the recovery in the baseline
  flow is slow during the 1st week of life in IUGR
  infants
• Despite the recovery in baseline SMA and Coeliac
  axis flow, the dynamic response to 1st feed is
  still impaired in IUGR infants
• Gamsu 1997, Maruyama 2001, Murdoch 2003

4
Feeding preterm IUGR infants Perth data

• 38/220 (17.3) neonates lt 28 weeks during 2 year
  period had IUGR.
• Mean (IQR) age at start of feeds 7 (5-10) vs. 5
  (4-8) days, p??0.005
• Mean (IQR) age at 1?ml/2hourly feeds 12 (8-15)
  vs. 9 (7-13) days, p??0.034
• Shah et al JMFN Med 2014

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Feeding preterm IUGR infants

• Median (IQR) postnatal age at FEF
  (150?ml/kg/day) 32 (21-40) vs. 24 (17-31) days,
  p??0.009
• Postnatal growth restriction 73 vs. 45,
  p??0.003
• Definite NEC 18/220 (8.1)
• Conclusion Optimising enteral nutrition in
  extremely preterm IUGR neonates is a difficult
  proposition
• Shah et al JMFN Med 2014

6
Preterm IUGR infants and abnormal Dopplers

• Independent case series (N14)
• All NEC AREDF 85/659 vs Control 66/1178
• OR 2.13 (95 CI 1.49 to 3.03)
• Confirmed NEC (6 studies)
• OR 6.9 (95 CI 2.3 to 20)
• Dorling et al. ADC2005

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• Santulli theory for pathogenesis of NEC Triad of
  ischaemia, bacteria, and substrate
• Santulli et al. Pediatrics 1975
• Prolonging small feeding volumes early in life
  decreases the incidence of NEC in VLBW infants.
• Berseth et al. Pediatrics 2003

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Early feeding advancement in VLBW infants with
IUGR and ? UA resistance

• 124 inborn VLBW infants enrolled in a prospective
  trial evaluating early enteral nutrition after a
  standardized feeding protocol (daily feed
  increment 16 ml/kg)
• Feeding tolerance assessed by age at FEF (150
  ml/kg/day)
• Mihatsch et al. JPGN2002

9
Results

• FEF achieved at 15 days (12-21 days) of age for
  all infants.
• IUGR FEF 14 (12-21) days, ? UA resistance
  FEF 14 (11-16) days, and brain sparing FEF
  15 (14-20) days were not associated with early
  feed intolerance.
• Conclusion VLBW infants with IUGR, ? UA
  resistance, and brain sparing tolerated enteral
  feeds as well as AGA VLBW infants.

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Early versus delayed MEF and risk for NEC in
preterm IUGR infants with abnormal Dopplers.

• Aim Assess the effect of early (5 days) vs.
  delayed (6 days) MEF on the incidence of NEC and
  feed intolerance in preterm IUGR infants with
  abnormal Dopplers.
• Design Randomized, non-blinded pilot trial
  Early vs. Delayed MEF in addition to PN
  within 48 hours
• Karagianni et al. 2010 May

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Results

• 81/84 enrolled infants completed the trial
• 40 Early 2 (1-5) vs. 41 Delayed MEF 7 (6-14)
  days
• No significant difference in NEC (p0.353) and
  feeding intolerance (p0.533)

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Results

• Birth weight was an independent risk factor for
  NEC in both groups.
• Early MEF may not have a significant effect on
  NEC or feed intolerance in preterm IUGR infants
  with altered Dopplers.

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Predictors of NEC in preterm IUGR neonates

• Even when Doppler variables are taken into
  consideration, birthweight remains the
  predominant risk factor for NEC.
• Manogura AC et al. Am J Obstet Gynecol. 2008

14

• Early vs. delayed enteral feeding for preterm
  growth-restricted infants a randomized trial
• Leaf et al. Pediatrics 2012 May

15
Background

• Preterm IUGR infants are at increased risk of NEC
  and delayed initiation of feeds
• No evidence that this delay is beneficial and
  might further compromise nutrition and growth

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Methods

• Infants with gestation lt35 weeks, BW lt10th
  centile and abnormal UA Doppler waveforms
  randomly allocated to
• Start feeds "Early" (D2) or "Late" (D6) after
  birth
• Feeds ? gradually by a feeding protocol, equal
  rate of increase for both groups
• Primary outcomes Time to FEF sustained for 72
  hrs and NEC

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Sample size estimation

• Unpublished data from a UK regional database of
  VLBW revealed an SD of 9 days in the time to
  reach FEF
• 380 infants needed to show a 3 day difference in
  time to FEF with 90 power
• NEC15, so recruiting 400 infants would be
  sufficient to show a 50 change in the incidence
  of NEC with 60 power

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Results

• 404 infants from 54 hospitals in UK and Ireland
  (202/group)
• Median gestation 31 weeks
• FEF (Median) Early 18 vs. Late 21 days (HR
  1.36 95 CI 1.11-1.67)
• All Stage NEC Early 18 vs. Late 15 (RR 1.2
  95 CI 0.77-1.87)
• Stage II/III NEC 8 in both groups
• Early feeds Shorter duration of TPN and
  high-dependency care, ? cholestasis, and ? SD
  score for weight at discharge

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Conclusion

• Early introduction of feeds in preterm IUGR
  infants resulted in earlier achievement of FEF
  without increasing the risk of NEC

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Applicability of ADEPT trial results

• Gestation lt29 weeks 44 vs. 42 infants
• Birth weight lt1000 grams 86 vs. 105 infants
• Birth weight lt 750 grams 33 vs. 41 infants
• Not powered adequately for detecting a minimum
  significant change in incidence of NEC, the real
  concern
• Enrolment from 64 centres
• No real justification for late starting of feeds
  (after 6 days)

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Post-hoc analysis ADEPT subgroup

• IUGR neonates lt29 weeks failed to tolerate even
  the careful feeding and reached FF significantly
  later than predicted
• Median (IQR) age at FEF in lt29 vs 29 weeks
• 28 (22-40) vs. 19 (17-23) days, HR 0.35 (95 CI
  0.3 to 0.5)
• Incidence of NEC significantly higher in lt29 vs
  29 weeks
• 32/83 (39) vs. 32/312 (10), RR 3.7, (95 CI
  2.4 to 5.7)
• Kempley et al. ADC 2013 Aug

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Other risk factors

• PDA
• Ibuprofen
• Phototherapy
• CPAP
• Proinflammatory cytokines (PIH)
• Oxidative stress
• Sepsis (neutropenia)
• Polycythemia

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Minimising the risk of NEC in IUGR neonates

• Early trophic enteral feeds
• Early preferential use of mothers milk
• PDHM if mothers milk is unavailable/Avoid
  formula
• Feeding protocol (Conservative vs. Aggressive)
• Ideal vs realistic nutritional goals
• Prevention and treatment of sepsis
• Probiotic supplementation

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NEC Unusual presentation in preterm IUGR

• No significant abdominal distension, minimal bile
  stained gastric residuals, no/no significant
  pneumatosis but
• Significant widespread necrosis of the gut on
  autopsy

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Feeding preterm IUGR infants lt28 weeks

• Start colostrum as soon as available (Day 0)
• Early trophic feeds lt10 ml/kg/day, Duration 5
  days
• Nutritional feeds Start at 15 ml/kg/day and ? by
  15 ml/kg/day
• Consider continuous feeds for persistent feed
  intolerance
• Reach 60 ml/kg/day to promote gut development and
  function
• Worsening volume and colour of gastric residuals
  Take a break!!
• Clinical examination, and awareness of coexisting
  risk factors for NEC are important
• Probiotic supplementation (Will they work?)