2 Birmingham Children’s Hospital, Birmingham Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants: systematic review. 1Morgan J, 1,2 Young L, 1 McGuire W. 1 Centre for Reviews and Dissemination, Hull York Medical School, University of York. 2 Birmingham Children’s Hospital, Birmingham Partly funded by the National Institute for Health Research Academic Clinical Fellowship Programme

Is it really important though? 15 million 11% 1 million 7% of babies born in UK, or 70,000 The global average preterm birth rate is 11%, that’s 15 million preterm babies every year 3 million infants die in the first 28 days of life 1 million die as a result of preterm birth complications

5% of preterm births

5% of preterm births 20% mortality

Stay in hospital longer Get more infections More long-term disability 5% of preterm births 20% mortality Grow more slowly Stay in hospital longer Get more infections More long-term disability Compared with their peers, infants who develop NEC have a higher incidence of long-term neurological disability, which may be a consequence of infection and under-nutrition during a critical period of brain development (Stoll 2004; Soraisham 2006; Rees 2007; Pike 2012).

Prolonged PN Infections Reduce NEC?

Prolonged PN Infections Reduce NEC?

Prolonged PN Infections Reduce NEC? enteral feeding is introduced earlier and feeding volumes advanced more quickly tend to have higher incidences of NEC (Uauy 1991). Observational studies have suggested that delaying the introduction of enteral feeds beyond the first few days after birth, or increasing the volume of feeds by less than about 20 ml/kg to 24 ml/kg body weight each day, is associated with a lower risk of developing NEC in very preterm or VLBW infants (Brown 1978; McKeown 1992; Patole 2005; Henderson 2009).

395g Slow postnatal growth has been associated with long term growth restriction, neuro-developmental impairment and poorer educational outcomes in later childhood, and cardiovascular disease, obesity and insulin resistance in later life.

Slow Prolonged PN Infections Reduce NEC?

Fast Prolonged PN Infections Reduce NEC?

Results Six trials 618 infants Slow advancement of 15 ml/kg to 20 ml/kg Faster advancement of 30 ml/kg to 35 ml/kg. Good methodological quality included – mostly very preterm and very low birth weight infants.

Does not increase the risk of NEC Advancing enteral feeds at 30 ml/kg to 35 ml/kg does not increase the risk of NEC in very preterm or VLBW infants. Increasing the volume of enteral feeds at slow rates (less than 24 ml/kg/day) results in several days delay in the time taken to regain birth weight and establish full enteral feeds.

Takes longer to reach full feeds Longer to regain birthweight ££££££ IUGR, borderline increase mortality in slow group Slow expensive tortoise

Research Question To assess and compare the effects of a fast (30 ml/kg/day) and a slow (18 ml/kg/day) increase in milk feed volumes on survival of very preterm (<32 weeks) or VLBW (<1,500 g) infants without moderate or severe disability at 24 months of age corrected for prematurity

Why is this important?

Future research questions How fast should we increase feeds? Should we feed IUGR/SGA infants differently to non-IUGR/SGA infants? What are the longterm outcomes e.g neurological? Does rapid growth have adverse effects?

References to included studies Bisquera 2002 Brown 1978 Caple 2004 Flidel-Rimon 2004 Guthrie 2003 Henderson 2009 Holman 1997 Karagol 2012 Krishnamurthy 2010 McKeown 1992 Mukhopadhyay 2014 Patole 2005 Pike 2012 Rayyis 1999 Rees 2007 Salhotra 2004 Soraisham 2006 Stoll 2004 Uauy 1991

Methods • Cochrane systematic review: Search: CENTRAL (The Cochrane Library, Issue 8, 2014), MEDLINE, EMBASE, and CINAHL (until Sep 2014), conference proceedings, and previous reviews. Data collection and analysis: Standard method of the Cochrane Neonatal Group, with separate evaluation of trial quality and data extraction by two authors, and synthesis using a fixed effect model for meta-analysis.

Nectrotising enterocolitis (NEC) Acute intestinal necrosis of unknown aetiology, affects about 5% of very preterm (<32 wks) or very low birth weight (VLBW) (<1500g) infants (Holman 1997), mortality rate is more than 20%. Infants who develop NEC experience more nosocomial infections, have lower levels of nutrient intake, grow more slowly, and have longer durations of intensive care and hospital stay than gestation-comparable infants who do not develop NEC (Bisquera 2002; Guthrie 2003) Compared with their peers, infants who develop NEC have a higher incidence of long-term neurological disability, which may be a consequence of infection and under-nutrition during a critical period of brain development (Stoll 2004; Soraisham 2006; Rees 2007; Pike 2012).

How do you feed premature infants? Or Breast feed Via naso-gastric tube Or Expressed breast milk Formula milk

Slow versus faster rates of feed advancement: effect on incidence of NEC. STUDY/SUBGROUP Risk Ratio M-H, Fixed (95% CI ) All trials Mukhopadhyay 0.50 (0.05, 4.94) Karagol 1.25 (0.36, 4.36) Krishnamurthy 0.50 (0.05, 5.34) Salhotra 0.21 (0.01, 4.12) Caple 0.57 (0.11, 3.01) Rayyis 1.44 (0.63, 3,32) Subtotal 0.96 (0.55, 1.70) Trials with most infants SGA/IUGR 0.50 (0.05, 4,94) 0.34 (0.06, 2.04) 0.01 0.1 1 10 100

Slow versus faster rates of feed advancement: effect on mortality. STUDY/SUBGROUP Risk Ratio M-H, Fixed (95% CI ) All trials Rayyis 0.59 (0.10, 3.46) Salhotra 1.78 (0.83, 3.81) Krishnamurthy 1.50 (0.45, 4.99) Karagol 1.33 (0.32, 5.63) Mukhopadhyay 7.00 (0.39, 124.83) Subtotal 1.57 (0.92, 2.70) Trials with most infants SGA/IUGR 2.12 (1.02, 4.47) 0.01 0.1 1 10 100