Feeding for Preterm Synthesis

Research gaps from Cochrane Reviews

(Cochrane Library Issue 3, 2006)

The faces indicate the direction of findings in each review:

JLikely to be effective
KBenefits and risks balanced
? Uncertain or limited effect
L Likely to be ineffective or potentially harmful

? Thus, important research implications are more likely to arise from reviews with uncertain findings.

J If a review shows an intervention to be beneficial,

K or that the risks and benefits are reasonably balanced, there may be less need for further research (at least for the major review question).

L If a review indicates that the intervention is likely to be ineffective or potentially harmful, or has been superseded, then this will often indicate that these research questions are of lower importance.

Timing of Feeding

? Not clear if ad-libitum, demand, semi-demand or scheduled feeds are more effective (Tosh 2006)

Need a large RCT of ad libitum or demand/semi-demand feeding versus scheduled interval feeding; focusing first on those preterm infants at the transition from enteral tube to oral feeding. Involvement of parents would inform the selection of the most relevant outcomes, including those related to parental satisfaction

? Not enough data to determine the optimum time for commencement of enteral feeds in pre-term infants being fed parenterally (Kennedy 2000)

Needs to be determined as there are risks and benefits associated with both early (less than 4 days) and late commencement. This will require a large RCT in which the clinicians do not have strong preferences for age at which enteral feeding should start. Trial outcomes should include: death before discharge, death or NEC requiring surgical resection before discharge, death or very prolonged hospital stay, death or major morbidity (including severe developmental delay and short bowel syndrome) at follow-up

? Using a formal feeding readiness assessment instrument compared with no formal instrument in preterm infants deemed ready to commence feeds (Crowe 2006)

Cochrane protocol, Cochrane review in progress

? The effect of different rates of advancement of enteral feeding beginning at the same postnatal age in premature infants as measured by feeding tolerance and neonatal outcome (Kennedy 1998)

Need a large trial comparing different rates of advancement of feeding among infants less than 1000g birth weight which assesses death before discharge; death or NEC requiring surgical resection before discharge home; death or very prolonged hospital stay (outcome associated with major long-term morbidity and addressing NEC, sepsis, other major long-term major complications of prolonged parenteral nutrition); death or major morbidity at follow-up

Breast feeding

? Not clear if there is any advantage in avoiding bottle feeds in preterm infants (Collins 2005)

Cochrane protocol, Cochrane review in progress

?Not clear if cup feeding is better in achieving breastfeeding than other forms of supplemental enteral feeding in (preterm) infants unable to fully breastfeed (Flint 2005)

Cochrane protocol, Cochrane review in progress

Methods of feeding

? Not clear if intermittent nasogastric tube milk feeding is more effective than continuous feeding (Premji 2002)

Future trials need to rigorously define feeding protocols and feeding intolerances and stratification should be attempted for birthweight, gestation and severity of illness

? Not clear if home (early discharge) gavage is more effective than hospital gavage although one trial of home gavage shows some promise (Collins 2003)

Need for trials with concealed random allocation, complete follow-up and adequate sample size to evaluate infection rates, feeding and growth, health care costs, impact of family, complications of gavage feeding and long term developmental outcomes of preterm infants allocated to early discharge with home gavage feeding compared with traditional hospital care

? Short-term benefits of early lipid administration for parenterally fed infants not seen (Simmer 2005)

Need RCT with sample size adequate to estimate effects on long-term growth, respiratory and neurodevelopmental outcomes, concentrating on infants less than 28 weeks gestation as these infants have high risk of short term morbidity, mortality and long term neurodevelopmental sequelae

? Early i.v. nutrition versus routine i.v. fluids for preterm infants who are not being fed enterally to prevent jaundice (Faber 2003)

No trials of early i.v. nutrition versus routine i.v. fluids for preterm infants who are not being fed enterally, which report outcomes for neonatal jaundice

? No studies of feed thickeners for gastro-oesophageal reflux in preterm (or term) infants (Huang 2002)

Need RCT ofsample size at least 50 infants, outcomes should include GOR (regurgitation, posseting, vomiting, haematemesis, failure to thrive, irritability, disturbed sleep, cough, apnoeas, oxygen desaturation, bradycardias), gastric and oesophageal acidity based on pH monitoring and side effects of the therapy (bowel obstruction, diarrhoea, aspiration, cough and colic)

JNon-nutritive sucking has some benefits such as reduced hospital stay (Pinelli 2005)

Studies addressing long-term outcomes and using similar outcomes to existing studies are needed

JPercutaneous central venous catheters versus peripheral cannulae for delivery of parenteral nutrition in neonates (Ainsworth 2004)

Need data on longer term growth and developmental outcomes, which is particularly important for very preterm infants

? Push feeding versus gravity feeding for more rapid establishment of full gavage tube feeds in preterm and/or low birth weight infants who require intermittent bolus tube feeding (Dawson 2005)

Cochrane protocol, Cochrane review in progress

? Effects of commencing TPN at higher amounts of amino acid (Thomas 2006)

Cochrane protocol,not yet covered in a Cochrane review

LTranspyloric versus gastric tube feeding for preterm infants (McGuire 2002)

Not a priority for further research due to lack of evidence of benefit combined with finding of an increased risk of gastrointestinal disturbance

? Trophic feeding for parenterally fed infants (Tyson 2005)

Large multi-centre trial of trophic feedings is needed among infants 1000g birthweight or less
Requires a trial sufficiently large to identify important effects on outcomes such as death, major morbidity and hospital stay, and longer term follow-up

Human milk composition

? Calcium and phosphorus supplementation of human milk for preterm infants (Kuschel 2001)

No trials of calcium and phosphorus supplementation alone located

? Carbohydrate supplementation of human milk for preterm infants(Kuschel 1999)

No trials of carbohydrate supplementation located

? Fat supplementation of human milk for preterm infants (Kuschel 2000a)

Any future trials of fat supplementation should focus on short term, long term and adverse outcomes (feed intolerance, NEC, diarrhoea) associated with medium-chain triglyceride supplementation and should contain adequate sample sizes in order to demonstrate any effect

? Protein supplementation of human milk for preterm infants (Kuschel 2000b)

Some benefits from protein supplementation but the long-term benefits have not been explored and further trials including large sample sizes are required

? High versus low medium chain triglyceride content of formula for promoting short term growth of preterm infants (Klenoff-Brumberg 2002)

Further studies are needed with larger sample sizes and careful blinding of outcome assessors (to assess gastrointestinal intolerance) in order to adequately answer effect of high versus low MCT formula on short and long term growth parameters and long term neurodevelopmental outcomes

JMulticomponent fortified human milk for promoting growth in preterm infants (Kuschel 2004)

Future research should be aimed at determining the �optimal� composition of multicomponent fortifiers

? Multicomponent fortified human breast milk versus unfortified breast milk in preterm or low birth weight infants following hospital discharge (McGuire 2004b)

Cochrane protocol, Cochrane review in progress

Formula milk composition

?Calorie and protein-enriched formula milk versus standard formula (Henderson 2005)

Need larger trials that assess long term outcomes such as final height, body composition and neurodevelopment (and participants in existing trials need to be followed up long term)

KHigh protein formula (Premji 2006)

Some benefits (such as weight gain) but short- and long-term growth and neurodevelopmental morbidities associated with increasing protein intake are still unclear - protein intakes above 4g/kg/day should be considered experimental
Future research should also aim to determine the precise protein requirements of preterm infants according to birth weight and gestational age

KLongchain polyunsaturated fatty acid supplementation in preterm infants (Simmer 2004)

Any future studies should be in very preterm infants who may derive more benefit

? Preterm compared with term formula among low birth weight or preterm infants (Bell 2003)

Cochrane protocol, Cochrane review in progress

? Soy formula in preterm infants (Osborn 2006)

This review has been withdrawn as of Cochrane Library Issue 2, 2006

Formula versus human milk

? Formula milk versus term preterm human milk for feeding term or low birth weight infants (Henderson 2001a)

Need to compare nutrient fortified preterm breast milk with formula milk
Could compare donated preterm breast milk versus formula milk

? Formula milk versus term human milk for feeding preterm or low birth weight infants (Henderson 2001b)

Old studies show improved short term growth for formula compared with unfortified human term milk - further studies are needed comparing enteral feeding with nutrient-enriched �pre-term� formula milk versus nutrient-fortified term human milk in a population at increased risk of NEC (e.g. very low birth weight infants (<1500grams))

� When no breast milk is available, could the supplementation of formula milk with a breast milk factor, such as immunoglobulin, reduce the incidence of NEC?

� Future trials should attempt to ensure that carers and assessors are blinded to treatment group allocation

� Future trials regarding risk of NEC would require a sample size of approximately 900 infants

? Not clear if calorie and protein-enriched formula milk is more effective than human breast milk in preterm or low birth weight infants following hospital discharge (McGuire 2004a)

Cochrane protocol, Cochrane review in progress

Formula or human milk

? Increased energy intake compared with standard energy intake in preterm infants with (or developing) bronchopulmonary dysplasia/chronic lung disease (Lai 2006)

No RCTs were located, so need to assess the optimal levels of energy intake, the best methods of delivering such levels of intake, and the optimal combination of various constituents of energy in preterm infants at risk of lung disease, as well as possible adverse effects from various methods of increasing energy intake. Target population should include all preterm infants with established or developing CLD/BPD. Outcomes should include short and long term respiratory morbidities and mortality, growth and neurodevelopment. Complications that might be related to CLD/BPD, like death from respiratory causes, should be assessed as an outcome and not constitute grounds for exclusion

? Lactase treated feeds to promote growth and feeding tolerance in preterm infants (Tan-Dy 2005)

Need RCTs of lactase-treated feeds enrolling very preterm infants when enteral feeds are commenced measuring primary outcomes such as weight gain and growth assessed at birth and at 40 weeks post-menstrual age; and days to achieve full enteral feeds and secondary outcomes such as duration of parenteral nutrition; days enteral feeds held; number of times enteral feeding is interrupted for gastric residuals; duration of hospitalisation; incidence of NEC; incidence of bacteraemia and sepsis; incidence of CLD; and other adverse effects

Drug interventions

? Erythromycin for feeding intolerance in preterm infants (Ng 2001)

No studies including only infants with feeding intolerance were located - need large RCTs including only infants with feeding intolerance and using lower than antimicrobial doses

References

Ainsworth SB, Clerihew L, McGuire W. Percutaneous central venous catheters versus peripheral cannulae for delivery of parenteral nutrition in neonates The Cochrane Database of Systematic Reviews Issue 2, 2004
Bell JC, Askie LM, Simmer K. Preterm formula milk versus term formula milk for feeding preterm or low birth weight infants. (Protocol) The Cochrane Database of Systematic Reviews 2003, Issue 2
Collins CT, Makrides M, McPhee AJ. Early discharge with home support of gavage feeding for stable preterm infants who have not established full oral feeds. The Cochrane Database of Systematic Reviews 2003, Issue 4
Collins CT, Makrides M, Gillis J, McPhee AJ. Avoidance of bottles during the establishment of breast feeds in preterm infants. (Protocol) The Cochrane Database of Systematic Reviews 2005, Issue 2
Crowe LM, Chang AM, Wallace KL. Instruments for assessing readiness to commence suck feeds in preterm infants: effects on time to establish full oral feeding and duration of hospitalisation. (Protocol) The Cochrane Database of Systematic Reviews 2006, Issue 1
Dawson J, Summan R, Badawi N. Push verus gravity for intermittent bolus gavage tube feeding of premature and low birth weight infants (Protocol) The Cochrane Database of Systematic Reviews 2005, Issue 2
Faber BM, Mills JF. Early intravenous nutrition for the prevention of neonatal jaundice. The Cochrane Database of Systematic Reviews 2003, Issue 3
Flint A, New K, Davies MW. Cup feeding versus other forms of supplemental enteral feeding for newborn infants unable to fully breastfeed (Protocol) The Cochrane Database of Systematic Reviews 2005, Issue 1.
Henderson G, Fahey T, McGuire W. Calorie and protein-enriched formula versus standard term formula for improving growth and development in preterm or low birth weight infants following hospital discharge. The Cochrane Database of Systematic Reviews 2005, Issue 2
Henderson G, Anthony MY, McGuire W. Formula milk versus preterm human milk for feeding preterm or low birth weight infants. The Cochrane Database of Systematic Reviews 2001, Issue 3 � [2001a]
Henderson G, Anthony MY, McGuire W. Formula milk versus term human milk for feeding term or low birth weight infants. The Cochrane Database of Systematic Reviews 2001, Issue 4 � last searched October 2003. [2001b]
Huang R-C, Forbes DA, Davies MW. Feed thickener for newborn infants with gastro-oesophageal reflux. The Cochrane Database of Systematic Reviews 2002, Issue 3
Kennedy KA, Tyson JE, Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants. The Cochrane Database of Systematic Reviews 2000, Issue 1
Kennedy KA, Tyson JE. Rapid versus slow rate of advancement of feeding for promoting growth and preventing necrotizing enterocolitis in parenterally fed low-birth-weight infants. The Cochrane Database of Systematic Reviews Issue 4, 1998
Klenoff-Brumberg HL, Genen LH. High versus low medium chain triglyceride content of formula for promoting short term growth of preterm infants The Cochrane Database of Systematic Reviews 2002, Issue 3