Enteral nutrition in preterm neonates

Enteral Nutrition in Enteral Nutrition in Preterm NeonatesPreterm Neonates

Dr Varsha Atul ShahDr Varsha Atul Shah

IntroductionIntroduction Proper nutrition in infancy is essential for Proper nutrition in infancy is essential for

– normal growthnormal growth– immunity to infectionimmunity to infection– optimal neurologic and cognitive development.optimal neurologic and cognitive development.

Providing adequate nutrition to preterm infants is Providing adequate nutrition to preterm infants is challenging because of several problems, some of them challenging because of several problems, some of them unique to these small infants. These problems include:unique to these small infants. These problems include:– immaturity of bowel functionimmaturity of bowel function– inability to suck and swallowinability to suck and swallow– high risk of necrotizing enterocolitis (NEC)high risk of necrotizing enterocolitis (NEC)– illnesses that may interfere with adequate enteral illnesses that may interfere with adequate enteral

feeding (feeding (e.g.e.g. RDS, patent ductus arteriosus) RDS, patent ductus arteriosus) – medical interventions that preclude feeding (medical interventions that preclude feeding (e.g.e.g., ,

umbilical vessel catheters, exchange transfusion, umbilical vessel catheters, exchange transfusion, indomethacin therapy)indomethacin therapy)

Long term outcome and Long term outcome and Barker’s HypothesisBarker’s Hypothesis

There is evidence that adaptations in the metabolic and There is evidence that adaptations in the metabolic and hormonal milieu in the fetal and immediate neonatal period hormonal milieu in the fetal and immediate neonatal period can result in immediate benefit but adverse long-term can result in immediate benefit but adverse long-term outcome.outcome.

Nutritional insults at a vulnerable period of brain Nutritional insults at a vulnerable period of brain development, for example, have been shown to be development, for example, have been shown to be associated with effects on brain size, cell number, behavior associated with effects on brain size, cell number, behavior and learning memory.and learning memory.

The emergence of cardiovascular disease, hypertension, The emergence of cardiovascular disease, hypertension, insulin resistance and obesity in low birth weight infants is insulin resistance and obesity in low birth weight infants is another concern raising the issue of long-term another concern raising the issue of long-term ‘‘programming.’’‘‘programming.’’

In addition, there may be transgenerational effects as In addition, there may be transgenerational effects as evidenced by the association of low maternal birth weight evidenced by the association of low maternal birth weight and higher offspring hypertension in adulthood.and higher offspring hypertension in adulthood.

These changes may be exacerbated by postnatal These changes may be exacerbated by postnatal malnutrition and poor growth that preterm infants malnutrition and poor growth that preterm infants experience.experience.

PHYSIOLOGY AND PHYSIOLOGY AND PATHOPHYSIOLOGYPATHOPHYSIOLOGY

The gut has formed and has completed its rotation back The gut has formed and has completed its rotation back into the abdominal cavity by into the abdominal cavity by 10 weeks10 weeks of gestation. of gestation.

By By 16 weeks16 weeks, the fetus can swallow amniotic fluid. , the fetus can swallow amniotic fluid. GI motor activity is present before 24 weeks, but GI motor activity is present before 24 weeks, but

organized peristalsis is not established until organized peristalsis is not established until 29-30 weeks29-30 weeks and is facilitated by antenatal corticosteroid treatment. and is facilitated by antenatal corticosteroid treatment.

Coordinated sucking and swallowing develops at Coordinated sucking and swallowing develops at 32-34 32-34 weeksweeks..

By term, the fetus swallows about 150 cc/kg/day of By term, the fetus swallows about 150 cc/kg/day of amniotic fluid, which has 275 mOsm/L, contains amniotic fluid, which has 275 mOsm/L, contains carbohydrates, protein, fat, electrolytes, immunoglobulins carbohydrates, protein, fat, electrolytes, immunoglobulins and growth factors, and plays an important role in and growth factors, and plays an important role in development of GI function. Preterm birth interrupts this development of GI function. Preterm birth interrupts this development. development.

Even if nutrients are provided parenterally, lack Even if nutrients are provided parenterally, lack of enteric intake leads to of enteric intake leads to – decreased circulating gut peptidesdecreased circulating gut peptides– slower enterocyte turnover and nutrient transportslower enterocyte turnover and nutrient transport– decreased bile acid secretiondecreased bile acid secretion– increased susceptibility to infection due to impaired increased susceptibility to infection due to impaired

barrier function by intestinal epithelium, lack of barrier function by intestinal epithelium, lack of colonization by normal commensal flora and colonization colonization by normal commensal flora and colonization by pathogenic organisms. by pathogenic organisms.

For fat digestion, the newborn depends on lingual For fat digestion, the newborn depends on lingual lipase, which is stimulated by sucking and lipase, which is stimulated by sucking and swallowing and by nutrients in the stomach but swallowing and by nutrients in the stomach but not the small bowel. not the small bowel.

Importance of Enteral Feeding

How should we feed?How should we feed?

Trophic feedings for parenterally Trophic feedings for parenterally fed infants (Review)fed infants (Review)2008 The Cochrane 2008 The Cochrane

CollaborationCollaboration Trophic feedingTrophic feeding defined as dilute or full strength feedings providing < = defined as dilute or full strength feedings providing < = 25 ml/kg/d for > = 5d (5-10days)25 ml/kg/d for > = 5d (5-10days)

Trophic feedings vs. no feedings (10 trials):Trophic feedings vs. no feedings (10 trials): Among infants given Among infants given trophic feedings, there was an overall reduction in days to full feeding trophic feedings, there was an overall reduction in days to full feeding (weighted mean difference [WMD] = -2.6 [95% confidence limits = -4.1, -(weighted mean difference [WMD] = -2.6 [95% confidence limits = -4.1, -1.0]), total days that feedings were held (WMD = -3.1 [-4.6, -1.6]), and 1.0]), total days that feedings were held (WMD = -3.1 [-4.6, -1.6]), and total hospital stay (WMD = -11.4 [-17.2, -5.7] compared to infants given no total hospital stay (WMD = -11.4 [-17.2, -5.7] compared to infants given no enteral nutrient intake. enteral nutrient intake.

Tests for heterogeneity were significant in analyses of days to full enteral Tests for heterogeneity were significant in analyses of days to full enteral feedings, days to regain birth weight, days of phototherapy, and hospital feedings, days to regain birth weight, days of phototherapy, and hospital stay. stay.

There was no significant difference in necrotizing enterocolitis, although There was no significant difference in necrotizing enterocolitis, although the findings do not exclude an important effect (relative risk = 1.16 [0.75, the findings do not exclude an important effect (relative risk = 1.16 [0.75, 1.79]; risk difference = 0.02 [-0.03, 0.06].1.79]; risk difference = 0.02 [-0.03, 0.06].

Trophic feedings vs. advancing feedings (one trial):Trophic feedings vs. advancing feedings (one trial): Infants given Infants given trophic feedings required more days to reach full enteral feeding (13.4 trophic feedings required more days to reach full enteral feeding (13.4 [8.2, 18.6]) and tended to have a longer hospital stay (11.0 [-1.4, 23.4]) [8.2, 18.6]) and tended to have a longer hospital stay (11.0 [-1.4, 23.4]) than did infants given advancing feedings. With only eight total cases of than did infants given advancing feedings. With only eight total cases of necrotizing enterocolitis, trophic feedings were associated with a necrotizing enterocolitis, trophic feedings were associated with a marginally significant reduction in necrotizing enterocolitis (relative risk marginally significant reduction in necrotizing enterocolitis (relative risk =0.14 [0.02, 1.07]; risk difference = -0.09 [-0.16, -0.01].=0.14 [0.02, 1.07]; risk difference = -0.09 [-0.16, -0.01].

Authors’ conclusionsAuthors’ conclusions

In both comparisons, the group with the greater enteral intake (trophic In both comparisons, the group with the greater enteral intake (trophic feedings in the first comparison and advancing feedings in the second feedings in the first comparison and advancing feedings in the second comparison) required significantly less time to reach full feedings and had comparison) required significantly less time to reach full feedings and had a significant or near significant reduction in hospital stay. a significant or near significant reduction in hospital stay.

In both comparisons, the group with the greater intake also had a higher In both comparisons, the group with the greater intake also had a higher incidence of NEC although the difference was not statistically significant. incidence of NEC although the difference was not statistically significant. The concern is greatest for the advancing feeding regimen. Even when The concern is greatest for the advancing feeding regimen. Even when trophic feedings were compared to no feedings, the relative risk for NEC trophic feedings were compared to no feedings, the relative risk for NEC was 1.16 (0.75 - 1.79), a finding consistent with a 16% increase in NEC and was 1.16 (0.75 - 1.79), a finding consistent with a 16% increase in NEC and a NNH of 50. A true increase of this magnitude might outweigh any shorter a NNH of 50. A true increase of this magnitude might outweigh any shorter or long-term benefits of trophic feedings. Moreover, the 95% CI does not or long-term benefits of trophic feedings. Moreover, the 95% CI does not exclude the possibility that trophic feedings increase NEC by as much as exclude the possibility that trophic feedings increase NEC by as much as 79% with a NNH of 17.79% with a NNH of 17.

Whether no feedings, trophic feedings, or advancing feedings should Whether no feedings, trophic feedings, or advancing feedings should initially be used is difficult to discern for a variety of reasons—the inherent initially be used is difficult to discern for a variety of reasons—the inherent difficulty of assessing enteral feedings in high-risk infants, the limited difficulty of assessing enteral feedings in high-risk infants, the limited sample size and methodologic limitations of most studies to date, sample size and methodologic limitations of most studies to date, unexplained heterogeneity with respect to a number of outcomes, the unexplained heterogeneity with respect to a number of outcomes, the potential for bias to affect the findings in unblinded studies, and the large potential for bias to affect the findings in unblinded studies, and the large number of infants who must be studied to assess the effect on necrotizing number of infants who must be studied to assess the effect on necrotizing enterocolitis. enterocolitis.

One or more large, well designed, multi-center trials are needed to One or more large, well designed, multi-center trials are needed to compare these approaches to early feeding with respect to important compare these approaches to early feeding with respect to important clinical outcomes. A conclusive evaluation would assess effects on not only clinical outcomes. A conclusive evaluation would assess effects on not only the survival rate without necrotizing enterocolitis prior to discharge from the survival rate without necrotizing enterocolitis prior to discharge from the neonatal unit but also on the survival rate without severe the neonatal unit but also on the survival rate without severe gastrointestinal or neurodevelopmental disability at >= 18 months age.gastrointestinal or neurodevelopmental disability at >= 18 months age.

Nasal versus oral route for placing feeding Nasal versus oral route for placing feeding tubes in preterm or low birth weight infants. tubes in preterm or low birth weight infants.

2008 Cochrane Collaboration2008 Cochrane Collaboration

Main resultsMain results Two small randomised trials were identified. Two small randomised trials were identified. Only one trial reported data on the pre-specified primary Only one trial reported data on the pre-specified primary

outcomes for this review. This trial found no evidence of outcomes for this review. This trial found no evidence of effect on the time taken to establish enteral feeding nor the effect on the time taken to establish enteral feeding nor the time taken to regain birth weight. However, the trial was time taken to regain birth weight. However, the trial was underpowered (N= 46) to exclude modest effect sizes.underpowered (N= 46) to exclude modest effect sizes.

Authors’ conclusionsAuthors’ conclusions There are insufficient data available to inform practice. A There are insufficient data available to inform practice. A

large randomised controlled trial is required to determine if large randomised controlled trial is required to determine if the use of naso vs oro-enteric feeding tubes affects feeding, the use of naso vs oro-enteric feeding tubes affects feeding, growth and development, and the incidence of adverse growth and development, and the incidence of adverse consequences in preterm or low birth weight infants.consequences in preterm or low birth weight infants.

Continuous nasogastric milk feeding Continuous nasogastric milk feeding versus intermittent bolus milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 for premature infants less than 1500 grams, 2008 Cochrane collaborationgrams, 2008 Cochrane collaboration

Main resultsMain results Overall, the seven included trials, involving 511 infants, found no Overall, the seven included trials, involving 511 infants, found no

differences in time to achieve full enteral feeds between feeding differences in time to achieve full enteral feeds between feeding methods (weighted mean difference (WMD 2 days; 95%CI -0.3, 3.9) . methods (weighted mean difference (WMD 2 days; 95%CI -0.3, 3.9) .

In the subgroup analysis of those studies comparing continuous In the subgroup analysis of those studies comparing continuous nasogastric vs. intermittent bolus nasogastric milk feedings the nasogastric vs. intermittent bolus nasogastric milk feedings the findings remained unchanged (WMD 2 days, 95% CI -0.4, 4.1). findings remained unchanged (WMD 2 days, 95% CI -0.4, 4.1).

There was no significant difference in somatic growth and incidence of There was no significant difference in somatic growth and incidence of NEC between feeding methods irrespective of tube placement. NEC between feeding methods irrespective of tube placement.

One study noted a trend toward more apneas during the study period One study noted a trend toward more apneas during the study period in infants fed by the continuous tube feeding method compared to in infants fed by the continuous tube feeding method compared to those fed by intermittent feedings delivered predominantly by those fed by intermittent feedings delivered predominantly by orogastric tube placements [mean difference (MD) 14.0 apneas during orogastric tube placements [mean difference (MD) 14.0 apneas during study period; 95% CI -0.2, 28.2].study period; 95% CI -0.2, 28.2].

In subgroup analysis based on weight groups, one study suggested In subgroup analysis based on weight groups, one study suggested that infants less than 1000 grams and 1000 - 1250 grams birth weight that infants less than 1000 grams and 1000 - 1250 grams birth weight gained weight faster when fed by the continuous nasogastric tube gained weight faster when fed by the continuous nasogastric tube feeding method compared to intermittent nasogastric tube feeding feeding method compared to intermittent nasogastric tube feeding method (MD 2.0 g/day; 95% CI 0.5, 3.5; MD 2.0 g/day; 95% CI 0.2, 3.8, method (MD 2.0 g/day; 95% CI 0.5, 3.5; MD 2.0 g/day; 95% CI 0.2, 3.8, respectively). respectively).

A trend toward earlier discharge for infants less than 1000 grams A trend toward earlier discharge for infants less than 1000 grams birth weight fed by the continuous tube feeding method compared birth weight fed by the continuous tube feeding method compared to intermittent nasogastric tube feeding method (MD -11 days; to intermittent nasogastric tube feeding method (MD -11 days; 95% CI -21.8, -0.2).95% CI -21.8, -0.2).

Authors’ conclusionsAuthors’ conclusions Small sample sizes, methodologic limitations, inconsistencies in Small sample sizes, methodologic limitations, inconsistencies in

controlling variables that may affect outcomes, and conflicting controlling variables that may affect outcomes, and conflicting results of the studies to date make it difficult to make universal results of the studies to date make it difficult to make universal recommendations regarding the best tube feeding method for recommendations regarding the best tube feeding method for premature infants less than 1500 grams. premature infants less than 1500 grams.

The clinical benefits and risks of continuous vs. intermittent The clinical benefits and risks of continuous vs. intermittent nasogastric tube milk feeding cannot be reliably discerned from nasogastric tube milk feeding cannot be reliably discerned from the limited information available from randomized trials to date.the limited information available from randomized trials to date.

Transpyloric versus gastric tube feeding for Transpyloric versus gastric tube feeding for preterm infants. 2008 Cochrane Collaborationpreterm infants. 2008 Cochrane Collaboration

Data from nine trials were available. Data from nine trials were available. No evidence of an effect on short term growth rates was found: No evidence of an effect on short term growth rates was found:

weight:WMD -0.7 g/week (95% confidence interval (CI) -25.2, weight:WMD -0.7 g/week (95% confidence interval (CI) -25.2, 23.8); crown heel length: WMD -0.7 mm/week (95% CI -2.4, 1.0); 23.8); crown heel length: WMD -0.7 mm/week (95% CI -2.4, 1.0); head circumference: WMD 0.6 mm/week (95% CI -0.9, 2.1). head circumference: WMD 0.6 mm/week (95% CI -0.9, 2.1).

Longer term growth was reported in one study. There were not Longer term growth was reported in one study. There were not any statistically significant differences between the groups in the any statistically significant differences between the groups in the mean body weight or occipitofrontal head circumference at three mean body weight or occipitofrontal head circumference at three months or at six months corrected age.months or at six months corrected age.

None of the included studies provided data on None of the included studies provided data on neurodevelopmental outcomes. neurodevelopmental outcomes.

Transpyloric feeding was associated with a greater incidence of Transpyloric feeding was associated with a greater incidence of gastro-intestinal disturbance (RR 1.45, 95% CI 1.05, 2.09). There gastro-intestinal disturbance (RR 1.45, 95% CI 1.05, 2.09). There was some evidence that feeding via the transpyloric route was some evidence that feeding via the transpyloric route increased mortality (RR 2.46, 95% CI 1.36, 4.46). However, the increased mortality (RR 2.46, 95% CI 1.36, 4.46). However, the outcomes of the study that contributed most to this finding were outcomes of the study that contributed most to this finding were likely to have been affected by selective allocation of the less likely to have been affected by selective allocation of the less mature and sicker infants to transpyloric feeding.mature and sicker infants to transpyloric feeding.

No statistically significant differences in the incidence of other No statistically significant differences in the incidence of other adverse events, including necrotising enterocolitis, intestinal adverse events, including necrotising enterocolitis, intestinal perforation, and aspiration pneumonia was found.perforation, and aspiration pneumonia was found.

Authors’ conclusionsAuthors’ conclusions No evidence of any beneficial effect of transpyloric feeding in No evidence of any beneficial effect of transpyloric feeding in

preterm infants was found. However, evidence of adverse effects preterm infants was found. However, evidence of adverse effects was noted. Feeding via the transpyloric route cannot be was noted. Feeding via the transpyloric route cannot be recommended for preterm infantsrecommended for preterm infants

Ad libitum or demand/semi-demand feeding Ad libitum or demand/semi-demand feeding versus scheduled interval feeding for versus scheduled interval feeding for

preterm infants, 2008 Cochrane preterm infants, 2008 Cochrane collaborationcollaboration

Seven randomised controlled trials that compared ad libitum or demand/semi-Seven randomised controlled trials that compared ad libitum or demand/semi-demand regimes with scheduled interval regimes in preterm infants in the demand regimes with scheduled interval regimes in preterm infants in the transition phase from intragastric tube to oral feeding were found. transition phase from intragastric tube to oral feeding were found.

The trials were generally small and of variable methodological quality. The The trials were generally small and of variable methodological quality. The duration of the intervention and the duration of data collection and follow up in duration of the intervention and the duration of data collection and follow up in most of the trials is not likely to have allowed detection of measurable effects on most of the trials is not likely to have allowed detection of measurable effects on growth. growth.

The single trial that assessed growth for longer than one week found that the The single trial that assessed growth for longer than one week found that the rate of weight gain was lower in the ad libitum fed infants [mean difference -3.30 rate of weight gain was lower in the ad libitum fed infants [mean difference -3.30 (95% confidence interval -6.2 to -0.4) grams per kilogram per day]. (95% confidence interval -6.2 to -0.4) grams per kilogram per day].

Two trials reported that feeding preterm infants using an ad libitum or Two trials reported that feeding preterm infants using an ad libitum or demand/semi-demand feeding regime allowed earlier discharge from hospital, demand/semi-demand feeding regime allowed earlier discharge from hospital, but the other trials did not confirm this finding. but the other trials did not confirm this finding.

Not able to undertake meta-analyses because of differences in study design and Not able to undertake meta-analyses because of differences in study design and in the way the findings were reported. in the way the findings were reported.

Authors’ conclusionsAuthors’ conclusions There are insufficient data at present to guide clinical practice. A large There are insufficient data at present to guide clinical practice. A large

randomised controlled trial is needed to determine if ad libitum of demand/semi-randomised controlled trial is needed to determine if ad libitum of demand/semi-demand feeding of preterm infants affects clinically important outcomes. This demand feeding of preterm infants affects clinically important outcomes. This trial should focus on infants in the transition phase from intragastric tube to oral trial should focus on infants in the transition phase from intragastric tube to oral feeding and should be of sufficient duration to assess effects on growth and time feeding and should be of sufficient duration to assess effects on growth and time to oral feeding and hospital discharge.to oral feeding and hospital discharge.

What should we What should we feed?feed?

Breast milk lah, no Breast milk lah, no need to ask… need to ask…

Really?Really?

Formula milk versus maternal breast milk for Formula milk versus maternal breast milk for feeding preterm or low birth weight infants feeding preterm or low birth weight infants

2008 Cochrane Collaboration.2008 Cochrane Collaboration.

Main resultsMain results No eligible trials were identified.No eligible trials were identified.Authors’ conclusionsAuthors’ conclusions There are no data from randomised trials of formula milk There are no data from randomised trials of formula milk

versus maternal breast milk for feeding preterm or low birth versus maternal breast milk for feeding preterm or low birth weight infants.weight infants.

This may relate to a perceived difficulty of allocating an This may relate to a perceived difficulty of allocating an alternative feed to an infant whose mother wishes to feed alternative feed to an infant whose mother wishes to feed with her own breast milk. with her own breast milk.

Maternal breast milk remains the default choice of enteral Maternal breast milk remains the default choice of enteral nutrition because observational studies, and meta-analyses nutrition because observational studies, and meta-analyses of trials comparing feeding with formula milk versus donor of trials comparing feeding with formula milk versus donor breast milk, suggest that feeding with breastmilk has major breast milk, suggest that feeding with breastmilk has major non-nutrient advantages for preterm or low birth weight non-nutrient advantages for preterm or low birth weight infants.infants.

Results: •Seven studies (including five randomised controlled trials), all from the 1970s and 1980s, fulfilled the inclusion criteria. All studies compared the effect of sole donor breast milk with formula (combined n = 471). One of these also compared the effect of donor breast milk with formula given as a supplement to mother’s own milk (n = 343). No studies examined fortified donor breast milk. •A meta-analysis based on three studies found a lower risk of NEC in infants receiving donor breast milk compared with formula (combined RR 0.21, 95% CI 0.06 to 0.76). •Donor breast milk was associated with slower growth in the early postnatal period, but its long-term effect is unclear.

Conclusion: •Donor breast milk is associated with a lower risk of NEC and slower growth in the early postnatal period, but the quality of the evidence is limited. Further research is needed to confirm these findings and measure the effect of fortified or supplemented donor breast milk.

Donor breast milk versus infant formula for preterm infants: systematic review and meta-analysis Cochrane collaboration 2006

Protein supplementation of human milk for Protein supplementation of human milk for promoting growth in preterm infantspromoting growth in preterm infants

Cochrane collaboration 2000Cochrane collaboration 2000

MAIN RESULTS: •Protein supplementation of human milk results in increases in short term weight gain (WMD 3.6 g/kg/day, 95% CI 2.4 to 4.8 g/kg/day), linear growth (WMD 0.28 cm/week, 95% CI 0.18 to 0.38 cm/week) and head growth (WMD 0.15 cm/week, 95% CI 0.06 to 0.23 cm/week). •There are insufficient data to evaluate long term neurodevelopmental and growth outcomes. There are too few infants studied to be certain that adverse effects of protein supplementation are not increased. Blood urea levels are increased (WMD 1.0 mmol/l, 95% CI 0.8 to 1.2 mmol/l).

REVIEWER'S CONCLUSIONS: •Protein supplementation of human milk in relatively well preterm infants results in increases in short term weight gain, linear and head growth. Urea levels are increased, which may reflect adequate rather than excessive dietary protein intake. •Further research should be directed towards the evaluation of specific levels of protein intake in preterm infants and the clinical effects of supplementation with protein, including long term growth and neurodevelopmental outcomes. This may best be done in the context of refinement of available multicomponent fortifier preparations.

MAIN RESULTS• Supplementation of human milk with multicomponent fortifiers (in the form of protein, calcium, phosphate, and carbohydrate, as well as vitamins and trace minerals) is associated with short term increases in weight gain, linear and head growth. There is no effect on serum alkaline phosphatase levels; it is not clear if there is an effect on bone mineral content. Nitrogen retention and blood urea levels appear to be increased. •There are insufficient data to evaluate long term neurodevelopmental and growth outcomes, although there appears to be no effect on growth beyond one year of life.•Use of multicomponent fortifiers does not appear to be associated with adverse effects, although the total number of infants studied and the large amount of missing data reduces confidence in this conclusion. Blood urea levels are increased and blood pH levels minimally decreased, but the clinical significance of this is uncertain.

REVIEWER'S CONCLUSIONS: •Multicomponent fortification of human milk is associated with short-term improvements in weight gain, linear and head growth. Despite the absence of evidence of long-term benefit and insufficient evidence to be reassured that there are no deleterious effects, it is unlikely that further studies evaluating fortification of human milk versus no supplementation will be performed. •Further research should be directed toward comparisons between different proprietary preparations and evaluating both short-term and long-term outcomes in search of the "optimal" composition of fortifiers.

Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane collaboration 2004

Fortification of Preterm Human Milk for Fortification of Preterm Human Milk for Feeding Preterm Infants – Yale Pediatric Feeding Preterm Infants – Yale Pediatric

ProtocolProtocol Preterm human milk (PTHM) is milk expressed by a mother for her infant following a Preterm human milk (PTHM) is milk expressed by a mother for her infant following a

preterm delivery. preterm delivery. – may be stored in the Breast Milk Refrigerator for up to 48 hours. may be stored in the Breast Milk Refrigerator for up to 48 hours. – If the milk will not be fed to the infant within that time, it should be frozen as early as possible If the milk will not be fed to the infant within that time, it should be frozen as early as possible

after expression in appropriate-sized volumes and then gently thawed prior to use. Once after expression in appropriate-sized volumes and then gently thawed prior to use. Once thawed, it should be used within about 4 hours. thawed, it should be used within about 4 hours.

Infants should be fed full strength human milk as their initial enteral feeding. Infants should be fed full strength human milk as their initial enteral feeding. When to fortify:When to fortify:

– After an infant tolerates full enteral feeding of full-strength human milk for 5-7 daysAfter an infant tolerates full enteral feeding of full-strength human milk for 5-7 days– Or, after he/she tolerates about 75% his/her total daily volume (IV + NG) as full strength Or, after he/she tolerates about 75% his/her total daily volume (IV + NG) as full strength

human milkhuman milk How to fortifyHow to fortify

– adding a powdered Human Milk Fortifieradding a powdered Human Milk Fortifier– by mixing human milk with an equal volume of Premature Formulaby mixing human milk with an equal volume of Premature Formula

Mixing equal volumes of human milk and Premature Formula or Natural Care results in a nutrient Mixing equal volumes of human milk and Premature Formula or Natural Care results in a nutrient concentration that equals an average between human milk and formula concentration that equals an average between human milk and formula

– Or, by mixing human milk with an equal volume of Natural Care(similac) Human Milk Fortifier. Or, by mixing human milk with an equal volume of Natural Care(similac) Human Milk Fortifier. The decision on which method of fortification to use will depend upon the mother's The decision on which method of fortification to use will depend upon the mother's

milk production with discussion with Lactation Consultant. milk production with discussion with Lactation Consultant. Why fortifyWhy fortify

– Increases the content of nutrients in the infant's diet, esp calcium and phosphorus. (See table Increases the content of nutrients in the infant's diet, esp calcium and phosphorus. (See table next page) next page)

– The composition of PTHM varies with the duration of lactation; an approximate composition of The composition of PTHM varies with the duration of lactation; an approximate composition of "mature" PTHM is also shown "mature" PTHM is also shown

Special Formula Use Special Formula Use RecommendationsRecommendations

Preterm formula and Human Milk Fortifier: Preterm formula and Human Milk Fortifier: generally for infants generally for infants weighing less than 1,850 to 2,000 gm (about 4 to 4 ½ lbs). It is weighing less than 1,850 to 2,000 gm (about 4 to 4 ½ lbs). It is inappropriate for most infants who weigh more than 2.5 kg (5 ½ lbs) inappropriate for most infants who weigh more than 2.5 kg (5 ½ lbs) or are taking in over 500 ml daily to be fed premature formulas or are taking in over 500 ml daily to be fed premature formulas (Enfamil Premature Lipil or Similac Special Care) or Human Milk (Enfamil Premature Lipil or Similac Special Care) or Human Milk Fortifiers (Similac HMF, Similac Natural Care or Enfamil HMF) for all Fortifiers (Similac HMF, Similac Natural Care or Enfamil HMF) for all their feeds because of the higher vitamin A and vitamin D content of their feeds because of the higher vitamin A and vitamin D content of these formulas and the possible risk of hypervitaminosis. these formulas and the possible risk of hypervitaminosis.

Transitional Formulas: Transitional Formulas: (also called “post-discharge premature (also called “post-discharge premature formulas”) Formulas such as Enfamil EnfaCare Lipil and Similac formulas”) Formulas such as Enfamil EnfaCare Lipil and Similac Neosure Advance provide 22 kcal/oz and have higher levels of protein, Neosure Advance provide 22 kcal/oz and have higher levels of protein, calcium, phosphorus, vitamins and other minerals than standard infant calcium, phosphorus, vitamins and other minerals than standard infant formulas. Research has shown that premature infants fed these formulas. Research has shown that premature infants fed these formulas have improved growth and bone mineralization compared to formulas have improved growth and bone mineralization compared to those fed standard infant formulas.those fed standard infant formulas.

*See recommendation below for length of time an infant needs to remain *See recommendation below for length of time an infant needs to remain on a transitional formula. on a transitional formula.

Nutrition Practice Care Guidelines for Preterm Infants In the Community. Revised August 2006.Developed by Child Development and Rehabilitation Center, Nutrition Services, Oregon Department of Human Services, Nutrition & Health Screening – WIC Program. Oregon Pediatric Nutrition Practice Group

Specialized formulas Specialized formulas – These include Pregestimil, Alimentum, Nutramigen, Neocate These include Pregestimil, Alimentum, Nutramigen, Neocate

and Elecare, and may be indicated based on feeding and Elecare, and may be indicated based on feeding intolerance. intolerance.

– Enfamil AR is not indicated for preterm infants due to the risk Enfamil AR is not indicated for preterm infants due to the risk of the formation of lactobezoars (hard clumps of undigested of the formation of lactobezoars (hard clumps of undigested milk curds). These are “term” formulas and thus have less milk curds). These are “term” formulas and thus have less calcium, phosphorus, and protein than transitional formulas. If calcium, phosphorus, and protein than transitional formulas. If preterm infants are given these formulas, they should be preterm infants are given these formulas, they should be followed more closely by an RD and the appropriate labs followed more closely by an RD and the appropriate labs should be checked.should be checked.

Soy-based formulas Soy-based formulas are are not not recommended for preterm infants. recommended for preterm infants. Preterm infants receiving soy formula have suboptimal Preterm infants receiving soy formula have suboptimal carbohydrate and mineral absorption and utilization than cow’s carbohydrate and mineral absorption and utilization than cow’s milk-based formula. AAP doesn’t recommend soy formula for milk-based formula. AAP doesn’t recommend soy formula for infants born < 1800 g since preterm infants showed significantly infants born < 1800 g since preterm infants showed significantly less weight gain, less linear growth, and lower serum albumin less weight gain, less linear growth, and lower serum albumin levels than those infants receiving cow’s milk-based formulas. levels than those infants receiving cow’s milk-based formulas. Studies also have shown lower levels of bone marker formation in Studies also have shown lower levels of bone marker formation in the premature population which can lead to osteopenia.the premature population which can lead to osteopenia.

Goat’s milk Goat’s milk is is not not recommended for preterm infants. Goat’s milk recommended for preterm infants. Goat’s milk is deficient in folic acid and vitamin B6. It is also higher in protein is deficient in folic acid and vitamin B6. It is also higher in protein than human milk and infant formula which puts the premature than human milk and infant formula which puts the premature infant at risk for dehydration due to the higher renal solute load. infant at risk for dehydration due to the higher renal solute load.

Dorset County Hospital Neonatal Dorset County Hospital Neonatal Unit Unit

Guidelines for enteral feeding Guidelines for enteral feeding (Mar05)(Mar05)

Milk of choice, in order of preference, is:Milk of choice, in order of preference, is: – 1. Breast milk – suckled by baby from the breast 1. Breast milk – suckled by baby from the breast – 2. Mother’s expressed breast milk (EBM), fresh 2. Mother’s expressed breast milk (EBM), fresh – 3. Mother’s EBM, frozen 3. Mother’s EBM, frozen – 4. Donor EBM* 4. Donor EBM* – 5. Formula feed appropriate to gestational age and birth weight 5. Formula feed appropriate to gestational age and birth weight

* * consider consider using when: using when: baby deemed at high risk of developing necrotising baby deemed at high risk of developing necrotising

enterocolitis (NEC) – see section 3 enterocolitis (NEC) – see section 3 if it is available, to intensive care babies if it is available, to intensive care babies poor tolerance of formula feeds poor tolerance of formula feeds

NB parental consent should be sought prior to a baby being NB parental consent should be sought prior to a baby being given donor EBM given donor EBM

This hospital actively promotes the benefits of breast This hospital actively promotes the benefits of breast feeding for all infants. There are particular benefits of feeding for all infants. There are particular benefits of breast milk for the preterm infant and sick neonate (eg breast milk for the preterm infant and sick neonate (eg reduced incidence of necrotising enterocolitis - ref 1). reduced incidence of necrotising enterocolitis - ref 1).

All mothers should be encouraged to produce milk for their baby All mothers should be encouraged to produce milk for their baby as soon as possible as soon as possible after delivery if their baby is not able to after delivery if their baby is not able to feed naturally. Even if the mother is not planning to breast feed in feed naturally. Even if the mother is not planning to breast feed in the longer term or unwilling to breast feed, they should be advised the longer term or unwilling to breast feed, they should be advised why EBM is the best nutritional support for their baby. why EBM is the best nutritional support for their baby.

For premature infants whose mother’s wish to breast feed in the For premature infants whose mother’s wish to breast feed in the longer term, skin to skin contact should be strongly encouraged longer term, skin to skin contact should be strongly encouraged from an early stage. Cup feeding is often possible from 30 weeks from an early stage. Cup feeding is often possible from 30 weeks gestation. Bottle feeding should be avoided if at all possible given gestation. Bottle feeding should be avoided if at all possible given the different technique a baby uses to bottle feed compared to the different technique a baby uses to bottle feed compared to feeding at the breast. feeding at the breast.

If formula feeds are being used, the baby should not be started on If formula feeds are being used, the baby should not be started on a preterm formula until they are tolerating 150 ml/kg/day of a a preterm formula until they are tolerating 150 ml/kg/day of a standard formula feed.standard formula feed.

Dorset County (cont’d) Early nutrition in the preterm group

a) Under 2kg a) Under 2kg For babies with a birth weight of less than 1.2 kg (and occasionally For babies with a birth weight of less than 1.2 kg (and occasionally

larger babies) parenteral nutrition will normally be necessary during larger babies) parenteral nutrition will normally be necessary during the first 1-2 weeks of life. This should be written up the first 1-2 weeks of life. This should be written up as soon as as soon as possible possible after delivery so that it can be commenced within 1-2 days after delivery so that it can be commenced within 1-2 days of delivery (see TPN guidelines). of delivery (see TPN guidelines).

i) Non-nutritive feeding (minimal enteral nutrition): i) Non-nutritive feeding (minimal enteral nutrition): – Small amounts of breast milk started in the first few days of life (day 1 if Small amounts of breast milk started in the first few days of life (day 1 if

possible) possible) – encourage gut maturity (ref 2)encourage gut maturity (ref 2)– Start at 1ml every 4-6 hours if <1kg (ref 5) and 1ml/hr if >1kg (ref 3). Start at 1ml every 4-6 hours if <1kg (ref 5) and 1ml/hr if >1kg (ref 3).

Maternal EBM is preferable to donor breast milk. Maternal EBM is preferable to donor breast milk. – Please note section on management of infants at high risk of NEC Please note section on management of infants at high risk of NEC

(section 3) (section 3)

ii) Rate of increase of feed: ii) Rate of increase of feed: – Once tolerating minimal enteral nutrition, increase the volume given at Once tolerating minimal enteral nutrition, increase the volume given at

each feed. The rate of increase should be decided for each individual each feed. The rate of increase should be decided for each individual baby but would normally be less than 35ml/kg per 24 hours for babies baby but would normally be less than 35ml/kg per 24 hours for babies less than 1200gm (ref 4). Larger babies will possibly tolerate faster less than 1200gm (ref 4). Larger babies will possibly tolerate faster increments in feed volume. increments in feed volume.


iii) Final feed volume: iii) Final feed volume: – Increase feed volumes up to a maximum of: Increase feed volumes up to a maximum of: – 200-220 ml/kg/day for EBM 200-220 ml/kg/day for EBM – 180 ml/kg for term formula (or Nutriprem 2) 180 ml/kg for term formula (or Nutriprem 2) – 160 ml/kg/day for preterm formula* 160 ml/kg/day for preterm formula*

Once an infant is tolerating >50% of their total fluid volume Once an infant is tolerating >50% of their total fluid volume enterally, lipid can be discontinued in the TPN (see TPN enterally, lipid can be discontinued in the TPN (see TPN guidelines). guidelines).

* If formula feeds are being used, the baby should not be started * If formula feeds are being used, the baby should not be started on a preterm formula until they are tolerating 150 ml/kg/day of a on a preterm formula until they are tolerating 150 ml/kg/day of a standard formula feed. standard formula feed.

b) greater than 2kg b) greater than 2kg Where possible allow to demand feed. Where possible allow to demand feed. For well infants below 37 weeks gestation, consider starting feeds For well infants below 37 weeks gestation, consider starting feeds

at 60ml/kg/day on day 1 of feeding aiming to reach 150ml/kg/day at 60ml/kg/day on day 1 of feeding aiming to reach 150ml/kg/day within 4 days depending on progress.within 4 days depending on progress.


3. High risk groups for NEC 3. High risk groups for NEC Particular high risk groups include: Particular high risk groups include:

– Preterm infants < 1kg Preterm infants < 1kg – Severe intrauterine growth retardation Severe intrauterine growth retardation – Absent/reversed end diastolic flow on umbilical artery Doppler Absent/reversed end diastolic flow on umbilical artery Doppler – Sepsis Sepsis

For infants with absent or reversed end diastolic flow do not feed For infants with absent or reversed end diastolic flow do not feed enterally for 3 days. enterally for 3 days.

For at risk groups consider waiting for maternal EBM before For at risk groups consider waiting for maternal EBM before starting feeds. In these circumstances feeding human milk at a starting feeds. In these circumstances feeding human milk at a rate 1 ml every 4-6 hours is recommended (ref 5). If maternal EBM rate 1 ml every 4-6 hours is recommended (ref 5). If maternal EBM is not available for these groups consider the use of donor EBM. is not available for these groups consider the use of donor EBM.

For babies at high risk of necrotising enterocolitis (NEC) there is For babies at high risk of necrotising enterocolitis (NEC) there is some evidence that a rate of increase not exceeding 20ml/kg per some evidence that a rate of increase not exceeding 20ml/kg per 24 hours reduces the incidence of NEC (ref 6). 24 hours reduces the incidence of NEC (ref 6).

* After a suspected episode of NEC feeds should be reintroduced * After a suspected episode of NEC feeds should be reintroduced using EBM (maternal if possible but donor if not available). If using EBM (maternal if possible but donor if not available). If maternal EBM not available and mother refused permission to use maternal EBM not available and mother refused permission to use donor EBM, consider using Pregestimil (see section 9 for advise on donor EBM, consider using Pregestimil (see section 9 for advise on increasing calorie intake if inadequate growth on this formula). increasing calorie intake if inadequate growth on this formula).


References: References: 1. Lucas A, Cole TJ. Breast milk and neonatal necrotising 1. Lucas A, Cole TJ. Breast milk and neonatal necrotising

enterocolitis. Lancet 1990; 336: 1519-1523. enterocolitis. Lancet 1990; 336: 1519-1523. 2. McClure RJ and Newell SJ. Randomised controlled trial of trophic 2. McClure RJ and Newell SJ. Randomised controlled trial of trophic

feedingand gut motility. Arch Dis Child Neonatal Ed 1999; 80: F54-feedingand gut motility. Arch Dis Child Neonatal Ed 1999; 80: F54-58. 58.

3. Child Nutrition Panel “Feeding the preterm infant”. Z740127 3. Child Nutrition Panel “Feeding the preterm infant”. Z740127 May 2002 May 2002

4. Kennedy KA et al. Rapid versus slow rate of advancement of 4. Kennedy KA et al. Rapid versus slow rate of advancement of feeding in parenterally fed low birth weight infants. Cochrane feeding in parenterally fed low birth weight infants. Cochrane Review. 2001. Review. 2001.

5. King C. Neonatal Unit Enteral Feeding Policy. Hammersmith 5. King C. Neonatal Unit Enteral Feeding Policy. Hammersmith Hospital NHS Trust 2000. Hospital NHS Trust 2000.

6. Anderson DM and Kliegman RM. The relationship of neonatal 6. Anderson DM and Kliegman RM. The relationship of neonatal alimentation practice to the occurrence of endemic necrotising alimentation practice to the occurrence of endemic necrotising enterocolitis. Am J Perinatol 1991; 8: 62-67. enterocolitis. Am J Perinatol 1991; 8: 62-67.

7. Cooke RJ and Embleton ND. Feeding issues in preterm infants. J. 7. Cooke RJ and Embleton ND. Feeding issues in preterm infants. J. Pediat. Neonatal Ed 2000; 83: F215-218. Pediat. Neonatal Ed 2000; 83: F215-218.

8. Nutrition in low birth weight infants. Clinical Paediatric Dietetics 8. Nutrition in low birth weight infants. Clinical Paediatric Dietetics 2001. 2001.

Enteral Feeding guidelines for the preterm infantwithin the neonatal service ofthe Leeds Teaching Hospitals NHS Trust

GROUP 1. 34-36 weeks gestational age and birthweight > 1.5Kg who GROUP 1. 34-36 weeks gestational age and birthweight > 1.5Kg who is on the neonatal unit due to a lack of transitional care capacity.is on the neonatal unit due to a lack of transitional care capacity.

Timing of enteral: ImmediatelyTiming of enteral: Immediately Mode of enteral: NG or oralMode of enteral: NG or oral Type of milk: EBM or Nutriprem (as per policy)Type of milk: EBM or Nutriprem (as per policy) Rate of increase: Full feeds as soon as ableRate of increase: Full feeds as soon as ableGROUP 2. 34-36 weeks gestational age and birthweight > 1.5Kg GROUP 2. 34-36 weeks gestational age and birthweight > 1.5Kg

admitted to Neonatal Unit for whatever reasonadmitted to Neonatal Unit for whatever reason Feeding will depend on primary pathology. If considered ready for feeding, Feeding will depend on primary pathology. If considered ready for feeding,

then feed as Feeding Group 1.then feed as Feeding Group 1.GROUP 3. 34-36 weeks gestational age and birthweight < 1.5KgGROUP 3. 34-36 weeks gestational age and birthweight < 1.5Kg These infants are under the 2nd centile.These infants are under the 2nd centile. Timing of enteral: Delay for up to 24 hours in marked IUGR, or make Timing of enteral: Delay for up to 24 hours in marked IUGR, or make

decision to feed immediatelydecision to feed immediately Mode of enteral: NG or oralMode of enteral: NG or oral Type of milk: EBM or Nutriprem 1 (as per policy)Type of milk: EBM or Nutriprem 1 (as per policy) Rate of increase: 60mls/kg increasing at a maximum of 1ml/Kg per dayRate of increase: 60mls/kg increasing at a maximum of 1ml/Kg per day (0.5ml 12 hourly) up to total of 150/ml/kg/day(0.5ml 12 hourly) up to total of 150/ml/kg/dayGROUP 4. 31-33 weeks, GROUP 4. 31-33 weeks, NONO IUGR or A/REDF on antenatal Doppler IUGR or A/REDF on antenatal Doppler Timing of enteral: ImmediatelyTiming of enteral: Immediately Mode of enteral: NGMode of enteral: NG Type of milk: EBM or Nutriprem 1(as per policy)Type of milk: EBM or Nutriprem 1(as per policy) Rate of increase: 60mls/kg, max increase per day < 25ml/kgRate of increase: 60mls/kg, max increase per day < 25ml/kg (0.5ml/h, 8 hourly) as tolerated*(0.5ml/h, 8 hourly) as tolerated*

GROUP 5. <= 30 weeks, GROUP 5. <= 30 weeks, NoNo IUGR (> 2nd centile) or A/REDF on IUGR (> 2nd centile) or A/REDF on antenatal Dopplerantenatal Doppler

Timing of enteral: Delay for 24 hours after birthTiming of enteral: Delay for 24 hours after birth Mode of enteral: NGMode of enteral: NG Type of milk: EBM or Nutriprem 1(as per policy)Type of milk: EBM or Nutriprem 1(as per policy) Rate of increase: 1ml/kg, increasing maximum 8 hourly as tolerated* for Rate of increase: 1ml/kg, increasing maximum 8 hourly as tolerated* for

first 72 hours. Increase to 0.5ml/kg 6 hourly maximum as tolerated* after first 72 hours. Increase to 0.5ml/kg 6 hourly maximum as tolerated* after 72 hours of age.72 hours of age.

Note: Slow feeding to 12 hourly if evidence of failure to tolerate*.Note: Slow feeding to 12 hourly if evidence of failure to tolerate*. Maximum daily increase Maximum daily increase not not to exceed 25 mls/kg per day.to exceed 25 mls/kg per day.GROUP 6. <= 33 weeks, GROUP 6. <= 33 weeks, IUGR (<= 2nd centile) or A/REDFIUGR (<= 2nd centile) or A/REDF on antenatal on antenatal

DopplerDoppler Timing of enteral: Delay at least 24 hoursTiming of enteral: Delay at least 24 hours Mode of enteral: NGMode of enteral: NG Type of Milk: EBM or Donor EBM (see below)Type of Milk: EBM or Donor EBM (see below) Rate of increase: Rate of increase:

– <= 1kg: 0.5ml/hr initially increasing by 0.5 ml/24 hours as tolerated<= 1kg: 0.5ml/hr initially increasing by 0.5 ml/24 hours as tolerated– > 1kg 1ml/hr initially increasing by 1ml/24 hours as tolerated> 1kg 1ml/hr initially increasing by 1ml/24 hours as tolerated

When full feeds established continue, if using Donor EBM, continue on full When full feeds established continue, if using Donor EBM, continue on full feeds (maximum 165ml/Kg per day) for at least 5 days. Switch to feeds (maximum 165ml/Kg per day) for at least 5 days. Switch to Nutriprem 1 after this time.Nutriprem 1 after this time.

Parenteral Nutrition (PN) will be required for this group (see PN protocol)Parenteral Nutrition (PN) will be required for this group (see PN protocol)*Tolerating enteral feeds*Tolerating enteral feeds Babies are considered to be tolerating enteral feeds ifBabies are considered to be tolerating enteral feeds if • • 4 hourly NG aspirates are < 25% of total infused in the preceding 4 hours4 hourly NG aspirates are < 25% of total infused in the preceding 4 hours • • No significant abdominal distensionNo significant abdominal distension • • No significant vomitingNo significant vomiting • • No bile-stained aspiratesNo bile-stained aspirates

What about What about supplements/adjunctssupplements/adjuncts

??

Main results•Of the eleven randomised trials included in the review, two of these were not classified as of high quality despite blinded assessment and complete follow-up, due to problems with assessment methodology.

Visual acuity Visual acuity over the first year was measured by Teller acuity cards in six studies, by VEP in four studies and by ERG in two studies. Most studies found no significant differences in any visual assessment between supplemented and control infants.

Development Most of the trials have used Bayley Scales of Infant Development (BSID) at 12 to 24 months postterm and shown no significant effect following supplementation. Meta-analysis of BSID of three studies (Fewtrell 2002, O'Connor 2001, van Wezel 2002) shows no significant effect of supplementation on development. Carlson 1993 and Carlson 1996 demonstrated lower novelty preferences (possibly predictive of lower intelligence) in the supplemented compared with the control group. The investigators however concluded that supplemented infants may have more rapid visual information processing given that they had more looks and each look was of shorter duration.

Longchain polyunsaturated fatty acid supplementation in preterm infantsCochrane collaboration 2003

Growth Most trials have reported no significant effect of LCPUFA supplementation on growth of preterm infants. Two trials (Carlson 1993, Carlson 1996) suggest that LCPUFA supplemented infants grow less well than controls, possibly due to a reduction in AA levels which occurs when n-3 supplements are used without n-6 supplements. Recent trials with addition of AA to the supplement have reported no significant effect on growth. Fewtrell 2002 reported mild reductions in length and weight z scores at 18 months. Contrary to these results, the meta-analysis of five studies (Uauy 1992, Carlson 1996, Hansen 1997, Vanderhoof 1999, Innis 2002) showed increased weight and length at two months post-term in supplemented infants.

Side effects Uauy 1992 reported no significant effect of LCPUFA supplementation on bleeding time and red cell membrane fragility.

Reviewers' conclusionsInfants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. No long-term benefits were demonstrated for infants receiving formula supplemented with LCPUFA. There was no evidence that supplementation of formula with n-3 and n-6 LCPUFA impaired the growth of preterm infants.

Is supplementary iron useful when preterm Is supplementary iron useful when preterm infants are treated with erythropoietin? infants are treated with erythropoietin? BestBets BestBets

20062006 In [a preterm infant who is receiving rHuEPO therapy] does [iron In [a preterm infant who is receiving rHuEPO therapy] does [iron

supplementation] reduce the requirement for [blood transfusion]? If so, what supplementation] reduce the requirement for [blood transfusion]? If so, what method of administration and dose reduces it most successfullymethod of administration and dose reduces it most successfully

Comment(s)

•Anaemia in premature infants is a common problem. Although erythropoietin is not used widely in neonatal practice, there is evidence of its efficacy in reducing the need for transfusion in preterm infants,(Shannon) especially if they are not extremely small or sick.(Soubasi). It is regularly used in situations where blood transfusion is unacceptable.

•Iron supplementation has been a standard in neonatal care for preterm infants for many years and helps to reduce late anaemia (Franz) if given with vitamins, especially vitamin E.(Jansson). However, when stimulating erythropoiesis with rHuEpo to reduce the need for transfusion, iron availability becomes critical.

• Several studies have investigated rHuEpo efficacy in preterm infants and most of them have used supplementary iron in either the oral or parenteral routes. The literature on the use of rHuEpo and iron mostly consists of studies on dose variation of rHuEpo rather than variation in the iron supplementation. •Our search yielded seven studies, but one(Pollak) was excluded owing to poor methodological quality. Two studies by Carnielli et al and Fujiu et al compared rHuEpo and oral iron supplementation with rHuEpo alone; however, the interpretation of the data is difficult because Carnielli et al reported their results only as mean values and logarithms, making statistical analysis difficult. Fujiu et al found that no infants in either arm of their study required a blood transfusion.

•Although this may suggest that there was no difference between the groups, the sample size was small, with only 24 infants in total, and the clinical equivalence could not be shown. In addition, the authors state that losses due to phlebotomy in their study were lower than those in other similar studies. This may be relevant, as one of the most common causes of the anaemia of prematurity is iatrogenic blood loss.

•Kivivuori et al and Meyer et al compared rHuEPO treatment and parenteral iron supplementation with rHuEPO treatment and oral iron supplementation. Combined data from the two studies showed that there was no significant difference between the groups for the number of blood transfusions given (odds ratio (OR) 1.65, 95% confidence interval (CI) 0.41 to 6.64). This seems to suggest that oral iron supplementation is at least sufficient. However, one study used intravenous iron supplementation whereas the other used intramuscular iron supplementation. Differences in absorption of these two different routes may be relevant, but no study has been carried out comparing intravenous with intramuscular iron supplementation.

•Bader et al and Nazir et al compared infants receiving rHuEPO treatment and high-dose oral iron supplementation with those receiving rHuEPO treatment and low-dose oral iron supplementation. There was no significant difference between the two groups, when combining data for the two studies, regarding the number of blood transfusions (OR 0.46, 95% CI 0.04 to 5.75).

Preterm infants on special-care baby units frequently become anaemic and Preterm infants on special-care baby units frequently become anaemic and require top-up blood transfusions. Preterm infants often have low iron require top-up blood transfusions. Preterm infants often have low iron stores; this becomes more evident if they do not receive transfusions or stores; this becomes more evident if they do not receive transfusions or iron supplementation. Erythropoietin is used occasionally to stimulate red iron supplementation. Erythropoietin is used occasionally to stimulate red cell production and prevent anaemia, and the increased erythropoiesis that cell production and prevent anaemia, and the increased erythropoiesis that occurs as a result of rHuEPO treatment will deplete iron stores. occurs as a result of rHuEPO treatment will deplete iron stores.

The studies currently available do not give an adequate answer to the The studies currently available do not give an adequate answer to the question as to which is the best mode and dose of iron supplementation question as to which is the best mode and dose of iron supplementation with rHuEpo treatment. On the basis of the principle of using the lowest with rHuEpo treatment. On the basis of the principle of using the lowest effective dose and the least invasive mode of administration, at present, effective dose and the least invasive mode of administration, at present, low-dose oral iron would seem appropriate for supplementation when low-dose oral iron would seem appropriate for supplementation when rHuEpo is used in preterm infants. rHuEpo is used in preterm infants.

Clinical Bottom LineClinical Bottom Line Evidence available to strongly support any specific recommendation for Evidence available to strongly support any specific recommendation for

iron supplementation with recombinant erythropoietin treatment in iron supplementation with recombinant erythropoietin treatment in premature infants (grade D) is insufficient. Low-dose oral iron premature infants (grade D) is insufficient. Low-dose oral iron supplementation is not inferior to other treatment regimens (grade B). supplementation is not inferior to other treatment regimens (grade B).

Glutamine supplementation to prevent Glutamine supplementation to prevent morbidity and mortality in preterm infantsmorbidity and mortality in preterm infants

Cochrane collaboration 2008Cochrane collaboration 2008

Main results•2365 preterm infants have participated in seven randomised controlled trials. All of the participating infants were of very low birth weight. •Three trials assessed enteral glutamine supplementation and four trials assessed parenteral glutamine supplementation. •The trials were generally of good methodological quality with adequate allocation concealment, blinding of caregivers and assessors to the intervention, and complete or near-complete follow-up of recruited infants. •Glutamine supplementation does not have a statistically significant effect on mortality: typical relative risk 0.98 (95% confidence interval 0.80 to 1.20); typical risk difference 0.00 (95% confidence interval -0.03 to 0.02). •The only trial that assessed long-term outcomes did not find any statistically significant differences in various assessments of neurodevelopment at 18 months corrected age. Glutamine supplementation does not have a statistically significant effect on other neonatal morbidities including invasive infection, necrotising enterocolitis, time to achieve full enteral nutrition, or duration of hospital stay.Authors' conclusions•The available data from good quality randomised controlled trials indicate that glutamine supplementation does not confer benefits for preterm infants. The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority.

Iodine supplementation for the Iodine supplementation for the prevention of mortality and adverse prevention of mortality and adverse

neurodevelopmental outcomes in neurodevelopmental outcomes in preterm infants (Review)preterm infants (Review)

Copyright © 2008 The Cochrane CollaborationCopyright © 2008 The Cochrane CollaborationMain resultsMain results We found only one randomised controlled trial (N = 121) that fulfilled the We found only one randomised controlled trial (N = 121) that fulfilled the

review eligibility criteria (Rogahn 2000).review eligibility criteria (Rogahn 2000). The participants were infants born before 33 weeks’ gestation (but most were The participants were infants born before 33 weeks’ gestation (but most were

of birth weight greater than 1000 grams). The primary aim of this trial was to of birth weight greater than 1000 grams). The primary aim of this trial was to assess the effect of iodine supplementation on thyroid function. The assess the effect of iodine supplementation on thyroid function. The investigators did not detect any statistically significant effects on the plasma investigators did not detect any statistically significant effects on the plasma levels of thyroxine (free and total), triiodothyronine, or thyrotrophin in levels of thyroxine (free and total), triiodothyronine, or thyrotrophin in preterm infants (measured up to 40 weeks’ post-conceptional age). Only one preterm infants (measured up to 40 weeks’ post-conceptional age). Only one infant died and the trial was therefore underpowered to detect an effect on infant died and the trial was therefore underpowered to detect an effect on mortality. The trial did not assess the effect of the intervention on mortality. The trial did not assess the effect of the intervention on neurodevelopmental morbidity. There was not a statistically significant neurodevelopmental morbidity. There was not a statistically significant difference in the incidence of chronic lung disease.difference in the incidence of chronic lung disease.

Authors’ conclusionsAuthors’ conclusions There are insufficient data at present to determine whether providing There are insufficient data at present to determine whether providing

preterminfants with supplemental iodine (to match fetal accretion rates) preterminfants with supplemental iodine (to match fetal accretion rates) prevents morbidity and mortality in preterm infants. prevents morbidity and mortality in preterm infants.

Future randomised controlled trials of iodine supplementation should focus Future randomised controlled trials of iodine supplementation should focus on extremely preterm and extremely low birth weight infants, the group at on extremely preterm and extremely low birth weight infants, the group at greatest risk of transient hypothyroxinaemia. These trials should aim to greatest risk of transient hypothyroxinaemia. These trials should aim to assess the effect of iodine supplementation on clinically important outcomes assess the effect of iodine supplementation on clinically important outcomes including respiratory morbidity and longer term neurodevelopment.including respiratory morbidity and longer term neurodevelopment.

Lactase treated feeds to promote growth and Lactase treated feeds to promote growth and feeding tolerance in preterm infants (Review)feeding tolerance in preterm infants (Review)

Copyright © 2008 The Cochrane CollaborationCopyright © 2008 The Cochrane Collaboration

Main resultsMain results One study enrolling 130 infants of 26 - 34 weeks postconceptual age (mean One study enrolling 130 infants of 26 - 34 weeks postconceptual age (mean

postnatal age at entry 11 days) was identified and no identified study was postnatal age at entry 11 days) was identified and no identified study was excluded. excluded.

The study was a double blind randomized controlled trial of high quality. The study was a double blind randomized controlled trial of high quality. Lactase treated feeds were initiated when enteral feedings provided > 75% of Lactase treated feeds were initiated when enteral feedings provided > 75% of daily intake. None of the primary outcomes outlined in the protocol for this daily intake. None of the primary outcomes outlined in the protocol for this review and only one of the secondary outcomes, necrotizing enterocolitis review and only one of the secondary outcomes, necrotizing enterocolitis (NEC), were reported on. The RR for NEC was 0.32 (95% CI(NEC), were reported on. The RR for NEC was 0.32 (95% CI

0.32 (0.01, 7.79); the RD was -0.02 (95% CI -0.06, 0.03) (a reduction which 0.32 (0.01, 7.79); the RD was -0.02 (95% CI -0.06, 0.03) (a reduction which was not statistically significant). There was a statistically significant increase was not statistically significant). There was a statistically significant increase in weight gain at study day 10 in the lactase treated feeds group but not at in weight gain at study day 10 in the lactase treated feeds group but not at any other time points. Overall, there was not a statistically significant effect any other time points. Overall, there was not a statistically significant effect on weight gain. No adverse effects were noted.on weight gain. No adverse effects were noted.

Authors’ conclusionsAuthors’ conclusions The only randomized trial to date provides no evidence of significant benefit The only randomized trial to date provides no evidence of significant benefit

to preterm infants from adding lactase to their feeds. to preterm infants from adding lactase to their feeds. Further research regarding effectiveness and safety are required before Further research regarding effectiveness and safety are required before

practice recommendations can be made. Randomized controlled trials practice recommendations can be made. Randomized controlled trials comparing lactase vs placebo treated feeds and enrolling infants when enteral comparing lactase vs placebo treated feeds and enrolling infants when enteral feeds are introduced are recommended. The primary and secondary feeds are introduced are recommended. The primary and secondary outcomes for effectiveness and safety should include those identified in this outcomes for effectiveness and safety should include those identified in this review.review.

Effect of taurine supplementation on growth and Effect of taurine supplementation on growth and development in preterm or low birth weight infants development in preterm or low birth weight infants

(Review)(Review)Copyright © 2008 The Cochrane CollaborationCopyright © 2008 The Cochrane Collaboration

Main resultsMain results Nine small trials were identified. Nine small trials were identified. In total, 189 infants participated. Most participants were greater than 30 weeks In total, 189 infants participated. Most participants were greater than 30 weeks

gestational age at birth and were clinically stable. In eight of the studies, taurine was gestational age at birth and were clinically stable. In eight of the studies, taurine was given enterally with formula milk. Only one small trial assessed parenteral taurine given enterally with formula milk. Only one small trial assessed parenteral taurine supplementation. supplementation.

Taurine supplementation increased intestinal fat absorption [weighted mean difference Taurine supplementation increased intestinal fat absorption [weighted mean difference 4.0 (95% confidence interval 1.4, 6.6) percent of intake]. However, meta-analyses did 4.0 (95% confidence interval 1.4, 6.6) percent of intake]. However, meta-analyses did not reveal any statistically significant effects on growth parameters assessed during the not reveal any statistically significant effects on growth parameters assessed during the neonatal period or until three to four months chronological age [rate of weight gain: neonatal period or until three to four months chronological age [rate of weight gain: weighted mean difference - 0.25 (95% confidence interval -1.16, 0.66) weighted mean difference - 0.25 (95% confidence interval -1.16, 0.66) grams/kilogram/day; change in length: weighted mean difference 0.37 (95% confidence grams/kilogram/day; change in length: weighted mean difference 0.37 (95% confidence interval -0.23, 0.98) millimetres/week; change in head circumference: weighted mean interval -0.23, 0.98) millimetres/week; change in head circumference: weighted mean difference 0.15 (95% confidence interval -0.19, 0.50) millimeters/week]. difference 0.15 (95% confidence interval -0.19, 0.50) millimeters/week].

There are very limited data on the effect on neonatal mortality or morbidities, and no There are very limited data on the effect on neonatal mortality or morbidities, and no data on long-term growth or neurological outcomes.data on long-term growth or neurological outcomes.

Authors’ conclusionsAuthors’ conclusions Despite that lack of evidence of benefit from randomised controlled trials, it is likely that Despite that lack of evidence of benefit from randomised controlled trials, it is likely that

taurine will continue to be added to formula milks and parenteral nutrition solutions taurine will continue to be added to formula milks and parenteral nutrition solutions used for feeding preterm and low birth weight infants given the putative association of used for feeding preterm and low birth weight infants given the putative association of taurine deficiency with various adverse outcomes. taurine deficiency with various adverse outcomes.

Further randomised controlled trials of taurine supplementation versus no Further randomised controlled trials of taurine supplementation versus no supplementation in preterm or low birth weight infants are unlikely to be viewed as a supplementation in preterm or low birth weight infants are unlikely to be viewed as a research priority, but there may be issues related to dose or duration of research priority, but there may be issues related to dose or duration of supplementation in specific subgroups of infants that merit further research.supplementation in specific subgroups of infants that merit further research.

Probiotics for prevention of Probiotics for prevention of necrotizing enterocolitis in necrotizing enterocolitis in

preterm infants preterm infants Cochrane review 2007Cochrane review 2007

Main resultsMain results Nine eligible trials randomizing 1425 infants were included. Nine eligible trials randomizing 1425 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth Included trials were highly variable with regard to enrollment criteria (i.e. birth

weight and gestational age), baseline risk of NEC in the control groups, timing, weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. extremely low birth weight infants (ELBW) could not be extrapolated.

In a meta-analysis of trial data, enteral probiotics supplementation significantly In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) [typical RR 0.32 (95% CI reduced the incidence of severe NEC (stage II or more) [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75]. There was no 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition (TPN) [WMD -1.9 (95% CI -4.6, 0.73, 1.19)] or days on total parenteral nutrition (TPN) [WMD -1.9 (95% CI -4.6, 0.77)]. 0.77)].

The included trials reported no systemic infection with the probiotics The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. and sepsis was insignificant.

Reviewers' conclusionsReviewers' conclusions Enteral supplementation of probiotics reduced the risk of severe NEC and Enteral supplementation of probiotics reduced the risk of severe NEC and

mortality in preterm infants. This analysis supports a change in practice in mortality in preterm infants. This analysis supports a change in practice in premature infants > 1000 g at birth. Data regarding outcome of ELBW infants premature infants > 1000 g at birth. Data regarding outcome of ELBW infants could not be extracted from the available studies; therefore, a reliable estimate could not be extracted from the available studies; therefore, a reliable estimate of the safety and efficacy of administration of probiotic supplements cannot be of the safety and efficacy of administration of probiotic supplements cannot be made in this high risk group. A large randomized controlled trial is required to made in this high risk group. A large randomized controlled trial is required to investigate the potential benefits and safety profile of probiotics supplementation investigate the potential benefits and safety profile of probiotics supplementation in ELBW infants.in ELBW infants.

Erythromycin for the prevention and Erythromycin for the prevention and treatment of feeding intolerance in preterm treatment of feeding intolerance in preterm

infants (Review)infants (Review)Copyright © 2008 The Cochrane CollaborationCopyright © 2008 The Cochrane Collaboration

Main resultsMain results Ten randomized controlled studies (three prevention and seven treatment Ten randomized controlled studies (three prevention and seven treatment

studies) were included. studies) were included. Studies varied greatly in the definition of feeding intolerance and how Studies varied greatly in the definition of feeding intolerance and how

outcomes were measured, analyzed and reported, so meta-analysis of outcomes were measured, analyzed and reported, so meta-analysis of most outcomes was impossible. It was observed, however, that the studies most outcomes was impossible. It was observed, however, that the studies using erythromycin at higher treatment doses (40 to 50 mg/kg/day) or in using erythromycin at higher treatment doses (40 to 50 mg/kg/day) or in infants > 32 weeks’ GA reported more positive effects in improving feeding infants > 32 weeks’ GA reported more positive effects in improving feeding intolerance.intolerance.

Meta-analysis of high dose prevention studies showed no significant Meta-analysis of high dose prevention studies showed no significant difference in NEC (typical RR 0.59, 95% CI 0.11, 3.01; typical RD-0.021, difference in NEC (typical RR 0.59, 95% CI 0.11, 3.01; typical RD-0.021, 95%CI -0.087, 0.045). Meta-analysis of high dose treatment studies 95%CI -0.087, 0.045). Meta-analysis of high dose treatment studies showed no significant difference in septicemia (typical RR 0.83, 95% CI showed no significant difference in septicemia (typical RR 0.83, 95% CI 0.47, 1.45; typical RD -0.04, 95% CI -0.17, 0.08).0.47, 1.45; typical RD -0.04, 95% CI -0.17, 0.08).

Authors’ conclusionsAuthors’ conclusions There is insufficient evidence to recommend the use of erythromycin in low There is insufficient evidence to recommend the use of erythromycin in low

or high doses for preterm infants with or at risk of feeding intolerance. or high doses for preterm infants with or at risk of feeding intolerance. Future research is needed to determine if there is a more precise dose Future research is needed to determine if there is a more precise dose

range where erythromycin might be effective as a prokinetic agent in range where erythromycin might be effective as a prokinetic agent in preterm infants > 32 weeks’ GA.preterm infants > 32 weeks’ GA.

The Role of Nutrition The Role of Nutrition in the Prevention and in the Prevention and

Management of Management of BPDBPDSeminars in Perinatology Seminars in Perinatology

30:200-20830:200-208

Nutritional IntakeNutritional Intake Preterm infants with BPD are at risk for undernutrition due to difficulties maintaining Preterm infants with BPD are at risk for undernutrition due to difficulties maintaining

appropriate nutritional intake appropriate nutritional intake – as a result of co-morbidities (Carlson, 2004) eg swallowing dysfunction, fatigue as a result of co-morbidities (Carlson, 2004) eg swallowing dysfunction, fatigue

during feeding, GERD, dysfunction of other organ system eg NEC, prolonged TPNduring feeding, GERD, dysfunction of other organ system eg NEC, prolonged TPN– medically indicated fluid restriction (Carlson, 2004; Oh et al., 2005), medically indicated fluid restriction (Carlson, 2004; Oh et al., 2005), – and elevated energy expenditure (Bauer et al., 2003; Leitch & Denne, 2000).and elevated energy expenditure (Bauer et al., 2003; Leitch & Denne, 2000).– Use of dexamethasoneUse of dexamethasone– Anemia of prematurityAnemia of prematurity– Medications eg methyl xanthines and beta sympthomimetics can increase Medications eg methyl xanthines and beta sympthomimetics can increase

energy consumptionenergy consumption BPD patients can have increased energy expenditure up to 25% above total caloric BPD patients can have increased energy expenditure up to 25% above total caloric

needsneeds– Increased work of breathingIncreased work of breathing– Higher resting metabolic ratesHigher resting metabolic rates

Enteral NutritionEnteral Nutrition

CaloriesCalories Breast milk requires HMF, multivitamin and iron Breast milk requires HMF, multivitamin and iron

supplementssupplements Alternatively use prem formulaAlternatively use prem formula

– Provides additional calories, proteins, calcium, phosphorus and Provides additional calories, proteins, calcium, phosphorus and vitaminsvitamins

Additional fat may be desirableAdditional fat may be desirable– Increases caloriesIncreases calories– Less CO2 production than carbohydratesLess CO2 production than carbohydrates– However, additional fat slows gastric emptying and may However, additional fat slows gastric emptying and may

worsen GERDworsen GERD Glucose polymersGlucose polymers

– Provide additional 4kcal/gProvide additional 4kcal/g– May cause hyperosmolar diarrhoeaMay cause hyperosmolar diarrhoea

Protein supplementation can be considered or provided by Protein supplementation can be considered or provided by using a high caloric formula eg 30 kcal/ozusing a high caloric formula eg 30 kcal/oz

Calcium, Phosphorus and Vit Calcium, Phosphorus and Vit DD

Osteopenia of prem more common in Osteopenia of prem more common in BPDBPD– Limited solubility of Ca and phosphorus Limited solubility of Ca and phosphorus

in TPNin TPN– Low enteral intakeLow enteral intake– Loop diuretics/urinary lossLoop diuretics/urinary loss

Provide above via prem formula or Provide above via prem formula or fortified BMfortified BM

NutrientsNutrients

Vit AVit A– Deficiency associated with impaired clearance Deficiency associated with impaired clearance

of lung secretions, impaired water homeostasis of lung secretions, impaired water homeostasis across tracheobronchial epithelium, loss of across tracheobronchial epithelium, loss of cilia, diminished lung injury repair and lack of cilia, diminished lung injury repair and lack of airway distensabilityairway distensability

– Well documented to result in BPD/death in Vit Well documented to result in BPD/death in Vit A deficiency (NICHD study). A deficiency (NICHD study).

– Dose of IM 5000 IU per dose 3x/week (12 Dose of IM 5000 IU per dose 3x/week (12 doses) for ELBW. Oral does not work. doses) for ELBW. Oral does not work.

Under study: inositol, Vit EUnder study: inositol, Vit E

Discharge in BPDDischarge in BPD 67% continue to have growth failure post 67% continue to have growth failure post

dischargedischarge Individualised nutrition planIndividualised nutrition plan Continue 22kcal/oz prem formula for 6-8 Continue 22kcal/oz prem formula for 6-8

monthsmonths Low salt/low volume/high calorie diet may be Low salt/low volume/high calorie diet may be

necessarynecessary Achieve solid intake slower than chronological Achieve solid intake slower than chronological

age, often tolerate spoon feeding (thicker age, often tolerate spoon feeding (thicker consistency) better than nipple (liquid). This consistency) better than nipple (liquid). This may begin at 3-4 mths post gestationmay begin at 3-4 mths post gestation

Discharge – planning Discharge – planning and post and post

Non-nutritive sucking for promoting Non-nutritive sucking for promoting physiologic stability andnutrition in preterm physiologic stability andnutrition in preterm

infants (Review) infants (Review) Copyright © 2008 The Cochrane Copyright © 2008 The Cochrane CollaborationCollaboration

Types of interventionTypes of intervention Non-nutritive sucking involving the use of a pacifier. The intervention occurred before, Non-nutritive sucking involving the use of a pacifier. The intervention occurred before,

during or after feeding by a naso/orogastric tube; before or after bottle feeding; or during or after feeding by a naso/orogastric tube; before or after bottle feeding; or outside of feeding times.outside of feeding times.

Main resultsMain results This review consisted of 21 studies, 15 of which were randomized controlled trials. This review consisted of 21 studies, 15 of which were randomized controlled trials. NNS was found to decrease significantly the length of hospital stay in preterm infants. NNS was found to decrease significantly the length of hospital stay in preterm infants.

The review did not reveal a consistent benefit of NNS with respect to other major clinical The review did not reveal a consistent benefit of NNS with respect to other major clinical variables (weight gain, energy intake, heart rate, oxygen saturation, intestinal transit variables (weight gain, energy intake, heart rate, oxygen saturation, intestinal transit time, age at full oral feeds and behavioral state). time, age at full oral feeds and behavioral state).

The review identified other positive clinical outcomes of NNS: transition from tube to The review identified other positive clinical outcomes of NNS: transition from tube to bottle feeds and better bottle feeding performance. bottle feeds and better bottle feeding performance.

No negative outcomes were reported in any of the studies.No negative outcomes were reported in any of the studies.

Authors’ conclusionsAuthors’ conclusions There were also a number of limitations of the presently available evidence related to the There were also a number of limitations of the presently available evidence related to the

design of the studies, outcome variability, and lack of long-term data. design of the studies, outcome variability, and lack of long-term data. Based on the available evidence, NNS in preterm infants would appear to have some Based on the available evidence, NNS in preterm infants would appear to have some

clinical benefit. It does not appear to have any short-term negative effects.clinical benefit. It does not appear to have any short-term negative effects. In view of the fact that there are no long-term data, further investigations are In view of the fact that there are no long-term data, further investigations are

recommended. In order to facilitate meta-analysis of these data, future research in this recommended. In order to facilitate meta-analysis of these data, future research in this area should involve outcome measures consistent with those used in previous studies. In area should involve outcome measures consistent with those used in previous studies. In addition, published reports should include all relevant data.addition, published reports should include all relevant data.

Early discharge with home support of gavage Early discharge with home support of gavage feeding for stable preterm infants who have feeding for stable preterm infants who have not established full oral feeds 2008 Cochrane not established full oral feeds 2008 Cochrane

CollaborationCollaborationMain resultsMain results Data from one quasi-randomised trial with 88 infants from 75 families were Data from one quasi-randomised trial with 88 infants from 75 families were

included in the review.included in the review. Infants in the early discharge program with home gavage feeding had a Infants in the early discharge program with home gavage feeding had a

mean hospital stay that was 9.3 days shorter [MD -9.3 (-18.49 to -0.11)] mean hospital stay that was 9.3 days shorter [MD -9.3 (-18.49 to -0.11)] than infants in the control group. Infants in the early discharge program than infants in the control group. Infants in the early discharge program also had a lower risk of clinical infection during the home gavage period also had a lower risk of clinical infection during the home gavage period compared with the corresponding time in hospital for the control group compared with the corresponding time in hospital for the control group [relative risk 0.35 (0.17 to 0.69)]. [relative risk 0.35 (0.17 to 0.69)].

There were no significant differences between groups in duration and There were no significant differences between groups in duration and extent of breast feeding, weight gain, re-admission within the first 12 extent of breast feeding, weight gain, re-admission within the first 12 months post discharge from the home gavage program or from hospital, months post discharge from the home gavage program or from hospital, scores reflecting parental satisfaction, or health service use.scores reflecting parental satisfaction, or health service use.

Authors’ conclusionsAuthors’ conclusions Experimental evidence to evaluate the benefits and risks in preterm infants Experimental evidence to evaluate the benefits and risks in preterm infants

of early discharge from hospital with home gavage feeding compared with of early discharge from hospital with home gavage feeding compared with later discharge upon attainment of full sucking feeds is limited to the later discharge upon attainment of full sucking feeds is limited to the results of one small quasi-randomised controlled trial. results of one small quasi-randomised controlled trial.

High quality trials with concealed allocation, complete follow-up of all High quality trials with concealed allocation, complete follow-up of all randomised infants and adequate sample size are needed before practice randomised infants and adequate sample size are needed before practice recommendations can be made.recommendations can be made.

Use of transitional formula: the Use of transitional formula: the evidence evidence

Post discharge Nutrition of Preterm Infants, Journal of Perinatology 2005; 25:S15–S16Post discharge Nutrition of Preterm Infants, Journal of Perinatology 2005; 25:S15–S16 feeding of specially designed post discharge formulas has feeding of specially designed post discharge formulas has

demonstrated better weight (at 9 but not at 18 months) and demonstrated better weight (at 9 but not at 18 months) and length (at 9 and 18 months) as well as higher bone mineral length (at 9 and 18 months) as well as higher bone mineral content when compared to term infant formulacontent when compared to term infant formula

– Lucas A, King F, Bishop NB. Postdischarge formula consumption in infants born preterm. Arch Dis Child 1992;67:691–2.Lucas A, King F, Bishop NB. Postdischarge formula consumption in infants born preterm. Arch Dis Child 1992;67:691–2.– Lucas A, Fewtrell MS, Morley R, Singhal A, Abbott RA, Isaacs E. Randomized trial of nutrient-enriched formula versus Lucas A, Fewtrell MS, Morley R, Singhal A, Abbott RA, Isaacs E. Randomized trial of nutrient-enriched formula versus

standard formula for post discharge preterm infants. Pediatrics 2001;107:683–9.standard formula for post discharge preterm infants. Pediatrics 2001;107:683–9.

the benefit appears restricted to males, a finding similar to the benefit appears restricted to males, a finding similar to that of Cooke et al.that of Cooke et al.

– Cooke RJ, Griffin IJ, McCormick K, Wells JC, Smith JS, Robinson SJ. Feeding preterm infants after hospital discharge: effect of dietary Cooke RJ, Griffin IJ, McCormick K, Wells JC, Smith JS, Robinson SJ. Feeding preterm infants after hospital discharge: effect of dietary manipulation on nutrient intake and growth. Pediatr Res 1998;43:355–60manipulation on nutrient intake and growth. Pediatr Res 1998;43:355–60

From the NICHD network, data demonstrate that in virtually From the NICHD network, data demonstrate that in virtually all infants less than 1500 g, appropriate-for-gestational-age all infants less than 1500 g, appropriate-for-gestational-age infants are ‘‘converted’’ to small for-gestational-age infants infants are ‘‘converted’’ to small for-gestational-age infants by 36 weeks postmenstrual age.by 36 weeks postmenstrual age.

Some recovery in these parameters has been reportedSome recovery in these parameters has been reported Chronic lung disease adds an additional burden as Chronic lung disease adds an additional burden as

demonstrated by 73% of infants in one study experiencing a demonstrated by 73% of infants in one study experiencing a decrease in weight z score between hospital discharge and 7 decrease in weight z score between hospital discharge and 7 monthsmonths

Use of transitional formula: Use of transitional formula: GuidelinesGuidelines

Post discharge Nutrition of Preterm Infants, Journal of Perinatology 2005; 25:S15–S16Post discharge Nutrition of Preterm Infants, Journal of Perinatology 2005; 25:S15–S16

Until more optimal strategies are developed, Until more optimal strategies are developed, striving toward achieving the best possible striving toward achieving the best possible gain without adverse effects may be gain without adverse effects may be appropriate.appropriate.

Guideline:Guideline: <1800 g: 24 kcal/oz preterm infant formula<1800 g: 24 kcal/oz preterm infant formula Transition to 22 kcal/oz at >1800 g if all growth Transition to 22 kcal/oz at >1800 g if all growth

parameters are 25th percentile or greater and parameters are 25th percentile or greater and infant is gaining 15 to 40 g/dayinfant is gaining 15 to 40 g/day

Transition from 22 kcal/oz to 20 kcal/oz term Transition from 22 kcal/oz to 20 kcal/oz term formula at 4–6 months corrected gestational formula at 4–6 months corrected gestational age if all growth parameters are above 25th age if all growth parameters are above 25th percentilepercentile

Nutrition Practice Care Nutrition Practice Care Guidelines for Preterm Guidelines for Preterm

Infants In the Community Infants In the Community (Revised August 2006)(Revised August 2006)

Developed by: Child Development and Developed by: Child Development and Rehabilitation Center, Nutrition Services Rehabilitation Center, Nutrition Services

Oregon Department of Human Services, Nutrition Oregon Department of Human Services, Nutrition

& Health Screening – & Health Screening – WIC Program Oregon WIC Program Oregon Pediatric Nutrition Practice GroupPediatric Nutrition Practice Group

Referral CriteriaReferral Criteria

These “red flags” should alert the community nutritionist of the need for further assessment, referral and follow-up

Anthropometric “Red Flags”: • Weight loss or significant decline in percentile ranking (“falling away” from expected growth curve percentile) • Poor rate of weight gain for corrected age as listed below:

Age Weight Gain term – 3 mos < 20 gm/day (< 5 oz/wk) 3 – 6 mos < 15 gm/day (< 3½ oz/wk) 6 – 9 mos < 10 gm/day (< 2 oz/wk) 9 – 12 mos < 6 gm/day (< 1½ oz/wk) 1 – 2 yrs < 1 kg or < 2 lbs in 6 mos 2 – 5 yrs < 0.7 kg or < 1½ lbs in 6 mos

VITAMIN-MINERAL SUPPLEMENTATIONVITAMIN-MINERAL SUPPLEMENTATION

Vitamins: Vitamins: Supplementation with a standard infant multivitamin Supplementation with a standard infant multivitamin (with vitamins A, D, B1, B2, B3, B6, B12, C, and iron) is generally (with vitamins A, D, B1, B2, B3, B6, B12, C, and iron) is generally needed initially after NICU discharge to meet the preterm infant’s needed initially after NICU discharge to meet the preterm infant’s vitamin needs, until the infant is consuming larger volumes of vitamin needs, until the infant is consuming larger volumes of feeds. feeds.

Vitamin DVitamin D: Per the American Academy of Pediatrics (AAP), all : Per the American Academy of Pediatrics (AAP), all infants fed unfortified breast milk should continue to receive a infants fed unfortified breast milk should continue to receive a supplement of 200 IU of Vitamin D for the first year. supplement of 200 IU of Vitamin D for the first year. – This 200 IU of Vitamin D can be provided by continuing the 0.5 ml daily This 200 IU of Vitamin D can be provided by continuing the 0.5 ml daily

of the standard infant multivitamin, or by changing to 0.5 ml daily of a of the standard infant multivitamin, or by changing to 0.5 ml daily of a tri-vitamin supplement (vitamins A, C, and D). Infants receiving 17 oz. tri-vitamin supplement (vitamins A, C, and D). Infants receiving 17 oz. (500 ml) or more of a vitamin D-fortified infant formula do not need (500 ml) or more of a vitamin D-fortified infant formula do not need any additional Vitamin D supplementation.any additional Vitamin D supplementation.

IronIron: Preterm infants have lower iron stores than term infants. By : Preterm infants have lower iron stores than term infants. By 2 months post birth (2 months post birth (not not 2 months corrected age), preterm infants 2 months corrected age), preterm infants should have an intake of 2-4 mg iron/kg/day (up to a maximum of should have an intake of 2-4 mg iron/kg/day (up to a maximum of 40 mg/day) from an iron-fortified infant formula and/or 40 mg/day) from an iron-fortified infant formula and/or supplement. This iron dose should be continued for the first year supplement. This iron dose should be continued for the first year of life.of life.

Osteopenia of prematurity is most commonly seen in: • Very-low-birth-weight infants (BW < 1500g). • Any IUGR infant with a birthweight < 1800 g regardless of gestational age. • Infants with chronic lung disease/bronchopulmonary dysplasia. • Infants requiring long-term parenteral nutrition at birth. • Infants on certain medications, including diuretics & corticosteroids, that affect mineral absorption. • Infants starting feedings of unfortified breastmilk or standard formula too early, or soy formula.

Recommendation for checking labs: • 1-month post-discharge for the infants born < 1500g and IUGR with birthweight < 1800 g. • 1-month post-discharge if any of the labs at discharge (if known) are outside the reference range. • If the premie is transitioning to the breast or a term formula < 3-6 months corrected age. • If the premie has had marginal intake and slower growth.

Bone health can be assessed using the following labs. •In the absence of other disease conditions, alkaline phosphatase provides an indirect indicator of bone cell activity. •Higher alkaline phosphatase along with lower calcium and phosphorus levels may indicate a need for further assessment and supplementation. These labs are usually done in the hospital setting, and may be done in the community up until 6-9 months corrected age.

One last example to put it all One last example to put it all together …together …

the ADHB (Auckland District the ADHB (Auckland District Health Board) guidelines Health Board) guidelines

More questions than More questions than answers?answers?Sighhh…Sighhh…

More questions than More questions than answers?answers?Sighhh…Sighhh…

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Enteral nutrition in preterm neonates

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