Nutrition: enteral nutrition for the preterm infant

This clinical guideline from Great Ormond Street Hospital (GOSH) discusses nutritional requirements for preterm infants receiving enteral nutrition. It does not give guidance on the prescription of parenteral nutrition (PN).

Definitions relating to prematurity and birthweight 

Prematurity

  • Preterm: birth date before 37 completed weeks gestation.Gestational age: time elapsed between the first day of the last menstrual period and the day of delivery.
  • Number of weeks preterm: 40 weeks minus gestational age. 
  • Chronological age: time elapsed since birth. 
  • Postmenstrual age: gestational age plus chronological age in weeks.
  • Corrected age: chronological age minus number of weeks preterm. 

(Royal College of Paediatrics and Child Health, (RCPCH) 2011)

Birthweight 

  • Birthweight is the first weight of the newborn obtained after birth (ideally within one hour of delivery). 
  • Low birthweight (LBW)<2,500 g. 
  • Very low birthweight (VLBW)<1,500 g.
  • Extremely low birthweight (ELBW) <1,000 g.  

(UNICEF & WHO, 2004)

Nutritional requirements

Introduction

Preterm infants have higher nutrient requirements than term infants (Rationale 1). Parenteral nutrition is necessary to meet nutritional requirements while enteral feeds are established in the following groups of infants:

  • Birthweight <1,000 g
  • Gestational age <30 completed weeks
  • Failure to establish enteral nutrition (≥100 ml/kg/day) by day 5 of life regardless of gestation or birthweight.

International references

There are no UK guidelines for enteral feeding of preterm infants and so international references are used (Tsang et al., 2006), (Agostoni et al., 2010) (Koletzko et al., 2014). The 2010 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines (Agostoni et al., 2010) form the basis of this document.

The ESPGHAN recommendations categorise infants according to body weight rather than birthweight.
Recommendations are expressed as ranges of enteral intakes for stable growing preterm infants up to a body weight of approximately 1,800 g, although most infants <2,000 g will benefit from them. See Appendix 1 for summary of ESPGHAN recommendations.

Working weight

Use the patient’s actual weight when calculating nutrient requirements, unless the actual weight is lower than the birthweight or their highest dry weight, in which case birthweight or highest dry weight should be used (a patient’s dry weight is their weight when they are not fluid overloaded).

Growth

Intrauterine growth rate (~15 g/kg/day) is the most commonly used and accepted standard for preterm growth, but it is difficult to achieve in practice (Tsang et al., 2006).

Energy and protein are the two major nutrients that affect growth, and so a key goal of nutritional management is to facilitate adequate delivery of both (Rationale 2).

Accelerated growth in preterm infants should be avoided (Rationale 3).

Energy requirements

Energy requirements for preterm infants are estimated to be 110–135 kcal/kg/day (Agostoni et al., 2010) compared to 96–120 kcal/kg/day for term infants (range for term infants depends on method of feeding) (Scientific Advisory Committee on Nutrition (SACN), 2011).

Infants with intrauterine growth restriction (IUGR) do not necessarily have higher requirements than their appropriately grown counterparts; understanding the cause of the IUGR should guide decision making relating to energy requirements for these babies.

Protein requirements

Recommended protein supply for preterm infants:

  • Infant body weight 1–1.8 kg 3.5–4 g/kg/day
  • Infant body weight <1 kg 4–4.5 g/kg/day 
  • There is no benefit to feeding >4.5 g/kg/day

Protein to energy ratio

Protein to energy ratios must be considered for all preterm infants (Rationale 4).

ESPGHAN recommended protein to energy ratios

  • Infant body weight 1–1.8 kg 3.2–3.6 g/100 kcal (12.8–14.4%)
  • Infant body weight <1 kg 3.6–4.1 g/100 kcal (14.4–16.4%)

Long-chain polyunsaturated fats (LCPs)

LCPs are conditionally essential in preterm infants (Rationale 5).  

Breast milk contains a full complement of all polyunsaturated fatty acids including precursors and metabolites.  

Nutriprem 1, Hydrolysed Nutriprem and SMA Gold Prem Pro contain docosahexaenoic acid (DHA) and arachidonic acid (AA) (see Appendix 2 for web-links to data cards from Cow & Gate and Nestle respectively) although further research is needed to determine the optimal level of LCP supplementation for preterm infants.

ESPGHAN recommended intakes for LCPs

  • DHA 12–30 mg/kg/day or 11–27 mg/100 kcal.
  • AA 18–42 mg/kg/day or 16–39 mg/100 kcal.

Prebiotics and probiotics

Probiotics are beneficial bacteria and prebiotics are their preferred substrate. Breast milk contains probiotics and >130 prebiotics.  At the time of writing, there is only one preterm formula available in the UK that contains prebiotics (Nutriprem 1) and none that contain probiotics. Probiotic supplements are not routinely prescribed to preterm infants at Great Ormond Street Hospital (Rationale 6).  

Choice of feed

Breast milk

Breast milk is the feed of choice for preterm infants (see

). The benefits of human milk for preterm infants are well documented and have been summarised below.
  • immune protection – resulting in less sepsis and NEC (Rationale 7)
  • superior nutrient bioavailability compared to formula (Rationale 8)
  • improved feed tolerance (Rationale 9)
  • neurodevelopmental advantages compared to formula fed infants (Rationale 10)
  • better long-term health outcomes (Rationale 11

Facilities must be provided for mothers to breast feed their babies in privacy and comfort (see clinical guideline: breast feeding: guidance for staff assisting the mother).

Babies who are <35 weeks or too immature to suckle may have their mother’s expressed breast milk fed via an orogastric or nasogastric tube (see clinical guideline: breast milk expressing and handling). 

Mothers at high risk of Vitamin D deficiency who are expressing breast milk should be encouraged to take supplements.  
Breast feeding mothers who are vegan should be encouraged to take a Vitamin B12 supplement.

Preterm infants >1,500 g 

Aim to feed at least 150 ml/kg, (ideally 180 ml/kg/day) expressed breast milk (EBM).  Some babies will tolerate volumes of up to 220 ml/kg/day and in cases of poor growth, feed volume should be maximised (if medically appropriate) before addition of breast milk fortifier (BMF) is considered. (Rationale 12).

Monitor growth and supplement with breast milk fortifier where necessary.  

Infants receiving unfortified EBM will require Abidec, iron, folic acid, phosphate and sodium supplementation. (Rationale 12).

Preterm infants <1,500 g

Unfortified EBM will not meet the nutritional needs of infants <1,500 g (Jones & King, 2005).

Infants <1,500 g should receive fortified EBM, with the main purpose of increasing their protein intake, but also for the additional vitamins and minerals that it provides (Rationale 13).

Infants receiving EBM fortified with Nutriprem BMF (2 x 2.2 g sachet/100 ml EBM) do not need Abidec or folic acid. Sodium, phosphate and calcium should be monitored and supplemented where necessary.  

Iron supplementation is required for babies receiving fortified EBM (Rationale 13).

Infants receiving unfortified EBM will require Abidec, iron, folic acid, phosphate and sodium supplementation. (Rationale 12).

Breast milk fortification

Instructions on adding BMF to EBM at ward level can be found in clinical guideline: expressed breast milk: fortification.

Breast milk should be fortified with a commercial multicomponent BMF that is designed for preterm infants (Rationale 14). Nutriprem BMF is used at GOSH.  

Safety of breast milk fortifier

Multicomponent BMF has not been associated with a significant increase in NEC (Rationale15).

Breast milk fortifiers made from human milk are not available in the UK. There are no studies to date that have directly compared outcomes in preterm infants fed human milk fortified with human milk fortifier against human milk fortified with bovine fortifier. (Rationale 16).  

Infants with an atopic family history requiring BMF

Infants should be carefully assessed on an individual basis to determine their risk of allergy and this should be documented in the medical notes. Some of these infants will be able to tolerate Nutriprem BMF (because the protein is extensively hydrolysed), while those identified as requiring amino acids will not (Rationale 17).  

High risk infants

Care should be taken when considering fortifiers in high risk preterm infants and multidisciplinary team (MDT) discussion and decision is recommended. High risk infants include:

  • <27 weeks or <1,000 g birthweight 
  • haemodynamically unstable on inotropes 
  • previous NEC or high risk for NEC
  • recent abdominal surgery 
  • growth restricted infants with absent or reversed end diastolic flow 

Infants should be tolerating 150 ml/kg EBM for 48 hours before starting BMF.

Stable preterm infants

BMF should be commenced in stable preterm infants <1,500 g when 150 ml/kg/day EBM has been tolerated for 48 hours (Rationale 18).

Fortification of EBM in infants <1,500 g should continue until the infant is thriving.

In infants >1500g who are failing to grow as well as expected on EBM alone consider fortifying feeds:

  • with BMF if they are still <37 weeks gestation 
  • with standard infant formula powder if they are term and >2.5 kg (Rationale 19

If supplementary preterm formula is given in addition to EBM and BMF, the BMF should be stopped once 50 per cent of requirements are given as formula (Rationale 20).

Serum urea levels are sometimes used as a proxy for assessing the adequacy of protein provision. It has been suggested that serum urea should be maintained at >2 mmol/L. Urea levels should not be considered in isolation but can be included as part of a thorough nutritional assessment (Rationale 21).

Donor expressed breast milk (DEBM)

Every effort should be made to encourage mothers to express breast milk before considering donor EBM.

Donor expressed breast milk should be used in the short term only as a tool for establishing enteral feeds.

Once the target volume (usually 180 ml/kg) has been established and tolerated for 48 hours, preterm formula should be graded in over a minimum of three days (Rationale 22).

Close nutritional monitoring of the preterm infant receiving donor EBM is required. See

.

Preterm formula

All infants <2,000 g <35 weeks, who are not receiving human milk, should receive a preterm formula. There are three preterm formula milks available in the UK; SMA Gold Prem Pro (partially hydrolysed formula), Nutriprem 1 (whole protein formula) and Hydrolysed Nutriprem (partially hydrolysed formula). See table 5 for comparison of Dalton sizes in SMA Gold Prem Pro and Hydrolysed Nutriprem. SMA Gold Prem Pro is used at GOSH. Infants receiving 150 ml/kg/day preterm formula don’t require additional vitamin/mineral supplementation (Rationale 23). 

Preterm formula should continue until the infant is thriving with a body weight of 2,000–2,500 g and/or discharged. Post discharge or term formula can be used on discharge if indicated (this will depend on the infant’s growth).

Partially hydrolysed formula (PHF), extensively hydrolysed formula (EHF) and amino acid formula (AAF)

Infants requiring a PHF are given the preterm formula SMA Gold Prem Pro. If a more hydrolysed feed is indicated then term formulas are used as there are no preterm EHF or AAF available in the UK.  

Infants requiring an EHF are given term preparations such as Pregestimil or Pepti-Junior.

Those requiring AAF are given Neocate LCP or Puramino. These formulations do not meet the needs of preterm infants even if fed at 180 ml/kg/day (Rationale 24). Close nutritional monitoring is required to include assessment of intake (energy, protein, fat soluble vitamins, phosphate, calcium and sodium), growth, U&Es, phosphate, ALP and urine sodium. Consideration should be given to concentrating the formula (accepting the resulting increase in osmolality) (Rationale 25) and the addition of supplements in which they are lacking.

Supplementation with vitamins and minerals

See table below for details of which supplements are required depending on feed type.

 

Supplements

Abidec

The purpose of prescribing Abidec is to supplement vitamin A and vitamin D intake although Abidec also contains vitamin C and some B vitamins. 

In the event that there is a supply issue with Abidec, Dalivit is often the suggested alternative.  Note Dalivit contains almost 4 times the amount of vitamin A compared to Abidec (Rationale 26).  

Vitamin A (Rationale 27)

Preterm infants have low Vitamin A status at birth and this has been associated with increased risk of developing chronic lung disease (CLD). 

ESPGHAN recommend an intake of 400–1,000 micrograms (1,333–3,330 IU) RE/kg/day.

Abidec provides 400 micrograms (1,333 IU) RE per 0.6ml.

Vitamin D (Rationale 28)

Vitamin D is required with calcium and phosphorus for bone mineralisation. 

A daily target of 20–25 micrograms (800–1,000 IU) per day is recommended by ESPGHAN, but this is difficult to achieve in practice and prolonged supplementation at this level might be harmful (McCarthy et al, 2013).  

Aim to provide at least 10 micrograms (400 IU)/day vitamin D (Tsang et al., 2005). It is acknowledged that some infants may need more than this and additional vitamin D should be prescribed in discussion with the Pharmacist.

Abidec provides 10 micrograms (400 IU) vitamin D per 0.6ml.

Iron (Rationale 29)

Iron deficiency results in poor neurodevelopmental outcome in preterm infants.

Excessive iron intake should be avoided. Withholding iron supplementation should be considered in preterm infants receiving multiple blood transfusions (Raghavendra et al., 2009). 

Iron supplements should not be given with calcium or phosphorus as an insoluble compound may be formed, reducing bioavailability (Agostoni et al., 2010).  

Sytron provides 5.5 mg iron per 1 ml.

ESPGHAN recommends starting 2-3 mg/kg/day at two to six weeks of age (two to four weeks in ELBW infants). Intakes of >5 mg/kg/day should be avoided.

Folic acid (Rationale 30)

ESPGHAN recommends 35-100 micrograms/kg/day. 

50 micrograms/day folic acid is prescribed to all preterm infants receiving unfortified breast milk.

Sodium (Rationale 31)

ESPGHAN recommends 69-115 mg/kg/day but serum/urinary sodium should be monitored and sodium supplementation adjusted accordingly.

Phosphate and calcium (Rationale 32)

ESPGHAN recommends 120-140 mg/kg/day calcium and 60-90 mg/kg/day phosphorus.  

The calcium to phosphorus ratio may be an important determinant of calcium absorption and retention.  

ESPGHAN recommends calcium to phosphorus ratio between 1.5 and 2.

Excessive calcium supplementation should be avoided.  

Vitamin E (Rationale 33)

Routine supplementation of vitamin E is not recommended (Brion et al., 2003).

Initiation and progression of feeds

A standard feeding protocol has been shown to reduce the incidence of NEC (Mactier & Weaver, 2005). 

When to start

Enteral feeds can be introduced from day two of life without an increased risk of NEC even in growth restricted preterm infants (Rationale 34).

Feed advancement

See frameworks for feed advancements (Appendix 3, Appendix 4, Appendix 5).

Growth restricted infants <29 weeks do not tolerate feeds as well as those >29 weeks and the incidence of NEC is higher in this group. Slower advancement of feeds may be required for these infants. (Rationale 35)

High risk infants should be assessed by the MDT before feeding is started. 

Feed frequency

Smaller infants should receive hourly feeds and increase to three- to four-hourly intervals as the infants grows.  

Monitoring for feed intolerance

Note: The whole clinical picture should be evaluated together with these indicators to determine whether feeds are tolerated.

Indicators

  • Infants <1,000 g: >2 ml gastric aspirates every four hours (10–20 ml/kg/day). 
  • Infants >1,000 g: >3 ml gastric aspirates every four hours (15–20 ml/kg/day). 

Other indicators

  • vomiting 
  • bile-stained aspirates
  • abdominal distension 
  • abdominal discolouration 
  • blood per rectum 
  • increase in stool frequency 

Feeding route and frequency of feeds

There is no evidence to suggest an advantage of continuous feeding over bolus feeding (Kamitsuka et al., 2000).

Continuous feeding (rather than bolus feeding) may be useful in infants with gut resection, severe respiratory problems and high output stomas. Infants receiving naso-jejunal feeds must be fed continuously (Rationale 36).

Most infants <35 weeks gestation will require oro-gastric, or naso-gastric tube feeding (Rationale 37). 

Naso-jejunal feeding can be considered for preterm infants with severe gastro-oesophageal reflux.

Growth monitoring

Ensure use of UK-WHO Growth Charts on the unit:

  • UK-WHO Neonatal and Infant Close Monitoring Chart (NICM) A4B (pack of 100) product code: UK-WHONICMA4B.  
  • UK-WHO Neonatal and Infant Close Monitoring Chart (NICM) A4G (pack of 100) product code: UK-WHONICMA4G.  

Correcting for gestation:

  • Gestation ≥37 weeks - no correction
  • Gestation 32 to 36+6 correct until age 1 year 
  • Gestation 23 to 31+6 correct until age 2 years

(RCPCH, 2009)

See clinical guidelines for measuring a child: head circumference, height and weight

Measure weight three times a week: Tuesday/Thursday/Sunday. Plot birth weight on admission, and weekly weights thereafter on centile charts.

Measure and plot length weekly (Tuesdays) until 40 weeks post-conceptional age. Then every two weeks until discharge. (Rationale 38)

Measure and plot head circumference weekly: Tuesday. Use a non-stretch plasticised tape. 

Aim for an average weight gain of 15 g/kg/day (Tsang et al., 2006).

A reasonable target to aim for is to maintain the infant on the centile to which they have initially dropped, not their birth centile.

Indications for inadequate growth:

  • Consistent weight loss over several days (other than when diuresis is expected). 
  • When weight, length and/or head circumference velocity decreases over one week. 
  • When weight velocity alone decreases over two weeks.  

(Decreased velocity is defined as growth at a lower rate than is needed to follow centile lines).

Weekly monitoring of serum sodium, potassium, phosphorus, calcium, urea and creatinine, CRP, Hb as well as urinary sodium is required for nutritional assessment.

If the infant is receiving PN routine blood measurements are required (see clinical guideline: parenteral nutrition).

The ‘nutrition phase’ at which preterm infants are at most nutritional risk is during the phase from PN to enteral nutrition. Close monitoring of intake is important at this time (Miller et al., 2013).

Post-discharge nutrition

It is recognised that by the time of discharge many preterm infants demonstrate poor growth. It does not appear to be a predictor of continued poor growth post-discharge and most infants catch up.

Frequent exclusive breast feeding should be encouraged post-discharge with added supplements as per table above.

A phosphorus supplement may be needed until approximately one month post-term in breast-fed infants with serum levels <1.5 mmol/l at discharge.

Formula fed infants who are growth restricted at discharge should have a nutrient-enriched post-discharge formula (NEPDF) such as Nutriprem 2 or SMA Gold Prem 2 until three months corrected age (assess for each individual infant as some may need NEPDF until six months corrected age). 

Refer growth restricted infants to local paediatric dietitian for assessment of nutritional requirements and growth monitoring.
After discontinuation of NEPDF, a term formula should be used until 12–18 months corrected age depending on the nutritional adequacy of the weaning diet. 

Summary

Summary feeding flowcharts are given in Appendix 3, Appendix 4, Appendix 5.

Rationale

Rationale 1  
Preterm infants have higher nutrient requirements than term infants because they have missed some or all of the third trimester of pregnancy which is a period of nutrient accretion and rapid growth. The foetus multiplies in weight five times from 24 weeks gestation to term (a period less than four months); in comparison term infants double their birth weight by four to five months (Fenton et al., 2013).

Rationale 2
Failure to meet energy and protein needs leads to growth failure which is associated with poor neurodevelopmental outcome (Ehrenkranz et al., 2006).  

Rationale 3
Accelerated growth has been shown to have detrimental consequences on long-term health outcomes such as cardiovascular disease (Singhal et al., 2004).

Rationale 4
"Synthesis of new tissue is energy intensive and strongly affected by the intake of protein and other nutrients; thus, achieving an adequate energy to protein ratio is as important as providing adequate energy intake." (Agostoni et al., 2010). Protein to energy ratios must be considered for all preterm infants, but in particular for those very rare occasions when modular supplements such as glucose polymer or fat emulsion are to be added to their feeds.

Rationale 5
Long-chain polyunsaturated fats (LCPs) are conditionally essential in preterm infants because they are largely accrued during the last trimester of pregnancy and preterm infants have missed some or all of this. Breast milk contains a full complement of all polyunsaturated fatty acids including precursors and metabolites. Some infant formulas contain only the precursor essential fatty acids linoleic acid and alpha linolenic acid from which formula fed infants must synthesise their own docosahexaenoic acid (DHA) and arachidonic acid (AA) respectively. Nutriprem 1, Hydrolysed Nutriprem and SMA Gold Prem Pro contain DHA and AA (See Appendix 2 for data cards from Cow & Gate and Nestle respectively). A Cochrane review (pooling of data from 17 RCTs) doesn’t indicate a long-term benefit of LCP supplementation on visual development, neurodevelopment or growth of preterm infants. However, the methodology varied considerably between included studies with different combinations of LCPs being used and they were carried out in relatively healthy formula fed infants. Importantly LCP supplemented formula was found to be safe (Schulzke et al., 2011).  

The placenta selectively favours the transfer of DHA over other fatty acids, including ARA, during the last trimester of pregnancy (Haggarty et al 2004). Studies focusing on DHA supplementation in preterm infants have had positive findings with one UK study demonstrating improved growth in all subjects and improved mental development in boys (Fewtrell et al., 2004). Updated lipid recommendations for preterm infants have been suggested (Lapillonne et al., 2013). It is noted that funding for this paper was provided by an infant formula company. Further research is needed to determine optimal levels of LCP supplementation in preterm formula.

Rationale 6
Breast milk contains prebiotics and probiotics which together exert a favourable effect on the bacterial flora of the preterm gut. It is acknowledged that probiotics may have a role in reducing the incidence of NEC, late onset sepsis and all-cause mortality (Olsen et al., 2016, Aceti et al., 2015 and Rao et al., 2016). However, interpreting published trials is complicated by the high degree of variability between studies in terms of population (gestation, weight and in some cases exclusion of infants perceived to be at high risk of complications) and probiotic preparation (strain, single/multiple organisms, timing of treatment onset and dose).  

Two large trials have been conducted, one in the UK (PiPS) and the other in the southern hemisphere (ProPrems).  

The PiPs trial was a randomised controlled phase 3 trial which aimed to test the effectiveness of a single strain probiotic Bifidobacterium breve BBG-001 in reducing necrotising enterocolitis (Bell Stage 2 or 3), late-onset sepsis, and death before discharge in preterm infants.  Data from 1310 infants from 23 and 30 weeks’ gestational age was analysed. The trial did not demonstrate any benefit for this intervention for any of the primary outcomes listed above. The authors highlighted that the major limitation has been concern that the high colonisation rate of the placebo group has masked any benefit of the probiotic intervention. (Costelloe et al., 2016)

ProPrems was a multicentre, double blind randomised placebo-controlled trial of 1099 infants born before 32 completed weeks’ gestation weighing <1,500 g. A probiotic combination of B infantis BB-02, S thermophilus Th-4, and B lactis BB-12 was used. The primary outcome was at least one episode of definite late-onset sepsis. This combination of probiotics did not have a significant effect on definite late-onset sepsis. A reduction in NEC (Bell stage 2 or more) was observed in the intervention group but the baseline rate of NEC was low. In that population the number needed to treat to prevent one case of NEC (Bell stage 2 or more) would be as many as 333 infants. (Jacobs SE., 2013)

No safety concerns regarding probiotic administration were reported in either Pips or ProPrems. 

Further studies are needed to inform practice about optimal strain(s), dose and timing of treatment in preterm infants.  

Rationale 7
Immune protection

NEC and sepsis are major causes of morbidity and mortality in preterm infants.  

NEC: The mortality rate for ELBW infants with NEC is 35 to 50 per cent and 10 to 30 per cent for VLBW infants (Luig & Lui, 2005). The outcome for survivors of NEC varies according to severity of disease with the worst outcomes in infants requiring surgery. Surviving infants are at increased risk of morbidities such as neurodevelopmental impairment, poor growth and long-term gastrointestinal problems (Rees et al., 2007)(Hintz et al., 2005) and (Hall et al., 2013).

Sepsis: Up to 20 per cent of all VLBW infant deaths are caused by sepsis, and infants with sepsis are nearly three times as likely to die as those without sepsis, even after adjusting for gestational age, sex and other comorbidities. Surviving VLBW infants are at increased risk for developing morbidities such as CLD and neurodevelopmental impairment and they have longer hospital stays (Hornik et al.,2012).

Human milk: The incidence of both NEC and sepsis is lower in infants receiving human milk because of the multitude of anti-infective factors in human milk including prebiotics, probiotics, immunoglobulins and lactoferrin (Jones & King, 2005).

Rationale 8
Fatty acids are better absorbed from human milk due to both the structure of the milk fat globule and the presence of bile salt stimulated lipase (Jones & King, 2005).

Rationale 9
Human milk contains enzymes, hormones and growth factors that play important roles in gastrointestinal growth and maturation and may accelerate the establishment of enteral feeding (Bertino et al., 2012).

Rationale 10
Lucas first described the relationship between IQ and breast milk feeding in preterm infants by publishing a follow up study of children born preterm who had participated in a feeding study in the 1980s (Lucas et al., 1992).

Other studies have since demonstrated the beneficial effect of feeding breast milk to preterm babies on later neurodevelopmental measures and there appears to be a dose dependent effect. Vohr et al (2006) found a relationship between the dose of human milk given throughout the NICU stay and neurocognitive tests at age 18 months and age 30 months in two studies based on secondary analysis of data collected for a glutamine trial in the USA of 1,034 ELBW infants. The first study showed that for each 10 ml/kg/day of human milk received in the NICU there was a dose-response increase in scores on standardised neurocognitive and developmental tests at 18 months of age. The most  striking difference was observed between the exclusively formula fed group and those receiving the most human milk (110 ml/kg) with a 5-point IQ advantage for the human milk group (Vohr et al., 2006). The relationship between each 10 ml/kg/day of human milk and increase in test scores persisted when the same cohort were followed up at 30 months (Vohr et al., 2007).

Rationale 11
Over the past two decades, attention has focused not only on short-term outcomes for preterm babies but also on the consequences of early diet for later health outcomes such as cardiovascular disease, type 2 diabetes and obesity. Feeding breast milk to preterm infants has been shown to improve such long term health outcomes (Embleton et al., 2013: Singhal et al., 2001).

Rationale 12
Table 1 shows why increasing breast milk provision up to 220 ml/kg/day will facilitate growth in some infants; namely because protein requirements can be met if their mother’s milk is high enough in protein. Feeding unfortified EBM at a higher volume should be time limited and if no improvement in growth is noted after five days then feed volume should be reduced to 180 ml/kg and BMF commenced (the decrease in volume is necessary to prevent over-feeding once BMF is added). 

Infants receiving unfortified EBM will require Abidec, iron, folic acid, phosphate and sodium supplementation. Serum calcium should be monitored and supplements prescribed if necessary.

Rationale 13 
Table 2 below demonstrates how EBM fortified with Nutriprem Breast Milk Fortifier meets the ESPGHAN recommendations for all nutrients except iron.

Infants receiving EBM fortified with Nutriprem BMF at full strength (2 x 2.2 g sachet/100 ml EBM) do not need Abidec or folic acid. Sodium, phosphate and calcium should be monitored and supplemented where necessary. Iron supplementation is required (see table below).

Rationale 14
Breast milk should be fortified with one of the commercially available, multicomponent breast milk fortifiers that are designed to meet the needs of preterm infants (as demonstrated in Table 2 above). There are two such fortifiers available in the UK; Nutriprem BMF (Cow & Gate) and SMA BMF (Nestle). The fortifiers contain protein, carbohydrate and vitamins and minerals. The SMA BMF contains a trace of fat, and Nutriprem BMF is fat free. Both fortifiers are produced in powder form and are packaged into sachets (Nutriprem BMF in 2.2 g sachets and SMA BMF in 1 g sachets). The protein in Nutriprem BMF is extensively hydrolysed whey, while the protein in SMA BMF is whole cow’s milk protein. Nutriprem BMF is used at GOSH. 

Rationale 15
The safety of multicomponent breast milk fortifier is often debated among both staff and parents on neonatal units. A Cochrane review in 2,000 presented the results of thirteen randomised controlled trials which examined the long and short term effects of feeding multicomponent fortified human milk to preterm infants. Infants fed fortified milk demonstrated improved weight gain, linear growth and head growth but no significant increase in NEC was noted (Kuschel & Harding, 2004).

Rationale 16
Breast milk fortifiers in the UK are based on bovine milk protein. Human milk fortifiers exist but are not available here. There are no published studies that directly compare the use of bovine breast milk fortifier to human breast milk fortifier in infants receiving only human milk. Two studies have compared diets composed exclusively of human milk products to diets that include or are solely based on bovine products. Both studies found that there was significantly less NEC in the groups fed an exclusively human milk diet. The clinical significance is however unclear because in one study the bovine diet consisted entirely of preterm formula (Cristofalou et al., 2013) and in the other, preterm formula was given in place of bovine fortified EBM if maternal milk wasn’t available (Sullivan et al., 2010). It is possible that the reduced incidence of NEC in the human milk groups may be a result of the apparent dose-related association of increased EBM feeding with a reduced risk of NEC (Meinzen-Derr et al., 2009) and (Martin & Jackson 2011).

Rationale 17

The protein in Nutriprem BMF is more extensively hydrolysed than that found in Pepti-Junior. The difficulty however is that the optimal extent of hydrolysis in the context of allergy is ambiguous because there is no definitive MW below which peptides are non-allergenic. Peptides with MW of <1,000–1,800 Da are not deemed allergenic per se, but by aggregating or cross-linking with each other or with other molecules they may become antigenic, and even allergenic.  Another concern is that methods used to calculate molecular weights of peptides in hydrolysed protein formulas are restricted by inaccuracies and sensitivity limits and so molecular distribution data stated by the manufacturer can be treated as approximate only and cannot guarantee non-allergenicity of formulations (Mäkinen-Kiljunen et al., 1993).

For these reasons it is recommended that efficacy is demonstrated clinically for each product. The European Society of Pediatric Allergy and Clinical Immunology (ESPACI), ESPGHAN and American Academy of Pediatrics (AAP) position is that products can only be determined as suitable for treatment of allergy if they have been proven in clinical trials to be tolerated by at least 90 per cent of infants with IgE-mediated cow’s milk protein allergy (CMPA) (Høst et al., 1999), (Businco et al., 1993) and (AAP, 2000).

Implications for practice

No clinical trials have been conducted to determine the suitability of Nutriprem BMF as a treatment for cow’s milk protein allergy. Infants considered to be at risk of CMPA (ie atopic family history) should be assessed on an individual basis. The only alternatives to breast milk fortifier are EHF or AA term formula or individual modular components. The risks of fortifying with an EHF or AA term infant formula should be weighed against the potential allergenicity of the BMF. It is possible that Nutriprem BMF would be suitable for ‘at risk’ infants and has the benefit of being fit for purpose but a definitive claim cannot be made in the absence of clinical trial data.  

Rationale 18
Unfortified EBM will not meet the high nutritional needs of infants <1,500 g as demonstrated in Rationale 12, Table 1. Inadequate energy and protein intake in the early weeks of life leads to nutrient deficits which can be directly related to subsequent postnatal growth retardation (Embleton, 2001). 

Rationale 19
Term formula powder is sometimes used to supplement EBM in infants >37 weeks. The formula powder is added to EBM in the Special Feeds Unit as a clean procedure. This procedure has been risk assessed locally.

Rationale 20 
BMF is stopped to avoid excessive protein intake.

Rationale 21
Urea levels below 2 mmol/l may indicate inadequate protein intake. Single measurements are unhelpful and a downward trend over time is probably more indicative of the need to increase protein provision (Polberger et al, 1990). It is acknowledged that urea is affected by other factors such as fluid status, renal function and steroid administration and many practitioners do not consider it to be a useful marker (Embleton, 2013).

Rationale 22
The process of donor milk banking adversely affects the nutritional and immune composition of human milk (Heiman & Schandler, 2006). Fat in donor milk is less well absorbed because the pasteurisation process denatures bile salt stimulated lipase. Due to its inferior nutritional profile in comparison to maternal EBM, donor EBM is recommended for short term use only, with the specific aim of establishing enteral feeds (Colaizy et al., 2012). Once enteral feeds are safely established, preterm formula should be graded in over a minimum period of three days. 

Rationale 23
All preterm infants requiring formula should receive a preterm formula (unless a specialist formula is indicated) because term formulas do not provide adequate nutrition to meet their needs as demonstrated in Table 4 below. Infants receiving 150 ml/kg/day preterm formula should not require additional vitamin/mineral supplementation.  

Rationale 24

 

Rationale 25
Osmolality – aim to keep <400 mOsm/kg H2O in preterm infants.

Rationale 26
The main purpose for prescribing Abidec is to provide addional vitamin A and vitamin D. The differences in composition between Abidec and Dalivit can be seen below.

Abidec Multivitamin Drops 0.6ml (contains vitamins A, D, C and some B vitamins):

  • 1,333 IU = 400 micrograms retinol (as vitamin A palmitate)
  • 400 IU = 10 micrograms ergocalciferol solution (vitamin D2)
  • 0.4 mg thiamine hydrochloride
  • 0.8 mg riboflavin
  • 0.8 mg pyridoxine hydrochloride
  • 8 mg nicotinamide
  • 40 mg ascorbic acid 
  • Allergy advice - Abidec contains arachis oil (peanut oil)

Dalivit 0.6ml (contains vitamins A, D, C and some B vitamins): 

  • 5,000 IU = 1,500 micrograms vitamin A (almost four times as much as Abidec)
  • 400 IU = 10 micrograms vitamin D2
  • 50 mg vitamin C
  • 1 mg Vitamin B1 
  • 0.4 mg Vitamin B2 
  • 0.5 mg Vitamin B6 
  • 5 mg Nicotinamide 
  • 50 mg Vitamin C

Dalivit also contains: Sodium Hydroxide BP, Polysorbate 80 BP, Sucrose BP, Sodium Methyl Hydroxybenzoate BP

Rationale 27
Vitamin A and its derivatives regulate growth and differentiation of a wide variety of cell types and these play a crucial role in the physiology of vision, integrity of the immune system, normal lung growth and the integrity of respiratory tract epithelial cells. 

Preterm infants have low Vitamin A status at birth and this has been associated with increased risk of developing CLD. The 'adequate' concentration of plasma vitamin A in very low birthweight infants is not known. Concentrations below 200 µg/L (0.70µ mol/L) have been considered as deficiency in preterm infants and concentrations below 100 µg/L (0.35 µmol/L) as indicating severe deficiency and depleted liver stores. Preterm infants have low plasma concentrations of retinol and retinol binding protein (RBP) at birth compared with term infants and this is reflective of low hepatic stores. A systematic review indicated that vitamin A appears to be beneficial in reducing death or oxygen requirement at one month of age in preterm infants (Darlow et al., 2011).

A retrospective case note review and an observational study have indicated that the vitamin A intake of preterm infants is much lower than the bottom end of the reference ranges recommended by both ESPGHAN and Tsang et al. (Mactier et al., 2011) and (Kositamongkol et al., 2011).

There is on-going debate around exactly how much vitamin A preterm infants require and the optimal route of administration. Plasma vitamin A levels are not routinely measured on neonatal units.  

ESPGHAN recommend an intake of 400–1,000 micrograms (1,333–3,330 IU) RE/kg/day.

Rationale 28
The ESPGHAN recommendation for Vitamin D is given as a daily amount and not per kg per day as for all other nutrients. ESPGHAN’s explanation for this is that preterm infants are born with poor stores of vitamin D because placental transfer occurs in the last trimester and vitamin D deficiency is prevalent in pregnant mothers. By recommending a total daily dose, preterm infants will receive a higher level of supplementation and this was thought necessary to correct the likely low plasma levels of 25-hydroxy vitamin D (25 OHD) in preterm infants at birth (Agostini et al., 2010). 

In practice, supplementing vitamin D levels to achieve ESPGHAN’s minimum suggested intake of 20 micrograms (800 IU)/day is difficult and this high dose has been questioned. Part of the problem in recommending intakes for preterm infants, is that there is no international consensus on optimal circulating levels of 25 OHD and bone health in preterm infants and this has meant that studies have used different end points as markers of sufficiency. A recent study demonstrated that nutritional intake of 10 micrograms (400 IU)/day from all sources (fortified feeds and supplements) achieves adequate vitamin D status in preterm infants (McCarthy et al., 2013). Adequacy in this study was defined as 25 OHD >50 nmol/l because this level is considered to be associated with covering requirements for skeletal health in the majority. Of note, this study demonstrated that prolonged supplementation resulted in 25 OHD levels >125, a level associated with potential harm. They recommended that further work was needed to determine the exact dose to safely meet target levels without overcorrection.  

ESPGHAN set a threshold for serum 25 OHD of 80 nmol/l.

Rationale 29
Without an exogenous source of iron, the preterm infant becomes depleted by about eight weeks. Iron deficiency leads to poor neurodevelopmental outcome in preterm infants.

Excessive iron intake should be avoided because there is no mechanism for regulated iron excretion from the human body. Excessive supplementation can lead to increased risk of infection, poor growth and disturbances in absorption of other minerals. Iron supplements should not be given with calcium or phosphorus as insoluble compound may be formed, reducing bioavailability.

Intakes >5 mg/kg/day should be avoided because of the possible risk of retinopathy of prematurity (ROP) (Agostoni et al, 2010).

Rationale 30
Inadequate folate can interfere with cellular differentiation, haematopoiesis and growth and development of the nervous system. Folate interacts with vitamin B12 and their common association with megaloblastic anaemia is well known.  

Rationale 31
Sodium is the major cation in extracellular fluid and is essential for regulating its volume. It is also involved in the regulation of blood pressure and in the absorption of amino acids, short peptides and monosaccharides. It is also thought to have a role in the development of bone and nervous tissue.

Rationale 32
Phosphate along with calcium and vitamin D is essential for bone mineralisation.

Eight per cent of the mineral content in the full-term newborn (30 g calcium and 16 g phosphorus) is accumulated in the last trimester.

Metabolic bone disease is a known complication of prematurity and is caused by prolonged PN, immobilisation, medication and inadequate nutrient supply (vitamin D, calcium, phosphorus).

ESPGHAN recommends 120–140 mg/kg/day calcium and 60–90 mg/kg/day phosphorus. It is less common to need to supplement with Calcium Sandoz than it is with phosphate as the latter is usually rate limiting.

Excessive calcium supplementation should be avoided to avoid problems with calcium soap formation and intestinal obstruction; oral supplementation decreases fat absorption from human milk and formula.

Rationale 33 
Vitamin E has anti-oxidant effects and it has been hypothesised that it may have a role in limiting the processes involved in CLD and ROP. However, a systematic review concluded that while giving extra vitamin E to preterm babies can provide some benefits, it also increases the risk of life-threatening infections.  

Rationale 34
The ADEPT trial demonstrated that introducing feeds on day two of life compared to day six resulted in earlier achievement of full enteral feeding and did not appear to increase the risk of NEC even in growth-restricted preterm infants (Leaf et al., 2012). 

Rationale 35
A subsequent sub group analysis of the babies born at less than <29 weeks from the ADEPT cohort showed that full feeds were achieved later (median age 28 days) compared with 19 days in infants 29 weeks or above. The incidence of NEC was also higher in this group (39 per cent compared to 10 per cent). Infants <29 weeks tolerated very little milk for the first 10 days of life and reached full feeds nine days later than predicted from the trial regimen. Growth-restricted infants failed to tolerate even the careful feeding regimen of ADEPT (full feeds should have been achieved by day 16 in the early group and day 20 in the late group). A slower advancement of feeds may be required for these infants (Kempley et al., 2014).

Rationale 36
The jejunum is designed to receive small volumes only. Bolus feeding is not physiological and is associated with severe feed intolerance and dumping syndrome.

Rationale 37
Preterm infants have an immature suck-swallow-breathe pattern that doesn’t usually develop until 35–37 weeks of life (Jones & King, 2005).

Rationale 38
Length measurement is more reflective of skeletal and organ growth than weight alone.

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Appendices

Document control information

Lead Author(s)

Kelly Larmour, Principal Dietitian, Dietetics

Additional Author(s)

Vanessa Shaw, Head of Dietetics, Dietetics

Document owner(s)

Kelly Larmour, Principal Dietitian, Dietetics

Approved by

Guideline Approval Group

Reviewing and Versioning

First introduced: 
01 December 2011
Date approved: 
24 March 2016
Review schedule: 
Three years
Next review: 
24 March 2019
Document version: 
3.0
Previous version: 
2.0