Neonatal Feeding Supplementation and Osteopenia

Publication: 01/11/2002  --
Last review: 18/01/2018  
Next review: 18/01/2021  
Clinical Guideline
ID: 205 
Approved By:  
Copyright© Leeds Teaching Hospitals NHS Trust 2018  


This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Feeding Supplementation and Osteopenia

Summary of Guideline

Choice of Milk:





<34 weeks

>34 weeks

1st Choice





2nd Choice




Term Formula

3rd Choice







Term Formula

Breast Milk Fortifier:
<2kg OR <34 weeks gestation
Have tolerated feeds of 150ml/kg for 24 hours
Are taking feeds of >1/2 EBM

<2kg OR <34 weeks gestation
Have tolerated feeds of 150ml/kg for 24 hours
Dose: 0.6ml once daily

<2kg OR <34 weeks gestation
Commenced on: Day 14 unless on GP1
Discharge if changing from GP1
Dose: 0.5ml if <1.5kg
1.0ml if >1.5kg

<1500g OR <32 weeks gestation
Tolerating Stage 1 feeds
Dose: ½ Capsule Acidophilus Extra 4

At risk groups <1500g OR <32 weeks 
Commence phosphate at 1mmol/kg/day in 2/3 divided doses if:

  • Phosphate <1.8mmol/L
  • ALP >700iu/L


The aim of this guideline is to provide a standardised approach to fortification and supplementation of milk feeds in preterm or growth restricted babies. This is with a view to improving growth parameters during admission and following discharge.

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The nutritional requirements of preterm or growth restricted babies are different to those born closer to term and of more normal birth weight. They have missed out on being able to develop nutrient stores in the final trimester either due to being born prematurely, or poor nutrient delivery secondary to placental failure or maternal chronic illness.
Because of this it is important to review the nutritional appropriateness of expressed breast milk and infant formulas for this population, while balancing the risk of adding things that increase the feed thickness or osmolality.

Risk population
The majority of nutrient stores are laid down in the final trimester of pregnancy, and relies on adequate placental function and maternal health and nutritional status. Babies who are born before 34 weeks have missed out on a significant period of nutrient delivery irrespective of other factors, and will require nutritional supplementation. The other important risk group are those born below the 2nd centile in combination with late prematurity. Subsequently any babies born greater than 34 week but below 2kg should also be considered for supplementation of feeds.

Nutritional Aims
The European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in 2010 produced guidance on daily requirements for macro and micro nutrients. This is summarized below:


Per kg/day

Per 100Kcal

Protein - <1kg

4.0 - 4.5g

3.6 - 4.1g

Protein - 1.0-1.8kg

3.5 - 4.0g

3.2 - 3.6g


11.6 - 13.2g

10.5 - 12g


3.0 - 5.0mmol

2.7 - 4.5mmol


1.7 - 3.4mmol

1.5 - 3.1mmol


3 - 3.5mmol

2.7 - 3.2mmol


1.8 - 2.8mmol

1.7 - 2.5mmol


2 - 3mg

1.8 - 2.7mg

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Choice of Milk

Expressed Breast Milk (EBM)
EBM should be the first choice of milk for babies of all gestations and weight. It has been shown to be associated with decreased rates of NEC when compared to preterm and term formulas, as well as reducing rates of late onset sepsis. However, EBM has on average only 2.1g/100Kcal of protein, as well as low levels of calcium, phosphate and no iron. Infants below 34 weeks of 2kg will require fortification with Breast Milk Fortifier (BMF) and supplementation with iron and multivitamins.

Donor Breast Milk (DBM)
Preterm and growth restricted infants have been shown to tolerate feeds better and subsequently establish feeds quicker when they are commenced on DBM. However, it’s impact on rates of NEC remain inconclusive and there have been no proven benefits in the rates of late onset sepsis, as it does not contain the immunological component in mother’s own breast milk. Because of this it should not be used for ‘trophic feeding’ in Stage 1 of feeding.

Currently it is used as a second choice milk for babies in the Red and Yellow feeding groups outlined in the Enteral Feeding Guideline (infants <1250g). DBM should be fortified at the same stage as mother’s own breast milk with the addition of multivitamins and Sytron. Transition from DBM to formula is discussed in the enteral feeding guideline.

Preterm formula
We currently use SMA Gold Prem Pro. This is a partially hydrolysed Whey protein formula which contains 3.6g/100Kcal of protein as opposed to 3.2g/100Kcal in Nutriprem 1. Because of this babies who are fully fed entirely with preterm formula do not need BMF. The iron content in SMA GP1 is 2.3mg/100Kcal, but this falls to just 1.0mg/Kcal in SMA GP2. Subsequently, Sytron should be commenced in all infants on SMA GP2.

Term Formula
Term formula is commenced for babies over 34 weeks gestation and with a birth weight of over 2kg. The nutritional content is similar across all brands so none is recommended over the other and it should be parental choice which formula is used.

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Fortification and Supplementation

Breast Milk Fortifier

  • <2.0kg OR <34 weeks
  • Feeding more than half EBM or DBM
  • Commence once tolerating feeds 150ml/kg for 24 hours
  • Discontinue once fully breast feeding or at discharge if >2.0kg

Breast Milk Fortifier is used to increase the nutritional content of breast milk to meet the additional requirements of preterm or growth restricted infants. It adds protein, sodium, potassium, calcium and phosphate to the levels recommended in the ESPGHAN guidance. It does not however boost vitamin levels (specifically Vitamin D) and does not contain any iron. Babies who require BMF should also receive Abidec and Sytron (see below).

Fortification of 150ml/kg provides significantly more nutrition than an increase in milk from 150 to 165ml/kg. BMF should therefore be commenced when babies have tolerated 150ml/kg of enteral feeds for 24 hours - this should not stop a subsequent increase up to 165ml/kg which is likely to be needed in this population.

It is administered in a stepwise manner to avoid any issues with feed tolerance:
First 48 hours: ½ sachet per 50ml EBM
Subsequent feeds: 1 sachet per 50ml EBM

BMF can be discontinued once fully breast feeding. If babies are going home NG feeding it can be discontinued once the weight is >2.0kg. Babies below this weight should be discussed with the dietitian prior to ceasing.


  • <2.0kg OR <34 weeks
  • Commence once tolerating feeds 150ml/kg for 24 hours
  • Continue until 6-12 months of age

BMF does not supply the additional Vitamins required by preterm or growth restricted infants. Therefore any infants <34 weeks gestation or <2.0kg birth weight should be commenced on Abidec. A dose of 0.6ml is given once daily and is continued until 6-12 months of age depending on growth.


  • <2.0kg OR <34 weeks
  • Feeding with either EBM, DBM, SMA GP2
  • Commence on Day 14 if tolerating feeds of 150ml/kg or when transitioned from GP1 to GP2
  • Use a dose of 0.5ml if <1.5kg, 1ml if >1.5kg
  • Continue until 6-12 months of age

Iron is important for brain development and is absent in breast milk and in BMF. Supplementation is therefore important but unlike other nutrients the body has no way to regulate iron excretion. It is therefore possible to give too large a dose of iron which is turn linked with increased rates of infection and poor absorption of other nutrients. In addition iron is a pro-oxidant, an effect increased when used in high doses as an adjunct to blood transfusion. High dose iron supplementation has been linked to increased rates of ROP.
There is no evidence to support doses of more than 3mg//kg/day and ESPGHAN currently recommends a dose of 2-3mg/kg/day.

The timing of iron supplementation also varies. ESPGHAN recommend 2-4 weeks of age for commencement of iron, but a recent Cochrane review found that many studies were too heterogenous to provide reliable guidance.

A large study in 2009 compared early vs late use of iron supplementation which showed a significant increase in levels of haemoglobin in the early group, and this was supported by a meta-analysis in 2012. This showed more stable haemoglobin levels by 8 weeks of age and lower rates of blood transfusion. There were no increased rates of NEC.

In view of this iron is commenced at 14 days of life once feeds of 150ml/kg have been established in all infants born at <34 weeks gestation or <2.0kg birth weight. It does not need to be commenced on infants taking GP1.

In order to avoid the risks of iron overload a dose of 0.5ml Sytron (5.5mg/ml) is used for infants weighing <1.5kg.
This dose is increased to 1ml for all infants weighing >1.5kg.

Due to the lower amounts of iron in GP2 vs GP1 (1.0mg/100Kcal vs 2.3mg/100Kcal) Sytron should also be commenced for all infants on GP2, either as the only milk or once transitioned from GP1.

Sytron should be continued until 6-12 months of age.


  • <1500g OR <32 weeks gestation
  • Tolerating Stage 1 feeds
  • Dose: ½ Capsule Acidophilus Extra
  • Continue until 34 weeks corrected gestation
  • If not tolerating full enteral feeds at 34 weeks, continue until the baby reaches 36 weeks gestation

Necrotising enterocolitis (NEC) occurs in about 5% of very preterm babies and has a mortality of 25%. The aetiology is multifactorial but colonization with pathogenic strains of bacteria is an important factor. There is evidence that use of breast milk, a structured feeding protocol and antenatal steroids all reduce the incidence of NEC. There is now evidence that NEC can be further reduced with the use of probiotics, to promote a healthy gut flora.

A variety of probiotics have been used in trials. Many contain strains of Bifidobacter and Lactobacillus, which are the predominant bacteria in breast fed babies. Meta-analyses show an overall risk ratio for NEC of 0.34 and for death of 0.4, with no increased incidence of sepsis.

Acidophilus Extra 4 is a probiotic capsule that contains approximately 4 billion colony forming units of Bifidobacterium and Lactobacillus acidophilis. It replaces Infloran which is the product we first used when starting to treat with probiotics and contains similar bacteria. An RCT showed Infloran reduces the incidence of NEC (OR=0.20) and Death (OR=0.22) in preterm babies.

Verbal consent needs to be taken prior to commencing Acidophilus and this should be documented in the notes.

Acidophilus should be commenced as soon as any baby <32 weeks gestation or <1500g is tolerating Stage 1 feeds of any feeding regime. It should be commenced as ½ a capsule of Acidophilus Extra 4 once daily and continued until the baby is 34 weeks gestation.

For infants not tolerating full enteral feeds by this gestation Acidophilus should be continued until 36 weeks corrected gestation.

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Phosphate and Osteopenia


  • Weekly bloods if <1500g or <32 weeks
  • Commence phosphate at 1mmol/kg/day in 2/3 divided doses if:
    • Phosphate <1.8mmol/L OR ALP >700iu/L
  • Review the need for phosphate at discharge based on blood results and growth
  • If biochemistry remains deranged or there are persistent radiological signs of osteopenia despite normal bloods, further investigation may be necessary
  • In these cases perform PTH/Vitamin D levels as well as urinary Calcium
  • Consider alfacalcidol to optimise Vitamin D or calcium supplementation if these results are abnormal

Osteopenia of prematurity affects 55% of infants <1000g and 23% of those <1500g. It often becomes symptomatic between weeks 8 and 12 postnatally but there are often biochemical markers to aid in its prevention prior to this.
Osteopenia of prematurity is characterized by the thinning of the bone cortex and the presence of fractures, but often there needs to be a reduction in bone density of 40% before this is apparent radiographically.

The focus on treatment is prevention and identification of those most at risk of developing osteopenia. Specifically:

Infants born <32 weeks or <1500g
Babies receiving PN for 4 weeks or more
Babies receiving treatment with diuretics or steroids

In these babies there should be at least weekly monitoring of calcium, phosphate and Alkaline Phosphatase (ALP) levels, though babies on PN may need bloods as often as daily.

Calcium is an inaccurate marker of osteopenia as serum levels are maintained at the expense of those in the bones via the action of PTH. Phosphate levels can often be maintained again by leaching from the bones but will fall more readily, so ALP is often used as a marker for the development of osteopenia. Levels >700units/L have been shown to be highly sensitive but not specific for osteopenia.

In order to avoid osteopenia in the above population phosphate should firstly be optimized in the PN. ESPGHAN guidance currently recommends daily Calcium amounts of 3-3.5mmol/kg and phosphate of 1.8-2.8mmol/kg, while maintaining a ratio of approximately 2:1. Unfortunately, this amount of calcium is unstable in PN and can cause precipitation within the solution.
Initial prescribed amounts should therefore be 2mmol/kg/day of phosphate and 2mmol/kg/day of Calcium within at risk groups.

Additional phosphate should be given - either as increased amounts in the PN or as oral supplements if:
Phosphate <1.8mmol/L
ALP >700units/L

Oral supplementation should consist of ensuring the provision of BMF (if feeding with breast milk) and Abidec for Vitamin D provision. Phosphate should initially be commenced at 1mmol/kg/day in 2/3 divided doses and its response on phosphate monitored. Adjustments should be made as follow:
<1.8mmol/L - Increase dose by 50%
1.8-2.3mmol/L - Continue current dose
>2.3mmol/L - Continue current dose and re-check 48 hours
>2.8mmol/L - Stop supplements and re-check in 48 hours

Calcium and Vitamin D

Some circumstances can make treatment difficult - sometimes despite treatment the levels of ALP continue to rise or there are radiographic changes suggestive of osteopenia but normal biochemistry. In these scenarios supplementation with calcium and/or additional Vitamin D may be required.

Calcium levels can be maintained through the action of PTH, so normal levels in biochemical testing are not representative of the quantities within the bones. It may therefore be necessary to supplement calcium further due to the historical deficit that has occurred.

Vitamin D has an important role in the absorption of calcium from the gut. ESPGHAN guidance currently recommends daily doses of 800-1000 units per day, though studies have shown there to be little benefit in giving doses in excess of 400 units/day.


Breast Milk





Vitamin D (Units)


200 /100ml


148 /100ml


When there is radiographic evidence of osteopenia despite normal biochemistry, or the ALP continues to rise despite adequate supplementation:

  • Check Vitamin D and PTH levels and urine Calcium to calculate Ca:Cr ratio (unless on furosemide)
  • If Vitamin D levels are below 75nmol/L commence alfacalcidol at a dose of 50ng/kg/day
  • Weekly monitoring of calcium and bone profile and urine Ca:Cr ratio (aiming for below 3.8mmol/mmol)
  • If PTH levels are raised (>10pmol/L) repeat in one week aiming for normal values
  • If PTH continues to be raised (>10pmol/L) despite normal repeated Vitamin D levels commencement of calcium supplements at 1mmol/kg/day should be considered in discussion with the nutrition team

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Record: 205
Clinical condition:

Preterm Infant Nutrition

Target patient group: Premature Neonates (less than 37 weeks gestation)
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

References and Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

World Health Organisation (2003); Global Strategy for Infant and Young Child Feeding; Geneva, World Health Organisation

Enteral Nutrient Supply for Preterm Infants: Commentary From the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition; JPGN Volume 50, Number 1, January 2010

Schanler et al; The use of human milk for premature infants; Pediatr Clin North Am. 2001 Feb;48(1):207-19

Kuschel et al; Multicomponent fortified human milk for promoting growth in preterm infants; The Cochrane Library 2009, Issue 1

Pereira-da-Silva et al; Early High Calcium and Phosphorus Intake by Parenteral Nutrition Prevents Short-term Bone Strength Decline in Preterm Infants; JPGN 2011;52(2):203-209

Pohlandt et al; Prevention of Postnatal Bone Demineralisation in VLBW Infants by Individually Monitored Supplementation with Calcium and Phosphorus; Pediatric Res 1994; 35(1):125-129

Hung et al; Serial measurements of serum alkaline phosphatase for early prediction of osteopaenia in preterm infants; J Paediatr Child Health. 2011 Mar;47(3):134-9

Hong-Xing Jin et al; Early and late Iron supplementation for low birth weight infants: a meta-analysis; Italian Journal of Pediatrics (2015) 41:16

Arnon et al; Vitamin E levels during early iron supplementation in preterm infants; Am J Perinatol. 2009 May;26(5):387-92

Mills et al; Enteral iron supplementation in preterm and low birth weight infants; Cochrane Database of Systematic Reviews 2012, Issue 3

Rehman et al; Metabolic bone disease in the preterm infant: Current state and future directions; World J Methodol 2015 September 26; 5(3): 115-121

Harding et al; Calcium and phosphorus supplementation of human milk for Preterm infants; Cochrane Database of Systematic Reviews 2017, Issue 2.

Holland et al; Prenatal Deficiency of Phosphate, Phosphate Supplementation and Rickets in Very Low Birthweight Infants; Lancet 1990 335(8691):697-701

Rigo et al; Enteral calcium, phosphate and vitamin D requirements and bone mineralisation in preterm infants; Acta Paediatr 2007; 96: 969-974

Harrison et al; Osteopenia of prematurity: a national survey and review of practice; Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 407–413

Bozzetti et al; Metabolic Bone Disease in preterm newborn: an update on nutritional issues; Italian Journal of Pediatrics 2009, 35:20

Deshpande et al; Evidence-based guidelines for use of probiotics in preterm neonates; BMC Medicine. 2011; 9 92-105.

Lin H-C et al; Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial; Pediatrics. 2008; 122 (4):693-700.

Al Faleh et al; Probiotics for prevention of necrotising enterocolitis in preterm infants; Cochrane Review 10th April 2014

Samuels N et al; Necrotising enterocolitis and mortality in preterm infants after introduction of probiotics - a quasi-experimental study; Scientific Reports 6, Article number: 31643, 2016

Aceti A et al; Probiotics for prevention of necrotising enterocolitis in preterm infants: systematic review and meta-analysis; Italian Journal of Paediatrics 2015; 41:89. Viewed via. PubMed

Dermyshi E et al; The “Golden Age” of Probiotics: A systematic review and meta-analysis of randomised and observational studies in preterm infants; Neonatology 2017; 112:9-23

Narendra Aladangady et al; Urinary excretion of calcium and phosphate in preterm infants; Pediatr Nephrol (2004) 19:1225–1231

Stacy E. Rustico et al; Metabolic bone disease of prematurity; Journal of Clinical & Translational Endocrinology 1 (2014) 85e91

Moreira et al; Parathyroid hormone levels in neonates with suspected osteopenia; J ped Child Health 2013 49(1)

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