As Dr Eason has pointed out, it is important Healthcare Professionals caring for preterm infants are aware and up-to-date on the preterm formulae available, and how they comply with guidelines. The Tsang R et al. 2005 guidelines¹ are regarded by many as the “bible” for nutrient requirements for preterm infants, setting international standards of nutritional care for premature infants. This article summarises the main formula nutritional adaptations that one manufacturer Cow & Gate has made to a preterm formula, Cow & Gate Nutriprem 1 in light of their recommendations.

Cow & Gate Nutriprem 1 preterm formula is formulated to meet the nutritional requirements of preterm and low birthweight infants, the formulation had been adapted previously to comply with previous guidelines by ESPGAN 1987, and Tsang R et al. 1993 First Edition. It provides energy and nutrients to support preterm growth rates, in an appropriate, smaller volume than term formulas and can be used in hospitals as a sole source of nutrition for preterm infants or to compliment breastmilk feeds.

Following international consultation with clinicians, researchers and academics over 18 months, Cow & Gate Nutriprem 1 has been updated to comply with the most recent scientific recommendations: the Tsang guidelines¹ as well as the Klein C et al., 2002 guidelines² for nutrient requirements for preterm formulas.

The Tsang recommendations distinguish between Extremely Low Birthweight (ELBW) (<1000g birth weight) and Very Low Birthweight (VLBW) (<1500g birth weight) infants, and Cow & Gate Nutriprem 1 meets the requirements of both groups of infants. Click here to download "Nutriprem 1 datacard"

The new Tsang guidelines give recommendations on energy, protein, nucleotides, carbohydrates, lipids and key vitamins and minerals which are reviewed in greater detail below. Click here to dowload "Comparison of Preterm Nutritional Guidelines"

Energy

The initial goal for preterm infants in early postnatal life is to provide sufficient energy intake to at least match the rates of energy expenditure in order to preserve body energy stores for growth and storage.

The recommended energy intake for healthy, growing preterm infants is 110-130 kcal/kg/day for VLBW and with 130-150 kcal/kg/day for ELBW infants. It is recommended that the higher energy intake for ELBW should also be accompanied by a proportional increase of protein intake; otherwise the weight gain is accompanied by a disproportional gain of fat which should be avoided.

The needed energy requirement for VLBW is divided up as follows:

	kcal/kg/d
Total Energy Expenditure (Resting Metabolic Rate) (Energy of Activity) (Thermoregulation)	65 (50) (5) (10)
Energy Excreted	15
Energy Stored	30-50
Recommended Energy Intake	110-130

Cow & Gate Nutriprem 1 has an energy density of 80kcal/100ml and therefore the recommended energy intake of 130kcal/kg/day can be achieved in a volume of 165ml/kg/day, which is within tolerated volumes for preterm infants and meets the requirements of both groups of infants.

Tsang guidelines recommend long-term follow-up studies of body composition of preterm infants fed various protein/energy ratio formulas, in order to detect potential consequences (insulin resistance, and cardiovascular disease) of different rates of growth and fat accretion. To avoid excess energy intake in infants consuming volumes of >165 ml/kg/day, the energy density of Cow & Gate Nutriprem 1 has not been increased from 80 kcal/100 ml.

Protein

As a result of cumulative nutritional deficits during early life of preterm infants, most growth parameters remain inadequate by the time the preterm infant reaches a corrected age of 40 weeks, and this phenomenon worsens in the case of VLBW and ELBW infants. This suggests that the current nutritional recommendations need to be re-evaluated in order to reduce the initial gap during the first days of life and to promote a compensatory preterm catch-up growth to intra-uterine growth rate. Today, lean body mass gain (mass without fat) and protein accretion can be estimated by modern techniques, and have been illustrated on some preterm growth charts.

The protein utilisation is known to be affected by protein and non-protein nitrogen intakes, the biological value of ingested proteins, the protein/energy ratio, nutritional status, catch-up growth, hormonal environment, and clinical status. Based on the recent data concerning protein metabolism it was concluded that preterm formulas with higher protein and higher protein/energy ratios should be developed to reduce postnatal growth restriction and to prevent long-term deleterious effects. Recent studies suggest that the use of a more aggressive nutrition strategy which promotes high protein supply from the first day of life results in positive nitrogen balance and reduces early postnatal cumulative nitrogen deficit in VLBW infants. Optimised lean body mass and early catch-up growth would be achieved. On the other hand - a very rapid catch-up growth is discussed with the risk to develop obesity later in life. Additionally, other nutritional and non-nutritional parameters can interfere with growth and need to be considered. Therefore it was concluded that further clinical research is necessary to provide data on the efficacy and safety of the proposed higher protein supply at short-term and around discharge, but also on neurodevelopmental outcome and health later in life.

The new Tsang guidelines recommend 2.5-3.4g protein/100 kcal (ELBW) and 2.6-3.8g protein/100 kcal (VLBW). The new recommended range of protein/energy ratio for ELBW infants is broader and for VLBW infants the upper limit has been increased. To meet the needs of both groups of preterm infants, the protein content of Cow & Gate Nutriprem 1 has been adapted to 3.1g protein per 100kcal (2.5 g/100 ml with 80kcal). The increased protein content in comparison with the previous formula has been compensated by a reduction of the carbohydrate.

Hydrolysate versus intact proteins

Cow & Gate Nutriprem 1 preterm formula is designed to meet the needs of the majority of preterm infants and therefore contains whole intact protein and not hydrolysed protein (required for a minority of infants with cows’ milk protein allergy, or those following surgery). Studies have indicated that preterm infants fed whole protein formulas show better weight gain, and lower excretion of amino acids than those fed hydrolysed formula³ and that whole protein formulas have a better nutritional value than hydrolysed formulas. In addition, the use of whole protein as opposed to hydrolysed protein results in a formula with a slightly lower osmolality. Evidence-based recommendations are required before using hydrolysates for the majority of healthy preterm infants⁴.

Nucleotides

There have been different beneficial effects cited for nucleotides in the literature as outlined in the Tsang guidelines. Such effects include strengthening of the immune system; promotion of iron absorption; influence of lipoprotein synthesis (leading to HDL & VLDL profiles similar in breastfed infants) and enhancement of gut maturation and growth. Therefore, the European Union has recognised nucleotides as semi-essential components of infant formulas.

Prebiotic Oligosaccharides

The beneficial effects of human milk oligosaccharides are well accepted and there is interesting data on their potential anti-infective and immune system benefits in term infants and those with a family history of atopic disease.

Tsang et al. also highlight that at the time of review and publication, no preterm formulae were supplemented with prebiotics, and therefore this demonstrates the necessity to supplement preterm formulae with prebiotics (Cow & Gate Nutriprem 1 and Nutriprem 2 post-discharge formula). Prebiotics have been added to Cow & Gate Nutriprem 1 and 2 at a level of 0.8g/100ml, in line with Cow & Gate term formulas, so that preterm infants can also have the same benefits of prebiotics as those demonstrated clinical studies with preterm and term infants.

Clinical studies have demonstrated the benefits of prebiotics, in preterm infants fed a formula with prebiotics (a mixture of 90% galacto-oligosaccharides and 10% fructo-oligosaccharides) versus standard formulas without prebiotics. These findings are consistent with those found in data on term infants fed formulas containing prebiotics, and the benefits are summarised below:

• Significant increase in Bifidobacteria in preterm infants over a 28 day period⁵.
• Significant reduction in clinically relevant pathogens⁶.
• Significantly softer stools, frequency, and reduction in transit time (median 6 hours) to breastfed range⁷. This may help in improving intestinal tolerance to enteral feeding in preterm infants⁵
• Significant reduction in pH⁷ for an acidic gut environment that is unfavourable for potentially pathogenic bacteria
• Significant reduction in the proportion and total number of clinically relevant pathogens⁶.
• Prebiotics may influence calcium absorption in preterm infants⁸. A sufficient supply of calcium is important for bone mineralisation, normal growth and development on the preterm infant, and breastmilk oligosaccharides may contribute to the efficient calcium absorption from breastmilk.

• This is an area of growing interest; Mihatsch W et al., 2006, concluded that `formula supplementation with prebiotics will as well facilitate enteral feeding advancement and increase tolerance of enteral nutrition`. Also a recent study by Modi N et al., 2008, concluded that `Oligasaccharide supplementation improves enteral tolerance in extremely preterm infants`⁹ which adds to the available published data with prebiotic oligosaccharides in term and preterm formulas.

Glucose polymers
Glucose polymers appear to be rapidly hydrolysed and absorbed by the neonate, and carbohydrate energy that is not absorbed in the small intestine is rapidly used by the colonic bacteria. Cow & Gate Nutriprem 1 contains glucose syrup.

Lipids

The quality of lipids is determined both by the lipid class (e.g. triglycerides, phospholipids and cholesterol) and by the fatty acids incorporated into the lipids. Most of the fat and fatty acids are stored as triglycerides.

Long Chain Polyunsaturated Fatty Acids (LCPs) are beneficial to the preterm infant’s growth and development of the brain, eyes and nervous system. They are deposited in large amounts during last trimester of pregnancy - therefore preterm infants have low stores.

Tsang et al. acknowledged that there is data indicating that LCPs from phospholipids can reduce Necrotising En-terocolitis (NEC) in preterm infants, possibly by enhancing one or more immature intestinal functions. Furthermore it has been shown that the absorption of LCPs and incorporation into the brain is better from phospholipids than from triglycerides. This implies that it is not only the amount but also the source of dietary LCPs that is important.

Arachidonic acid (AA) and docosahexaenoic acid (DHA) are key LCPs as recommended by expert opinion¹⁰.

Table 1

	Tsang 2005 recommendation/100kcal	Cow & Gate Nutriprem 1/100kcal
Linolenic acid (LA)	462-1309mg	703mg
Alpha linolenic acid (LA)	77-228mg	101mg
LA : ALA	ratio 5-15 : 1	ratio 7:1
Docosahexaenoic acid (DHA)	16-20mg	18.9mg
Arachidonic acid (AA)	22-34mg	24.6mg

“Preterm infants are born with much less total body DHA and AA, we suggest that preterm infant formulas should include at least 0.35% DHA and 0.4% AA”¹⁰.

Cow & Gate Nutriprem 1 preterm formula composition is in line with these recommendations.

Medium Chain Triglycerides (MCT)

Tsang guidelines acknowledge that MCTs are readily absorbed by the preterm infant. This results in a better fat absorption and rapid fatty acid oxidation, i.e. energy production and thermogenic effect, which may effectively reduce the oxidation of LCPs in preterm infants and enhance their availability for tissue incorporation and further elongation. MCTs can also reduce the formation of calcium and magnesium soaps with unabsorbed long-chain saturated fatty acids, which can thereby increase calcium and magnesium absorption. Cow & Gate Nutriprem 1 new formulation contains 18% of fat as MCTs.

Key Vitamins & Minerals


Folic acid

Nutritional folate deficiency results in growth restriction, anaemia, and abnormalities in neurological status and small intestinal morphology. The preterm infant appears to have several risk factors for folate deficiencies: diminished liver stores, rapid growth, potential for malabsorption, use of antibiotics, etc. The reasonable range for folate is given with 45 - 50 µg/kg/day and with 14 - 30 µg/100 ml for ELBW infants and 15 - 36 µg/100 ml for VLBW infants.
Cow & Gate Nutriprem 1 now contains 35µg/100kcal (28µg/100ml) in order to be also within the range given for ELBW infants for both Tsang and Klein guidelines.

Sodium, Potassium, Chloride

The high growth rate seen in preterm babies leads to a need for significant extra amounts of stored electrolytes, which has to be taken into account if electrolyte supplementation is calculated. There are different needs depending on the birth weight of the infants (ELBW, VLBW) and the different phases after birth; postnatal adaptation phase (3-5 days), intermediate phase with establishing of oral feeding (5-14 days) and stable growth phase with full enteral feeding.

The main challenge is to find a balanced sodium content technologically, without increasing the risk of development of hyponatraemia or hypernatraemia. In the established growth phase more minerals are recommended per kg/day than during the stabilisation phase.

The electrolyte composition of Cow & Gate Nutriprem 1 is based on the stable growth phase after reaching full enteral feeding. The proposed values for sodium, potassium and chloride are within the Tsang recommendations and are balanced in such a way that a metabolic acidosis will be avoided. With these values, the new Tsang recommendations are fulfilled.

Table 2

	Tsang 2005 mg/100kcal	Cow & Gate Nutriprem 1 mg/100kcal
Sodium	46-105	62.7
Potassium	52-106	103
Chloride	71-226	85.6

Calcium, Magnesium, Phosphorous and Vitamin D

The retention of calcium, phosphorous and magnesium of breastmilk fortified with these minerals is higher than from preterm formulas. The wide ranges observed in formula fed infants are related to the availability and absorption of the different sources of the minerals. The absorption is especially important with regard to the calcium phosphate ratio. If the absorption of calcium is low, the calcium : phosphorus ratio of the formula will have to be higher than the theoretical value derived from the ratio in bone apatite. To achieve an optimal growth and bone mineralisation, an approach is to adjust the supplemented amounts of calcium and phosphorus individually by measuring the urinary excretion. The molar ratio of calcium and phosphorous should be higher than 1.4 (high availability of the calcium source) and up to 2.2 (lower availability of the calcium source). The Ca:P ratio of Cow & Gate Nutriprem 1 is 1.8 which is also in line with recommendations by Mize (1995) with an optimal mass ratio of calcium to phosphorus for preterm formula from 1.6 : 1 to 1.8 : 1.

In the Klein Guidelines minimum content of phosphorous is given higher than in the Tsang recommendations (65.6 vs. 32 mg/100 ml). High phosphorous content is important for soft tissues. To fulfil both recommendations, the phosphorus content in Cow & Gate Nutriprem 1 is 66 mg/100 ml, and correspondingly the calcium content to 120 mg/100 ml.

Iron

The preterm infant requires iron for erythropoiesis (the production and differentiation of red blood cells - the largest iron need for the preterm infant), brain development, muscle function, and cardiac functions. The neonatal blood volume expands proportionately with growth. Preterm infants with birth weight between 1-2kg receiving low-iron formulas deplete their iron stores by 3 months of age and become anaemic.

Most studies suggest that 2mg/kg/day of enteral iron marginally supports erythropoiesis in the growing preterm infants. Iron values of 2mg – 4mg/kg/day are recommended for preterm infants in the stable phase. Therefore Cow & Gate Nutriprem 1 contains 1.4mg iron/100 ml (1.75mg/100kcal).

A supplementation with iron during the transitional period (0-14 days after birth) is not recommended in the Tsang 2005 guidelines.

Zinc

Zinc is involved in carbohydrate, protein, fat, and energy metabolism and helps support the immune system. As an important mineral, zinc is also essential for cell differentiation and growth. The total zinc stores of preterm infants are lower compared to term infants. Additionally, the absorption of zinc given in a preterm formula is clearly lower (14 - 24%) than given in human milk (>60%). Recent studies suggest that doses up to 1.8mg/kg/day are safe and promote better growth in the post-discharge period. The zinc content of Cow & Gate Nutriprem 1 is also within the Klein 2002 recommendations - with 0.9mg/100ml (1.1mg/100kcal) of zinc.

Comparison of preterm formulas available in the UK:

Per 100ml	Tsang 2005	Cow & Gate Nutriprem 1	SMA Gold Prem
Energy (kcal)		80	82
Protein (g)	2-3	2.5	2.2
LCPs-AA DHA	✔ ✔	✔ ✔	✔ ✔
Prebiotic Oligasaccharides	✔**	✔	✘
Nucleotides	✔	✔	✘*
Iron (mg)	1.07-2.91	1.4	1.4
Calcium (mg)	54-160	120	101
Phosphorus (mg)	32-102	66	61
Iodine (µg)	5.4-43.6	25	10
Selenium (µg)	0.7-3.3	1.9	1.7

*Values do not comply with Tsang 2005 guidelines.
^** Acknowledged benefits.

Manufacturers continually strive to ensure that their preterm products meet the latest recommendations in preterm nutrition. While the end product can never be a perfect substitute for mothers own milk, the result is a formula that meets the standards developed by international experts in preterm nutrition Tsang, Klein and others.

Click here for more information on the Cow & Gate Nutriprem range or to download a copy of our Specialist Infant Milks leaflet If parents would like information on feeding thier preterm baby why not tell them to visit the Cow & Gate website hereClick here to view the latest research on preterm infant milk formulas

References

1. Tsang RC et al., (Eds) 2005. Nutrition of the Preterm Infant. Scientific Basis & Practical Guidelines. 2nd Edn. Digital Education Publishing, Inc. ISBN 1-58352-100-3
2. Klein CJ (Ed) 2002. Supplement: Nutrient Requirements for Preterm Infant Formulas. J. Nutr. 132:1395S-1577S.
3. Maggio L et al., 2005. Int J Paediatr 94:75-84
4. Foucard T. Acta Paediatr Int J Paediatr 2005; 94:20-22
5. Boehm G. et al., 2002. Arch Dis Child Fetal Neonatal Ed 86:F178-F181
6. Knol J et al., 2005. Acta Pædiatrica; 94 (suppl. 449): 31–33
7. Mihatsch W et al., 2006. Acta Pædiatrica; 95: 843-848
8. Lidestri et al., 2003. Acta Pædiatrica. Suppl; 441:91-92
9. Modi N et al., 2008. Arch Dis Dis Child; 93: A58-A59
10. Koletzko B et al. 2001. Acta Pædiatrica; 90: 460-4.