A preterm infant by definition is one born before 37 weeks gestation. We further subdivide these infants by weight. Less than 2.5 kg (5lbs 8oz) is classified as Low birth weight. Very low birth weight is below 1.5kg (3lbs 5oz) and Extremely low birth weight is less than 1kg (2lbs 3oz). Infants born weighing less than 500 grams (1lb 1oz) are less likely to survive although there have been rare incidences where infants weighing less than 300 grams (10oz) have survived. The very low and extremely low birth weight infants present quite a challenge when it comes to feeding. The gut is just as immature as the rest of the infant and has its own maturation problems. Some mature but growth restricted infants may have had vital blood supplies to the gut compromised, causing these infants to also have feeding intolerances and so a longer time to reach full enteral nutrition.

The basic principle is to feed an infant with mothers’ breastmilk as soon as is practicable⁴. In order of preference, we would wish breastmilk for all infants and ideally fortified to attain a sufficient nutrient intake but for many reasons breastmilk is not always available. An alternative would be to have donated breastmilk from a milk bank.However there are few across the country and cost is often cited as a reason not to use, although compared to overall neonatal costs it is unlikely to be of great financial concern.

Preterm formulae are available for those infants less than 1800g (4lbs) where breastmilk is not available and these are specially formulated to supply the infants with all its nutritional needs. Infants greater than 1800g but less than 2500g for whom breastmilk is not available, are often commenced on a nutrient enriched formula, (Cow & Gate Nutriprem 2). This formula lies somewhere between a preterm and term formula, providing extra calories in the form of carbohydrate, protein and fat as well as addressing the need for additional sodium, iron, calcium, phosphorus, and other nutrients including nucleotides, prebiotics and long chain polyunsaturated fatty acids (LCPs). These infants can be discharged home on this formula for use up to the first 3-6 months corrected age. Randomised trials show growth benefits, particularly in boys^5,6.

There is however a big difference between the composition of a preterm formula and breastmilk. For this reason breastmilk fortifiers have been developed to enable the extremely low birth weight infant to grow adequately as well as having the benefit of mothers’ milk^7,8. At any time during the infant’s growth and maturation it is sensible to review the calorie intake and growth velocity. Some infants may gain weight too fast on these enriched formulae and cutting down a feed is just as important as increasing the amounts or type of feed an infant may have.

Milk Comparisons

Per 100 mls	Human Milk	Term Formula	Nutrient Enriched	Preterm Formula
Energy (kcal)	69	66	75	80
Protein (g)	1.3	1.3	2	2.5
Whey (%)	60	60	60	60
Casein (%)	40	40	40	40
Fat (g)	4.1	3.5	4.1	4.4
Saturated (%)	50	40	40	40
Carbohydrate (g)	7.2	7.3	7.5	7.6
Calcium (mg)	34	50	94	120
Phosphorus (mg)	15	28	50	66
Iron (ug)	70	530	1200	1400
Sodium (mg)	15	17	27	50
Potassium (mg)	58	63	77	82
Osmolality (mOsm/kgH2O)	276	340	340	360

We have seen many changes to infant formulae over the preceding years. Most of these changes have involved additions to the formula aiming to mimic breastmilk as much as possible for the benefit of the infant. These additions have included:

• Prebiotic oligosaccharides – These are natural sugars found in breastmilk and research indicates their support of infants natural immune system¹⁰.
• Nucleotides – found naturally in breastmilk promoting T-lymphocyte development and the growth of beneficial bacteria⁹.
• LCP’s – Docosahexaenoic acid (DHA) and Arachidonic acid (AA) are components of the developing brain and retina and have been found to improve visual function and cognitive development.

What are Tsang guidelines¹¹?
These were produced to guide us to the daily requirements of the growing and developing preterm infant.

This has become more and more relevant as there is increased survival of very low birth weight infants, and numerous studies emphasising the importance of early feeding on short and long-term development.

Recent nutritional recommendations have been based on healthy preterm infant studies and have not really addressed the additional needs in the early adaptive period. Recommendations for nutritional needs for preterm infants were developed between 1985 and 1995 from numerous nutritional bodies and panels including the American Academy of Pediatrics, the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the Canadian Paediatrics Society and Nutrition Committee, as well as the Life Science Research Office (LSRO). In 2005, these were revised recommendations for nutritional intake. Protein intake and protein:energy ratio appear to be the main determinants of growth and body composition during the stable growing period and some of these recommended changes are shown below.

Energy and protein requirements (Tsang 2005)

Extremely Low Birth Weight Infants (<1000g)

Nutrients and Fluids /kg/day	Day 1	Transition(up to 7 days)	Growing
Fluids/mls	90-120	90-140	160-220
Energy/kcal	50-60	90-100	130-150
Protein/g	2.0	3.5	3.8-4.4
Fat/g	1	1-3	6.2-8.4
Carbohydrate/g	7	8-15	9-20

Very Low Birth Weight Infants (<1500g)

Nutrients/kg/day	Day 1	Transition(up to 7 days)	Growing
Fluids/mls	70-90	90-140	135-190
Energy/kcal	50-60	75-90	110-130
Protein/g	2.0	3.5	3.4-4.2
Fat/g	1	1-3	5.3-7.2
Carbohydrate/g	7	5-12	7-17

The transition period will vary with gestation and the lower the gestation the more likely the infant is to lose weight and be metabolically unstable. Aggressive early parenteral nutrition is currently being evaluated^12,13. There is no doubt that early oral nutrition is indicated in preterm infants, as this promotes a decrease in morbidity, feeding tolerance and decreasing the time to reach full feeds.

The growing period is when an infant can tolerate its requirements and obtain catch up growth. The vast majority of these infants will be enterally fed and although one would always advocate breastmilk as a first choice milk for a multitude of reasons including neurodevelopmental benefits, anti-infective properties and mother-baby bonding, there may be an association with poor growth. Although there is a greater protein density in mother’s preterm milk allowing better early growth, there is a rapid decrease to term levels within a short period of time¹⁴.

Human Milk Fortifiers

These have been developed as discussed above to increase the protein, energy, mineral, electrolyte, trace element, and vitamin supply. They have been shown to improve growth⁷ and are widely used but there are concerns with the increased osmolality with storage of made-up feeds, as well as concerns about lysosyme activity and infection. These preparations are being modified and studies continue.

Per 100mls	Cow & Gate Nutriprem Breastmilk Fortifier (2 sachets)	SMA Breastmilk Fortifier (2 sachets)
Protein (g)	0.8	1.0
Energy (kcal)	15	14.6
Calcium (mg)	65	90
Phosphorus (mg)	45	46
Minerals	Na, K, Cl, Ca, P, Mg, Zn, Cu, I, Mn	Na. K, Cl, Ca, P, Mg, Zn, Mn
Vitamins	A,D,E,K,C,B1, B2, Niacin, B6,B12, Pantothenic acid, Biotin, Folic acid	A, D, E, K, C, B1, B2,Niacin, B6,B12, Pantothenic acid, Biotin, Folic acid
Presentation	2.1g sachet	2g sachet

Preterm Formulae

These formulae are designed to try to allow normal and catch up growth in preterm infants. There is no doubt that on the whole this is achieved, but calculating protein deficits in preterm infants would suggest the need for even higher protein:energy ratios in a preterm formula. We must remember that although these formulae are being constantly fine-tuned they do not contain any of the enzymes, hormones or growth factors found in human milk.

Nutrient Enriched Formula
This formula is often used after the use of a preterm formula at about a weight of 1800g or initiated in an infant weighing less than 2.5kg. The step from a term to a preterm formula is substantial from a protein/energy perspective. Infants at this stage in life need to continue their catch up growth and are able to do so by taking a formula higher in protein, calcium, iron, sodium and phosphorus than a term formula. How long this should be continued is an ongoing question due to concerns about long-term morbidity but it is often replaced by a standard term formula at about 3-6 months of corrected age.

The Tsang 2005 recommendations aim to reduce postnatal growth restriction and to prevent longer term unwanted effects on this infant population. The neurodevelopmental well-being and good health of these infants remains paramount, but we will need far more studies to determine whether ‘nutritional programming’ exists where at sensitive periods of an infant’s development a trigger could have a lifelong impact on the quality of survival.

The following tables show the changes made from the original collaborative recommendations in 1993¹¹.

In 2009 ESPGHAN produced a commentary on the ‘Enteral Nutrient Supply for Preterm Infants¹³. With increase survival of preterm infants and the goal to achieve growth similar to foetal growth as well as functional development a new guide has been produced. The recommendations are consistent with the LSRO and American Society for Nutritional Sciences as well as the `Nutrition in the Preterm Infants’ 2^nd ed edited by Tsang et al. The guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of 1800g. It is important to note that this does not specifically address the needs of infants with specific disease.

The best way to understand this is to study the table below¹³.

Recommended intakes for macro- and micronutrients expressed per mg/kg/d and per 100 kcal unless otherwise denoted. Calculation of the range of nutrients expressed per 100 kcal is based on a minimum energy intake of 110 kcal/kg.

Min-Max	Kg-1 d-1	/100 kcal
Fluid (ml)	135 - 200
Energy (kcal)	100 - 135
Protein (g) < 1kg body weight	4.0 - 4.5	3.6 - 4.1
Protein (g) 1kg - 1.8kg body weight	3.5 - 4.0	3.2 - 3.6
Lipids (g) (of which MCT < 40%)	4.8 - 6.6	4.4 - 6.0
Linolenic acid (mg)*	385 - 1540	350 - 1400
Alpha linolenic acid (mg)	> 55 (0,9% of fatty acids)	> 50
DHA (mg)	12 - 30	11 - 27
AA (mg)**	18 - 42	16 - 39
Carbohydrate (g)	11.6 - 13.2	10.5 - 12
Sodium (mg)	69 - 115	63 - 105
Potasssium (mg)	66 - 132	60 - 120
Chloride (mg)	105 - 177	95 - 161
Calcium Salt (mg)	120 - 140	110 -130
Phosphate (mg)	60 - 90	55 - 80
Magnesium (mg)	8 - 15	7.5 - 13.6
Iron (mg)	2 - 3	1.8 - 2.7
Zinc (mg)***	1.1 - 2.0	1.0 - 1.8
Copper (µg)	100 - 132	90 - 120
Selenium (µg)	5 - 10	4.5 - 9
Manganese (µg)	≤27.5	6.3 - 25
Fluoride (µg)	1.5 - 60	1.4 - 55
Iodine (µg)	11 - 55	10 - 50
Chromium (ng)	30 - 1230	27 - 1120
Molybdenum (µg)	0.3 - 5	0.27 - 4.5
Thiamin (µg)	140 - 300	125 - 275
Riboflavin (µg)	200 - 400	180 - 365
Niacin (µg)	380 - 5500	345 - 5000
Pantothenic acid (mg)	0.33 - 2.1	0.3 - 1.9
Pyridoxine(µg)	45 - 300	41 - 273
Cobalamin(µg)	0.1 - 0.77	0.08 - 0.7
Folic acid (µg)	35 - 100	32 - 90
L-asorbic acid (mg)	11 - 46	10 - 42
Biotin (µg)	1.7 - 16.5	1.5 - 15
Vitamin A (µg RE) (1µg ~3.33 IU)	400 - 1000	360 - 740
Vitamin D (IU/d)	800 - 1000 IU/d
Vitamin E (mg alpha-TE)	2.2 - 11	2 - 10
Vitamin K1 (µg)	4.4 - 28	4 - 25
Nucleotides (mg)		≤5
Choline (mg)	8 - 55	7 - 50
Inositol (mg)	4.4 - 53	4 - 48

* The linoleic acid to alpha-linolenic acid ratio is in the range of 5-15:1 (wt/wt).
** The ratio of AA to DHA should be in the range of 1.0-2.0 to 1 (wt/wt), and eicosapentaenoic acid (20:5n-3) supply should not exceed 30 % of DHA supply.
*** The zinc to copper molar ratio in infant formulae should not exceed 20.

As well as the above recommendations the authors have also reviewed the role of probiotics and prebiotic oligosaccharides in preterm infants. They acknowledge that the addition of galacto- and fructo-oligosaccharides to preterm formula has been shown to increase faecal bifidobacteria, reduce stool pH, reduce stool viscosity and accelerate gastrointestinal transport, whilst a recent meta-analysis on probiotics has shown that they may reduce the risk of necrotizing enterocolitis in preterm infants <33 weeks gestation.

However, the authors conclude that presently the available data on prebiotic oligosaccharides and probiotics is not sufficient to recommend their routine use in preterm infants. Ongoing trials in this area may well lead to differing conclusions in the future.

In summary the preferred food for the premature infant is fortified human milk from the infants own mother, or alternatively, formula designed for preterm infants.


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 their 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. Barker DJ, Bagby SP et al. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2006 Dec;2(12):700-7
2. Eriksson JG, Forsen T et al. Early growth and coronary heart disease in later life: longitudinal study. BMJ 2001 Apr 21;322(7292):949-53
3. Eriksson JG, Forsen T, et al. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 1999;318:427-431
4. American academy of Pediatrics, Work group on breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2005 Feb;115(2):496-506
5. Carver JD. Nutrition for preterm infants after hospital discharge. Adv Pediatr 2005;52:23-47
6. Fewtrell MS. Growth and Nutrition after discharge. Semin Neonatol 2003 Apr;8(2):169-76
7. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev 2004;(1):CD000343
8. Pieltan C, De Curtis M, et al. Weight gain composition in preterm infants fed fortified human milk or preterm formula. Pediatr Res 49, 2001:120-24
9. Cosgrove M. Nucleotides. Nutrition 1998; 14:748-51
10. Kunz C, Rudloff S, et al. Oligosaccharides in human milk: structural, functional, and metabolic aspects. Annu Rev Nutr 2000;20:699-722
11. Tsang R, Uauy R, et al. 2005. Nutrition of the Preterm Infant. Scientific Basis & Practical Guidelines. Second Edition. Digital Educational Publishing, Inc.
12. Premjii SS, Fenton TR, et al. Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane database Syst Rev 2006 Jan 25;(1):CD003959