Caroline King and Kate Tavener
A preterm infant is one born before 37 weeks completed gestation. An infant born <2500 g is termed low birthweight regardless of gestation, <1500 g very low birthweight (VLBW) and those <1000 g extremely low birthweight (ELBW). Categorisation of infants born smaller than expected is more contentious; however, they are often divided into small for gestational age (SGA) and/or intrauterine growth restricted (IUGR). Classification of SGA infants is usually defined as <9th percentile for weight at birth (depending on source of definition) and they constitute a heterogeneous group, i.e. those destined to be born small due to genetic influences and those who are IUGR. The former group tends to be proportionally small. Those who are IUGR will have a similarly low birthweight but may show head and/or length sparing depending on the timing of intrauterine nutrient restriction. These infants are at high risk of both perinatal and later problems . This chapter will deal predominantly with the nutritional needs of preterm infants.
The early nutritional management of preterm infants may be vital to their later outcome, but can be hampered by an immature or dysfunctional gastrointestinal tract and poor tolerance of parenteral and enteral nutrition.
Small term infants in general are mature with respect to oromotor function and can usually grow well if allowed breast or standard infant formula ad lib. Only where comorbidities exist may small term infants need specialised nutritional input. It is not recommended that these infants are given any formula designed for preterm infants as there may be adverse outcomes [2, 3].
Preterm infants have limited stores of many nutrients as accretion occurs predominantly in the last trimester . They are poorly equipped to withstand inadequate nutrition; theoretically endogenous reserves in a 1000 g infant are only sufficient for 4 days if unfed . In addition, the gastrointestinal system is immature; thus it is generally accepted that most infants of <30 weeks’ gestation will need some parenteral nutrition (PN) while enteral feeds are gradually increased to ensure an adequate nutritional intake. The most recent comprehensive reviews and recommendations for enteral and parenteral nutritional requirements are those of Tsang et al.  and Agostoni et al.  (Table 6.1). The interested reader is advised to refer to these publications for further information. There is also a review of recommendations for preterm infant formulas which although published in 2002 has some useful background information .
Table 6.1 Recommended enteral and parenteral nutrient intakes for very low birthweight infants
|Nutrient (per kg per day)||Tsang et al.  enteral||Agostoni et al.  (ESPGHAN) enteral||Term infant RNI (1991)* enteral||Tsang et al.  parenteral|
|Energy||110−130 kcal (460−545kJ)||110−135 (460−565kJ)||115−100 (480−420kJ)||90−100 (375−420kJ)|
|Protein (g), <1000 g body weight||3.8−4.4||4.0−4.5||N/S||N/S|
|Protein (g), 1000−1500 g body weight||3.4−4.2||3.5−4.0||N/S||3.2−3.8|
|Fat (g)||5.3−7.2||4.8−6.6 (<40% MCT)||N/S||3.0−4.0|
|Folic acid (µg)||25−50||35−100||8.5||56|
|Vitamin A (µg)||212−454||400−1000||59||212−454|
|Vitamin D (µg/day)†||10||20−25||8.5||1−4|
|Vitamin E (mg)||4−8||2.2−11||0.37||1.9−2.3|
DHA, docosahexaenoic acid; AA, arachidonic acid; RNI, reference nutrient intakes.
Agostoni et al. recommendations are for stable growing preterm infants up to a weight of 1800 g; no recommendations are made for infants <1000 g except for protein. Tsang et al. recommendations presented are for stable growing VLBW infants from 1000 to 1500 g; no recommendations are given for infants over 1500 g.
* Estimated average requirement for energy and reference nutrient intake for 0−3 months (Department of Health Report on Health and Social Subjects No. 41. Dietary Reference Values for Food. Energy and Nutrition for the United Kingdom. London: The Stationery Office, 1991).
† Vitamin D is per day not per kg. 1 µg vitamin A = 3.33 IU. 1 µg vitamin D = 40 IU. N/S = not specified.
Precise requirements for infants born between 1800 g and 2500 g are not given in these publications. This has led to varying interpretations of the weight cut-offs for feeding preterm formulas or fortifying breast milk. Higher nutrient density feeds are not routinely recommended for term SGA infants so gestational age as well as birthweight should dictate local feeding policy. In practice most infants born <2000 g and <34 completed weeks will benefit from the higher nutrient intakes recommended by Tsang et al.  and Agostoni et al. . At the time of going to print a new text containing nutrient recommendations for preterm infants has been published by Koletzko et al. and readers are also encouraged to refer to this publication. A brief review shows very few significant changes but the background discussion will be of great interest to anyone involved in preterm nutriiton Ref: Koletzko, B., Poindexter, B., Uauy, R. (2014) Nutritional Care of Preterm Infants. Scientific Basis and Practical Guidelines.
Caution must be exercised when interpreting recommendations for requirements for two reasons. First, the evidence base for nutrient requirements in preterm infants is not robust with very few randomised controlled trials (RCTs) having been undertaken, particularly in VLBW or ELBW infants. Recommendations for requirements are compiled from a variety of data sources including fetal tissue analysis, placental transfer studies, cohort studies, case reports of deficiency or toxicity, breast milk composition and a few RCTs of controlled intake. Much of the data for infants <1000 g is extrapolated. Second, preterm infants are a heterogeneous group and requirements are highly variable depending on post conceptional age (inversely related), accumulated nutrient deficit (prenatally and postnatally), body composition and variations in resting energy expenditure. In addition, as with other recommendations for requirements, these are for whole populations rather than individuals.
Recommended nutrient intakes are typically greater for enterally fed compared with parenterally fed infants, and greater for preterm compared with term. The following provides further information regarding certain key nutrients. Requirements refer to those via the enteral route unless specified.
During the initial phase of adaptation to extra-uterine life, fluid management is complicated as there is a delicate balance between matching high transcutaneous losses and avoiding fluid overload due to renal immaturity (although the former should be minimised by appropriate nursing techniques). Very sick preterm infants are often fluid restricted but nutritional intakes should always be optimised within the fluid allowed and restrictions lifted as soon as clinical condition permits. Recommendations from Agostoni et al.  suggest 135 mL/kg/day is the minimum requirement with an upper reasonable limit of 200 mL/kg/day. Between 150 and 180 mL/kg/day is likely to meet enteral requirements if feeding fortified human milk, and the lower end of the range if preterm formula is given.
Recommended energy intakes vary according to the baby’s birthweight and postnatal age but are generally higher than term requirements . There may be variations in resting energy expenditure with requirements potentially reduced in very sick, ventilated infants and increased in infants with increased respiratory effort. Some IUGR babies may have increased needs to facilitate catch-up growth but this will vary between individuals and can only be established by monitoring progress and adjusting intakes accordingly. Optimising body composition is essential and excessive energy intake may lead to excessive fat deposition. However, severity of illness rather than diet appears to be most closely linked to increased abdominal adiposity . It is recommended that >100 kcal (420 kJ)/kg/day is generally appropriate for enteral formula feeding as long as adequate protein, 3.0−3.6 g/100 kcal (420 kJ), is provided . There are currently only three preterm formulas that meet this requirement: Aptamil Preterm, Nutriprem 1 and Hydrolysed Nutriprem. Monitoring linear growth as a proxy for lean mass accretion is recommended.
Current recommendations for protein requirements assume an accumulated nutrient deficit due to an inability to provide full requirements during sickness and periods of fluid restriction and are therefore significantly higher than term requirements. Both Tsang et al.  and Agostoni et al.  have revised recommendations upwards compared with previous recommendations. Individual requirements will vary according to post conceptional age and degree of nutrient deficit. A requirement of 4 g/kg/day protein can be met with 180−200 mL/kg/day of fortified breast milk, 160 mL/kg/day Nutriprem 1 or 180 mL/kg/day SMA Gold Prem 1.
The benefits of early provision of amino acids (AA) in PN for preterm infants is generally well accepted; however, the amount required initially is the subject of debate. A recent RCT looked at 3.5 vs. 2.4 g AA/kg from day 1 and found equal nitrogen retention but more abnormal blood results in the 3.5 g AA/kg group . They also found better nitrogen retention if lipid was given on day 1 at around 2 g/kg. Another RCT showed that achieving 4 g AA/kg within the first 3 days led to improved head growth after 4 weeks ; in this study both groups received 1.8 g AA/kg for the first 2−3 days. In an observational study Poindexter et al.  found that the provision of early AA to ELBW infants (≥3 g/kg/day at ≤5 days of life) resulted in improved weight, length and head circumference at 36 weeks post conceptional age although there was no difference between groups at 18 months and no difference in neurodevelopmental outcome. Further research is required before firm conclusions can be drawn about the benefits of early, high protein provision and outcome.
Fat absorption can vary between individuals but the more immature the infant the higher the risk for malabsorption due to low bile salt pools  and reduced pancreatic lipase levels . Despite this, the fat component of both enteral and parenteral nutrition is crucial to attain the high energy requirements of preterm infants and to provide essential fatty acids. Feeding with non heat treated breast milk has the advantage of an endogenous lipase (bile salt stimulated lipase) which ensures optimum fat absorption .
For many years studies have investigated the theory that enteral medium chain triglycerides (MCT) lead to improved fat absorption. However, a systematic review found no consistent advantage . Agostoni et al  recommend that fat in the form of MCT should not exceed 40% of the total fat content of preterm formulas. Preterm formulas currently contain SMA Gold Prem 1 12.5% fat as MCT; Nutriprem 1, Hydrolysed Nutriprem and Aptamil Preterm 18% fat as MCT.
It has been recommended that the long chain polyunsaturated (LCP) derivatives of linoleic and α-linolenic acids, namely arachidonic and docosahexaenoic acids, are provided in the diet of preterm infants [7, 8]. However, controversy remains concerning their role with recent reviews concluding that there were few significant benefits although no evidence of harm [17, 18]. Outcomes with respect to neurodevelopment have been inconsistent which may be due to genetic variations between individuals in their ability to manufacture LCPs from precursors . There also appears to be risk of greater adiposity and blood pressure for preterm girls supplemented with LCP . Conversely, recent research suggests that girls may show positive effects of LCP supplementation with respect to neurodevelopment . Conclusions are made difficult by the heterogeneity of studies and they also generally include only mature and healthy preterm infants. Despite this, all current preterm formulas are supplemented with LCP whereas the standard lipid emulsions used for parenteral feeding are not.
Enteral requirements for fat are in the range 4.8−6.6 g/kg/day . Parenterally most infants will tolerate 3 g/kg/day of lipid, although extremely premature or very low birthweight infants may develop hypertriglyceridaemia at this level of administration and caution should be exercised. A healthy preterm infant will probably tolerate and grow well on 3.5 g/kg/day lipid. Preterm infants, particularly those born VLBW and ELBW, will develop essential fatty acid deficiency very rapidly without an exogenous supply. This can be obtained from as little as 0.5 g/kg/day of one of the current parenteral lipid emulsions .
Lactase activity is present from 10 to 12 weeks’ gestation and approaches levels expected at term at 36 weeks’ gestation. Exposure to lactose may help to induce intestinal lactase activity. In practice, lactose malabsorption is rarely seen.
A large range of oligosaccharides are present in breast milk, being highest in colostrum and decreasing with the duration of lactation. They may help to protect against gut problems, both by encouraging growth of a beneficial intestinal flora and by inhibiting binding of pathogens. They may improve feed tolerance and reduce stool viscosity ; however, a recent review of the literature by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) states that more research is required before firm conclusions about their benefits can be drawn . Oligosaccharides are currently added to Aptamil Preterm and Nutriprem 1 feeds.
Tolerance to carbohydrate load in PN needs close monitoring, especially in the sick or extremely preterm infant. Most preterm infants require 15 g/kg/day glucose in order to meet requirements and limits for glucose oxidation are approximately 18 g/kg/day, above which net lipogenesis occurs . Limits for glucose administration peripherally are approximately 10%−12% concentration.
Calcium, phosphorus and vitamin D
The homeostasis of calcium, phosphorus and magnesium is fundamental to the development of bone and this in turn is regulated by factors including hormones and vitamin D. Metabolic bone disease of prematurity is a recognised morbidity. Causes include an inadequate supply of nutrients (calcium, phosphorus, vitamin D), prolonged PN, immobilisation and medications. Immobilisation stimulates bone reabsorption whilst steroids (occasionally still used to treat chronic lung disease) reduce calcium absorption, increase urinary losses and have a direct effect on bone. Diuretics and methylxanthines such as caffeine, used to optimise respiratory status, increase renal calcium excretion. Premature infants are also born with poor reserves of calcium, phosphorus and vitamin D and have a high requirement in order to optimise bone mineralisation. Infants born IUGR or SGA are also more likely to show signs of osteopenia due to poor placental supply.
The recommendations provided by Tsang et al.  and Agostoni et al.  for calcium and phosphate are similar; however, vitamin D recommendations from Agostoni et al. are significantly higher. They argue that since the prevalence of maternal vitamin D deficiency is high, supplementation with 800−1000 IU (20−25 µg) per day is required to achieve optimal serum levels of 25-hydroxyvitamin D. There is no evidence that this higher amount of vitamin D is beneficial and there is some evidence that these higher levels will be excessive for some infants . However, babies of mothers with documented vitamin D deficiency will benefit from the higher levels as the placental supply will have been compromised. This will need to be given as a supplement as current breast milk fortifiers and preterm formulas do not contain sufficient vitamin D to match this recommendation. The ratio between calcium and phosphorus is also important for adequate bone mineralisation and Agostoni et al. recommend an enteral Ca:P ratio of 1.5−2.0.
In PN solutions, stability of these nutrients is a limiting factor as calcium and phosphate can bind and precipitate, although the introduction of organic phosphate salts has led to improved solubility and allows greater amounts to be given. The ideal Ca:P ratio should be no less than 1:1 in PN solutions .
At birth there is an abrupt reduction in erythropoiesis leading to early anaemia of prematurity which is not affected by iron supplementation. Preterm iron stores are low and infants may also lose significant volumes of blood through phlebotomy. Iron, in excess, is toxic and therefore supplementation needs to be carefully weighed up against potential overload. Babies receiving regular blood transfusions may benefit from delayed iron supplementation.
Preterm infants will become iron deplete by 8 weeks without supplementation . Current recommendations are that supplements should commence between 2 and 8 weeks of age (earlier in ELBW infants) as either a supplemented formula or medicinal iron at a dose of 2−4 mg/kg/day . These recommendations can easily be met by adequate volumes of currently available preterm infant formulas. Breast milk fortifiers in the UK and PN solutions do not provide iron and therefore supplementation will be required if these are used.
Conditionally essential nutrients
Beta-carotene, nucleotides and inositol are present in human milk and are often added to preterm infant formulas and breast milk fortifiers; however, there is currently no evidence of benefit in the preterm population.
PN has become the cornerstone of neonatal nutritional care in the very preterm infant, without which many infants would not survive. PN is required when adequate nutrients to sustain growth and development cannot be provided via the enteral route. PN should therefore be considered in infants
- born <30 weeks’ gestation
- with congenital gastrointestinal abnormalities, e.g. exomphalos, gastroschisis
- with gastrointestinal dysfunction, e.g. feeding intolerance, necrotising enterocolitis (NEC), short bowel syndrome
- who are at high risk of developing NEC (p. 100) and require prolonged minimal enteral nutrition
- with gastrointestinal dysfunction, e.g. feeding intolerance, necrotising enterocolitis (NEC), short bowel syndrome
PN can usually be started safely and effectively within the first few hours of birth in the preterm infant [10, 28]. Solutions used are the same as those for term infants; however, quantities provided vary in order to meet their nutritional needs. An example of a suitable parenteral feeding regimen for a preterm infant is given in Table 6.2 and a case study is presented in Table 6.3.
Table 6.2 Example parenteral feeding regimen for a preterm infant
|Nutrient (per kg per day)||Day 1||Day 2||Day 3, fluid limited||Day 3, standard PN|
|Sodium (mmol)||Variable *||Variable*||2.4||3.0|
|Vitlipid Infant (mL/kg/day)||4.0||4.0||4.0||4.0|
|Total energy (kcal/kg/day)||48||67||90||109|
PN, parenteral nutrition.
* Supplementation is usually delayed until a postnatal fluid loss has been demonstrated over the first few days.
Table 6.3 Case study: preterm infant on parenteral nutrition
|Baby girl, born at 27+3/40, birthweight 890 g (25th centile). Maternal premature rupture of membranes with maternal antenatal steroids given|
|1||Continuous positive airways pressure (CPAP) commenced Umbilical line inserted for fluid administration||NA||Standard bag of parenteral nutrition (PN) commenced at 60 mL/kg/day* providing 1.5 g protein†/kg/day, 6.7 g/kg/day glucose, total 48 kcal (200 kJ)/kg/day Lipid infused separately at 1.5 g/kg/day 15 mL/kg/day maternal expressed breast milk (MEBM) + donor breast milk (DBM) as bolus feeds|
|2||NA||NA||PN increased to 90 mL/kg/day* 30 mL/kg/day MEBM + DBM as bolus feeds|
|3||NA||NA||PN increased to 120 mL/kg/day* PN provides 3.5 g protein/kg/day, 15 g glucose/kg/day, 3.5 g lipid/kg/day, total 109 kcal (455 kJ)/kg/day 50 mL/kg/day MEBM as bolus feeds|
|5||Increased oxygen requirements Sepsis Intubated and ventilated Insulin started||Blood sugar levels increase to 9−11 mmol/L||PN kept at 120 mL/kg/day Feeds reduced to 15 mL/kg/day MEBM as bolus feeds|
|7||Worsening sepsis High nasogastric aspirate volumes Total fluids restricted to 100 mL/kg/day as intravenous fluids||Blood sugar levels remain >9 mmol/L Triglyceride levels raised at 4.5 mmol/L||Nil by mouth PN infusion rate reduced to 100 mL/kg/day giving glucose load of 12.5 g/kg/day Lipid reduced to 1 g/kg/day due to raised blood sugars and raised serum triglycerides|
|9||Nasogastric aspirates reducing||NA||20 mL/kg/day MEBM restarted as bolus feed|
|12||Chest improving Total fluids liberalised to 120 mL/kg/day Insulin stopped Weight = 920 g (9th centile)||Blood sugar levels normalising at 5−7 mmol/L||PN increased to provide 3.5 g/kg/day protein, 15 g glucose/kg/day, 3.5 g lipid/kg/day, total 109 kcal (455 kJ)/kg/day Feeds increased by 20 mL/kg/day|
|14||Extubated back to CPAP Total fluids = 150 mL/kg/day||NA||80 mL/kg/day MEBM, continues increasing by 20 mL/kg/day PN maintained at 70 mL/kg/day|