[clinical practice guidelines * guides de pratique clinique]

NUTRIENT NEEDS AND FEEDINGOF PREMATURE INFANTS

Nutrition Committee, Canadian Paediatric Society

Objective: To recommend appropriate intake of nutrients, food sources and feeding practices for prema-ture infants.

Options: Unfortified milk from the premature infant's own mother, fortified milk from the premature in-fant's own mother, formula designed for preterm infants and parenteral nutrition.

Outcomes: From birth to 7 days, the minimum achievable goal is the provision of sufficient nutrients toprevent deficiencies and catabolism of nutrient substrate in premature infants; from 7 days to dischargefrom the neonatal intensive care unit, growth and nutrient retention at a rate similar to that whichwould have been achieved had the infant remained in utero; and for 1 year following discharge, nutri-ent intake to achieve catch-up growth.

Evidence: Few randomized clinical trials of feeding infants specific nutrients or of feeding choices havebeen conducted. On the basis of a MEDLINE search of the literature, committee members prepared re-views of the available information on each nutrient and feeding choice. The reviews were critically ap-praised by the committee. Recommendations were based on the consensus of the committee.

Values: Whenever possible, the evidence was weighed in favour of randomized controlled trials. If suchtrials were unavailable, cohort studies were considered. If trials of either kind were unavailable, pub-lished data were reviewed and recommendations were based on consensus opinion.

Benefits, harms and costs: The advantages of feeding premature infants unfortified milk from their ownmothers are psychologic benefits for the mother as well as anti-infective benefits and possibly im-proved intellectual development for the infant. However, unfortified milk from the infant's own motheris inadequate as a sole source of nutrients. The use of fortified milk from the mother results in fastergrowth as well as having the other benefits of mother's milk. When formulas designed for prematureinfants are given in adequate volumes, they provide an intake of nutrients that allows the infant to du-plicate intrauterine growth without undue metabolic stress.

Recommendations: The preferred food for premature infants is fortified milk from the infant's own motheror, alternatively, formula designed for premature infants. This recommendation applies to infants withbirth weights of a minimum of 500 g to a maximum of 1800 to 2000 g, or with a gestational age at birthof a minimum of 24 weeks to a maximum of 34 to 38 weeks (until the infant is able to nurse effectively).

Validation: These guidelines are in line with, but not identical to, recent guidelines by the Committee onNutrition of the American Academy of Pediatrics and the Committee on Nutrition of the Preterm In-fant of the European Society of Paediatric Gastroenterology and Nutrition.

Sponsor: The preparation of these guidelines was sponsored and funded by the Canadian Paediatric Society.

Objectif: Recommander un apport approprie de nutriments, des sources d'aliments et des pratiques d'ali-mentation pour les nouveau-nes prematures.

Nuon Committee of the Canadian Paediatric Society: Drs. Tilak R. Maihotra (director responsible), Holy Family and Victoria Union Hospitals, Prince Albert, Sask.; Stanley H. Zlotkin (chair),

Department of Paediatrics, Hospital for Sick Children, Toronto, Ont.; Margaret P. Boland, Children's Hospital of Eastern Ontario, Ottawa, Ont.; Robert M. Issenman, Department of Paediatrics,McMaster University, Hamilton, Ont; Elizabeth Rousseau-Harsany, Hopital Sainte-Justine, Montreal, Que.; John E.E. Van Aerde, Department of Paediatrics, University of Alberta, Edmonton, Alta.

Scientific Review Subcommittee responsible for tie preparaton of these guidelines: Drs. Stanley H. Zlotkin (chair and principal coauthor), Hospital for Sick Children, Toronto, Ont.; Stephanie A.Atkinson, Department of Paediatrics, McMaster University, Hamilton, Ont; Ms. Joan Brennan, RPDt, Hospital for Sick Children, Toronto, Ont; Drs. Michael Dunn, Woman's College Hospital, Toronto,

Ont; Rhona Hanning, St. Michael's Hospital, Toronto, Ont; TiborHeim, Hospital for Sick Children, Toronto, Ont; Sheila M. Innis, Department of Paediatrics, University of British Columbia,Vancouver, BC; Gillian Lockitch, British Columbia's Children's Hospital, Vancouver, BC; Ms. Susan Merko, RPDt, Women's College Hospital, Toronto, Ont.; Drs. Paul B. Pencharz, Hospital forSickChildren, Toronto, Ont; Max Perlman, Hospital for Sick Children, Toronto, Ont.; lngeborg Radde, Hospital for Sick Children, Toronto, Ont; Reg Sauve, Department of Paediatrics, University of

Calgary, Alta.; and John E.E. Van Aerde, Department of Paediatrics, University ofAlberta, Edmonton.

Reprintrequests to: Nutrition Committee, Canadian Paediatnc Society, 401 Smyth Rd., Ottawa ON KlH8LH

*- For prescribing information see page 1924* JUNE 1, 1995; 152 (11) 1165

CAN MED ASSOC J o JUNE 1, 1995; 152 (1 1) 1765+- For prescribing information see page 1924

Options: Lait non fortifie de la mere du nouveau-ne premature, lait maternel fortifie de la mere du nou-veau-ne premature, lait maternise pour nouveau-nes prematures et alimentation parenterale.

Resultats: De la naissance 'a 7 jours, l'objectif minimum atteindre est un apport suffisant en nutrimentspour prevenir des carences et le catabolisme du substrat de nutriments chez les nouveau-nes pre-matures; de 7 jours a la lib6ration de l'unite des soins intensifs neonataux, croissance et retention desnutriments 'a un taux comparable au taux qui aurait et atteint si le nourrisson etait demeure dans le seinde sa mere; pendant I an apres la liberation, apport de nutriments pour realiser un rattrapage de crois-sance.

Preuve: Les essais cliniques randomises sur les nutriments specifiques absorbes par les nouveau-nes ou surles choix d'alimentation sont peu nombreux. S'appuyant sur une recension des ecrits dans MEDLINE,les membres du comite ont prepare des examens des renseignements disponibles sur chaque nutrimentet chaque choix dalimentation. Le comite a procede 'a une evaluation critique des revues. Ses recom-mandations sont fondees sur un consensus.

Valeurs: Lorsque ce fut possible, on a pondere les preuves en faveur des essais contr6les randomises.Lorsque de tels essais n'6taient pas disponibles, on a envisage des etudes de cohortes. S'il n'existait pasd'essais de l'un ou l'autre des deux types, on a examine les donnees publiees et fonde les recommanda-tions sur le consensus.

Avantages, prejudices et couits: Les avantages que presente pour les enfants prematures une alimentationfondee sur le lait maternel non fortifie sont d'ordre psychologique pour la mere et presentent aussi unmoyen de lutte contre l'infection et, peut-etre, de developpement intellectuel ameliore pour le nou-veau-ne. Le lait non fortifie de la mere du nouveau-ne ne suffit toutefois pas comme seule source de nu-triments. Le lait maternel fortifie accelere la croissance et offre aussi les autres avantages du lait mater-nel. Lorsqu'on donne aux nouveau-nes suffisamment de lait maternise pour prematures, le lait fournit unapport de nutriments qui reproduit chez les nouveau-n6s la croissance intra-uterine sans causer d'effortmetabolique inutile.

Recommandations: L'alimentation privilegi6e chez les nouveau-nes prematures est le lait fortifie de lamere du nouveau-ne ou, comme solution de rechange, le lait maternise pour prematures. Cette recomi-mandation vaut pour les nouveau-nes dont le poids la naissance varie d'au moins 500 g jusqu"a 1 8002 000 g, ou dont 1Sage de la grossesse 'a la naissance varie d'au moins 24 semaines a au plus 34 'a 38 se-maines (jusqu"a ce que le nouveau-ne puisse teter efficacement).

Validation: Ces lignes directrices sont conformes mais non identiques aux lignes directrices etablies recem-ment par le Committee on Nutrition de l'American Academy of Pediatrics et par le Committee on Nutri-tion of the Preterm Infant de la European Society of Paediatric Gastroenterology and Nutrition.

Commanditaire: La preparation de ces lignes directrices a et commanditee et financee par la Societecanadienne de pediatrie.

S ince the Canadian Paediatric Society (CPS) pub-lished recommendations concerning the feeding of

premature infants in 1981,' there have been enormousadvances in the type and quality of clinical care offeredto infants born prematurely. It is therefore appropriate torevise the recommendations concerning nutrition forpreterm infants. A subcommittee of the Nutrition Com-mittee of the CPS was formed to review the recent liter-ature on nutrient metabolism and feeding of prematureinfants and to make new nutrition recommendations.The subcommittee included neonatologists, clinical nu-tritionists and dietitians.

METHODS

For most nutrients it was impossible to derive recom-mendations through the use of established researchmethods for defining nutrient requirements (i.e., factor-ial analyses, information on nutrient balances, controlledstudies and epidemiologic data) because the data simplydo not exist. For term infants, mother's milk is the "goldstandard" for nutrient requirements. However, it is not

the reference standard for nutrients for premature infantsbecause of the risk of inadequate growth and nutrientdeficiencies when mother's milk is used without fortifica-tion. The committee therefore had to find a differentmethod to establish nutrition recommendations. Specificoutcome goals were predetermined on the basis of theinfant's birth weight and age after birth. Two birth-weight categories (below 1000 g and 1000 g or more)and three age categories (birth to 7 days, or the "transi-tion" period; stabilization to discharge from the neonatalintensive care unit (NICU), or the "stable-growing" pe-riod; and 1 year following discharge from the NICU, orthe "postdischarge" period) were defined. The birth-weight categories reflect the difference in accretion ofnutrients before birth, and the postnatal periods reflectthe changing growth and nutrient metabolism that ac-company postnatal maturation.

During the transition period, infants (particularlythose with a birth weight below 1000 g) are likely to beclinically and metabolically unstable and to lose weight,primarily as a result of shifts in water balance and rela-tive starvation. The minimum achievable goal during

1766 CAN MED ASSOC J * ler JUIN 1995; 152 (1 1)

this period is the provision of sufficient nutrients, par-enterally or enterally (by tube through the gastrointesti-nal tract), to prevent nutrient deficiencies and substratecatabolism. If the infant is stable, higher intakes can beprovided during the later part of the transition period.The stable-growing period begins when the infant ismetabolically and clinically stable and ends when the in-fant is discharged from the NICU. During this periodthe primary nutritional goal is growth and nutrient-retention rates similar to those that would have beenachieved in utero. According to Lubchenco and associ-ates,2 between 24 and 36 weeks of gestation, a fetus whogrows at a rate at the 50th percentile gains 14.5 g/kg perday. This means that a 1 kg infant needs to gain 14.5 gper day to grow as if in utero. An infant growing at a rateat the 90th percentile grows 12.2 g/kg per day; for an in-fant at the 1Oth percentile, the rate of weight gain is15.6 g/kg per day. During the postdischarge period thegoal is a nutrient intake that is adequate to achievecatch-up growth. Establishing recommendations for thisperiod was hampered by a marked lack of research.

The nutrient intake needed to achieve these outcomegoals is called the "preterm recommended nutrient intake"(P-RNI). If there was inadequate information available toestablish a P-RNI, a 'best estimate for safety and efficacy"was made. These estimates were based on the estimatednutrient intake from preterm-mother's milk (milk pro-duced by the mother of a preterm infant for her own in-fant, as distinguished from banked human milk) fed to theinfant at recommended volumes and on available clinicalstudies of efficacy. On the basis of the P-RNI for each nu-trient, the adequacy of preterm-mother's milk and of for-mula designed for premature infants was determined.

Few studies have examined the long-term outcomesamong infants fed with different nutrient sources or fedvia different routes. Therefore, estimates of need werebased mainly on short-term outcomes. The evidence in-cluded much more information on low-birth-weight(greater than 1000 g) infants than on those with ex-tremely low birth weights (less than 750 g). Thus, formany nutrients, estimates of the intake required by infantswith extremely low birth weights were extrapolated fromdata involving larger premature infants. Therefore, recom-mendations for these infants are more tentative than thosefor larger infants. As more data on infants with extremelylow birth weights are collected, the strength of future rec-ommendations for nutrient intake will likely improve.

Tthe first section of this article provides a brief discus-sion of the importance of each nutrient, followed byspecific recommendations for achieving an adequate in-take from preterm-mother's milk, formula and parenteralnutrition. The second section provides the options forfeeding preterm infants.

These guidelines are intended to assist health care

professionals in making informed decisions about infantfoods and feeding, to provide background informationfor regulation of infant foods, and to stimulate the in-fant-food industry to continue to manufacture productsthat meet the needs of premature infants. Wheneverpossible, the evidence supporting recommendations wasweighed in favour of randomized controlled trials. Ifsuch trials were unavailable, cohort studies were consid-ered. If both types of study were unavailable, publisheddata were reviewed and recommendations were based onconsensus opinion. The recommendations are in linewith, but not identical to, recent guidelines from theCommittee on Nutrition of the American Academy ofPediatrics and the Committee on Nutrition of thePreterm Infant of the European Society of PaediatricGastroenterology and Nutrition.34

RECOMMENDATIONSCONCERNING NUTRIENTS

P-RNIs established by the committee are given inTable 1.

WATER

Water intake must maintain normal fluid and elec-trolyte balances, through renal excretion of metabolicwastes and replacement of water lost through the skinand the respiratory and digestive tracts, and meet theneed for growth. Achieving these goals is complicatedby the immaturity of homeostatic mechanisms in pre-term infants, by any coexisting illnesses and by non-physiologic environmental conditions.56

During the transition period, preterm infants are clin-ically unstable, and devices or interventions that affectwater balance (e.g., warming the infant with a radiantheater) are frequently used. Therefore, water require-ments must be determined for each infant, and a stan-dard recommendation cannot be made. In the results oftwo randomized clinical trials, high-volume water intakewas associated with an increased risk of patent ductus ar-teriosus.7'8 However, intake must be sufficient to preventdehydration. Careful monitoring of water intake andoutput as well as at least one daily weight measurementand electrolyte assessment are needed. During the sta-ble-growing period, we recommend intake within arange (see Table 1) because of the wide variation in wa-ter needs for infants of different gestational and postna-tal ages and of varying clinical circumstances. The rangeis based on the assumptions that the infant is stable, notexposed to a radiant heater, heat shield or cellophanewrap and is not given phototherapy. Infants who aresmall for their gestational age lose less water through theskin than infants who are an appropriate size for their

CAN MED ASSOC J o JUNE 1, 1995; 152 (11) 1767

gestational age. Therefore, the former group may havelower water needs. Although feeding an infant in thisperiod 120 mlikg per day of preterm-mother's milk orformula may meet fluid needs, it is too low a volume tomeet P-RNIs for some nutrients (Table 2). During thepostdischarge period, water needs are assumed to beequivalent to those for term infants (Table 1).

EN[ERGY

Growth is very rapid during the third trimester of ges-tation, and total energy needs are very high. Infants inutero gain 12 to 16 g/kg per day.2 Energy expenditure dur-ing this period varies widely, depending on conditionsand diseases affecting the infant.' Energy expenditure by

rFable 1: Recommended nutrient intakes for premature infants (P-RNk

1768 CAN MED ASSOC J * ler JUIN 1995; 152 (11)

infants can be divided into four categories: the restingmetabolic rate (196 to 217 kJ/kg [47 to 52 kcal/kg] perday); the rate during activity (13 to 17 kJ/kg [3 to 4kcal/kg] per day); the loss of energy through excretion (46to 74 kJ/kg [i 1 to 18 kcal/kg] per day); and the energycost of weight gain (13 to 17 kJ [3 to 4 kcal] per gram ofweight gained).'9 Therefore, required energy intake varies

widely depending on the goal for weight gain; it is be-tween 209 and 250 kJ/kg (50 to 60 kcal/kg) per day for aninfant fed parenterally who is not growing and is in a ther-moneutral environment; however, it is 542 to 584 kJ/kg(130 to 140 kcal/kg) per day for an infant growing at a'catch-up" rate (faster than an intrauterine growth rate).Infants fed parenterally have lower total energy needs

Table 1 continued

Period after birth; P-RN per day

Transition (birthto 7 days)

Stable-growing(stabilization todischarge from

NICU*)

Postdischarge(1 year followingdischarge from

NICU)

Volume of preterm-mother's milk neededto meet P-RN during

stable-growi ngperiod, mLUkg per day

Zinc, pmol/kgCopper,t pmol/kg

Selenium,t pmol/kg

Chromium,t nmol/kg

Manganese,tjl nmol/kgMolybdenum,t nmol/kg

lodine,t pmol/kg

Vitamins

Vitamin D, IU

Vitamin A, pg/kg

Vitamin E, mg/kg

Vitamin C, mg/kg

Vitamin Bi, mg/kg

Vitamin B2, mg/kg

Vitamin B6, mg/g of protein

Vitamin B,, pg

Niacin, NEtt/5000 kJ

FoIate, pg

Biotin, pg/kg

Pantothenic acid, mg/kg

6.5

1.1-1.9

0.04-0.06

1.0-1.9

10-20

2.0-4.0

0.20

40-120(birth weight< 1000 g)40-260

(birth weight> 1000 g)

450

0.5-0.9

6-10

0.04-0.05

0.36-0.46

0.15

8.6

50

1.5

0.8-1.3

7.7-12.3

1.1-1.9**

0.04-0.06

1.0-1.9

10-20

2.0-4.0

0.25-0.50

400(800 for

certain infants;see text)

450(birth weight< 1000 g)200-450

(birth weight> 1000 g;

lower intake forlarger infants)

0.5-0.9

6-10

0.04-0.05

0.36-0.46

0.015

0.15

8.6

50

1.5

0.8-1.3

15.0 (estimate)

1.1-1.9**

0.04-0.06

1.0-1.9

10-20

2.0-4.0

0.25-0.50

400

400 pg

0.5**

20 mg

0.05

0.05

0.015

0.15

8.6

25

1.5

0.8-1.3

120-190

115-200

120-200

120-200

120-200

120-200

190-375

NA

NA

120-200

120-200

120-200

NA

120-200

120-200

120-200

NA

120-200

120-200

May be omitted from parenteral nutrition during the transition period.**For infants fed formula, this amount may differ; see discussion in text.ttNE = niacin equivalents.

CAN MED ASSOC J * JUNE 1, 1995; 152 (11) 1769

N utrient

I

labIe 2: intake frvom preterm-rnotht.r me)ilk (f 320 20(: mL/fkg per day) alone, and in combination with comnmerr:il fortifierS

1770 CAN MED ASSOC J * le, JUIN 1995; 152 (11)

than those fed enterally because of lower energy losses instools and, possibly, more efficient use of energy.20

During the transition period, weight gain is unlikely.Infants lose up to 15% of body weight during this pe-riod. The "maintenance" energy intake is 209 to 250kJ/kg (50 to 60 kcal/kg) per day if the infant is totallyparenterally fed and higher if the infant is fed enterally(Table 1). If the infant is metabolically stable, an energyintake higher than the P-RNI may be achieved. Duringthe stable-growing period, weight gain at the intrauter-ine rate of 12 to 16 g/kg per day can be reasonably ex-pected with the recommended energy intake.2 Since themean gross (metabolizable) energy content of preterm-mother's milk is about 3046 kJ/L (750 kcal/L) after thesecond week of life 9,21 an intake of 145 to 185 mlikg perday is needed. If the infant is fed parenterally, energyneeds are 334 to 459 kJ/kg (80 to 110 kcallkg) per day.2O

During the postdischarge period, growth rates equiv-alent to those of term infants or greater can be achievedwith the recommended energy intakes, unless the infanthas unusually high continuing energy needs as a result ofan illness such as chronic lung disease of infancy.22

PROTEIN

Preterm infants grow at similar rates despite varyingprotein intake, as long as energy intake does not limitgrowth.2023 However, premature infants are metabolicallyimmature; therefore, protein turnover is high24 and theendogenous synthesis of certain amino acids is delayedduring the first months of life.'9'7 This metabolic imma-turity affects the quantity of protein as well as the bal-ance of amino acids required by infants. A goal in pro-viding protein is optimal nitrogen retention, oftendefined as equivalent to the intrauterine protein gain of anormal fetus without metabolic stress, such as uremia ordistorted blood amino-acid patterns."3'28 Recently, how-ever, it has been suggested that optimal neurodevelop-mental outcome may be an equally important goal.29

During the transition period, protein (amino-acid) in-take should be sufficient to prevent breakdown of en-dogenous tissue; that is, approximately 1.5 g/kg per day.24If the infant is stable during the latter part of the transi-tion period, higher amounts of protein (amino acids) maybe given with safety. During the stable-growing period,the goal is to provide the protein intake needed toachieve intrauterine accretion. In infants with a birthweight lower than 1000 g, this goal can be achieved withthe P-RNI, as long as the energy intake is adequate. In in-fants fed parenterally, a range of 2.7 to 3.5 g/kg per day isrecommended. Preterm-mother's milk has a mean proteinconcentration of 16 to 18 g/L;9'2' hence, the average in-take volumes of milk may not meet the goals for proteinintake.26,30 A protein supplement to augment preterm-

mother's milk is therefore recommended (Table 2).The recommended postdischarge protein intake is

based on the Canadian RNI for term newborns. For prema-ture infants who are growing rapidly during this period,higher intakes are acceptable to achieve catch-up growth.,,

Clinical trials have not proved that taurine is an essen-tial component of nutrition for newborns; however, tau-rine is found in high concentrations in human milk. Allformulas based on cow's milk are currently supplementedwith taurine. Such supplementation should not exceedthe taurine content of human milk (0.25 to 0.75 mmol/L).

The use of formulas containing nucleotide supple-ments has not been shown to improve resistance againstinfections in premature infants;32 therefore, addition ofnucleotides to formulas for premature infants is not rec-ommended.

FAT

Fat, is the major source of dietary energy for prema-ture infants, and it constitutes 40% to 60% of the energyin human milk and infant formulas. Oxidation of fat pro-vides energy to support basal metabolic functions and tomeet the energy costs of tissue synthesis. The amount offat required by premature infants is determined by theenergy requirement, the limits to the amounts of proteinand carbohydrates that can be fed to the infant, and thevolume of food the infant can eat.33 Essential fatty acidsw6 and w3 are needed for cell-membrane function,eicosanoid metabolism and central-nervous-system de-velopment.34 Hence, the recommended fat requirementsare based on the amount needed to ensure adequate en-ergy intake for appropriate growth and the amount ofw3 and w6 essential fatty acids needed for optimal tissuefatty-acid composition and function.

During the transition period, providing a source of fatthat includes the essential fatty acids is critical. Biochemi-cal indices of essential-fatty-acid deficiency are commonin premature infants 2 to 3 days old with birth weights ofless than 1250 g.3 35 During the stable-growing period,the recommended total fat intake is based on the fat con-tent of human milk.36 Intake of linoleic and linolenic acidsshould be the same as during the transition period. Forinfants fed parenterally, fat intake may comprise 20% to45% of the total energy intake. Little is known about thefat needs of preterm infants during the postdischarge pe-riod. Therefore, the recommendation is identical to thatduring the stable-growing period.

Lipid composition

Long-chain fatty acids

There is no definitive information that arachidonic acid

CAN MED ASSOC J * JUNE 1, 1995; 152 (11) 1771

(20:4w6) and docosahexaenoic acid (22:6w3) are essentialdietary nutrients at any period of development. However,an exogenous source of these fatty acids, constituting0.25% of total energy intake, is likely needed. Althoughseveral sources of these fatty acids (such as fish oils) maybe available, their long-term safety and efficacy in infantnutrition has not been determined.37-3 Because suitablesources of oils have not been adequately tested and inap-propriate supplementation appears to present real risks ofdeleterious effects, we cannot make any specific recom-mendations for inclusion of these fatty acids in formulas.

Medium-chain triglycerides (MCTs)

MCTs usually constitute only 1 % to 2% of fatty acidsin human milk.36 Results of recent studies show thatgrowth is not improved with the use of MCTs and donot support its routine use in formula.40 Therefore, theamount in formula should approximate that found in hu-man milk without compromising total fat absorption ornecessitating the use of large amounts of linoleic acid.

Nutrients involved in fat metabolism

Inositol

The need to include this nutrient in parenteral or en-teral formulations cannot be confirmed. Inositol can besynthesized endogenously, and inositol deficiency inpremature infants has not been found.4

Choline

Choline can be synthesized endogenously from pro-tein and is found in mammalian milk. There is no docu-mentation of choline deficiency in premature infants;therefore, the addition of choline to formulas based oncow's milk or to human milk is unwarranted.42 Likewise,there is no documentation of the efficacy of addingcholine to formulations used for parenteral nutrition.

CARBOHYDRATE

Lactose makes up 40% to 50% of the nonprotein en-ergy in human milk. Most premature infants, even thosefed 200 mUkg per day (1 3.0 to 15.5 g of lactose/kg perday), can tolerate the high intake of lactose from humanmilk.43 A total carbohydrate intake higher than 15.5 g/kgper day may be acceptable for infants whose weight gainis poor. Many formulas for preterm infants now includeglucose polymers as their primary source of carbohy-drate. The activity of cx-glucosidases in the fetus reachesat least 70% of the activity in adults at a gestational ageof about 26 to 34 weeks, whereas lactase activity at that

gestational age is only 30% of adult activity."45 Salivaryand mammary amylases, along with small-intestinal glu-coamylase, partly compensate for the relative deficiencyof pancreatic amylase, thereby allowing premature in-fants to digest a-glucosides better than lactose.44,45 Al-though, theoretically, lactose digestion should be lim-ited, there is no evidence of clinical intolerance amongthese infants.4647 However, there are other reasons foradding glucose polymers to formulas: they may result infaster gastric emptying, and they may increase caloricdensity without a corresponding rise in osmolality.

Hence, despite these theoretic considerations, thereis no proof that lactose should be replaced by glucosepolymers in formulas for preterm infants to improve car-bohydrate absorption. Nevertheless, to ensure that theosmolality of formula is close to that of human milk,some lactose may need to be replaced by glucose poly-mers in formulas with high energy and mineral content.

During the transition period, the serum glucose con-centration in infants should be carefully monitored. In-fants who are small for their gestational age or whoweigh less than 1000 g are particularly vulnerable to hy-poglycemia and hyperglycemia during the first days oflife. In parenteral nutrition, carbohydrate (as glucose)should be supplied at a rate that allows the infant toremain euglycemic (Table 1 ).48 49 The use of lactose-containing milks should not be restricted during this pe-riod. During the stable-growing period, carbohydrate in-take should be 35% to 50% of total energy intake. Therecommended carbohydrate intake is based on the lac-tose content of human milk. Carbohydrate may be givenin the form of lactose, glucose polymers or both. For in-fants fed parenterally, glucose should comprise 50% to60% of total energy intake. The recommendation for car-bohydrate intake during the postdischarge period is iden-tical to that during the stable-growing period.

RECOMMEN DAriONS CONCERN ING MINERALS

Calcium and phosphorus

Neither preterm-mother's milk alone nor standard for-mulas provide sufficient calcium and phosphorus to meetthe predicted needs of growing premature infants.5o5 Theuse of prolonged total parenteral nutrition, preterm-mother's milk or standard formula has been associatedwith low serum and urine levels of phosphorus, hypercal-ciuria152 elevated levels of alkaline phosphatase53 and1,25-dihydroxyvitamin D3,54 low content of radial-boneminerals (compared with intrauterine standards)5556 andfractures and rickets in some infants.57 A consensus ofavailable studies of the calcium and phosphorus needs ofpremature infants is that feedings containing about 20 to30 mmol/L of calcium and 16 to 20 mmoUL of phospho-

1772 CAN MED ASSOCJ * lerJUIN 1995; 152 (11)

rus are appropriate in early neonatal life.' Caution mustbe taken if infants are fed large amounts of calcium andphosphorus in combination with loop diuretics or gluco-corticoids, both of which cause increased calciuria andincrease the risk of renal calcification.58

Some studies 59,60 but not all,566 have shown that cal-cium and phosphorus supplementation achieves postnatalbone-mineral content consistent with intrauterine accre-tion. Small increments in bone-mineral content in earlylife may be important to long-term skeletal development.62As well, some premature infants with a very low birthweight who have had long periods of fluid restriction andtherapy with calciuric drugs may benefit from receivingsupplements for 2 to 3 months to attain catch-up bonegrowth. The amount and duration of mineral supplemen-tation and the complications of prolonged infant feedingwith mineral-fortified milk require further study.

During the transition period, calcium and phosphorusintake should be adequate to achieve normal serum con-centrations of these minerals and to prevent hypercalci-uria (Table 1). If the infant is fed exclusively through totalparenteral nutrition, the upper limits of solubility withavailable salts (calcium gluconate and mixed monobasicand dibasic sodium or potassium phosphate) are 15mmol/L for both calcium and phosphorus.63 This concen-tration is only attainable when the amino-acid content ofthe parenteral formulation is 25 g/L or less; otherwise,there is a risk of calcium or phosphorus precipitation.During the stable-growing period, the goal is to achieveintrauterine calcium and phosphorus accretion and bonemineralization. Unfortunately, we cannot yet accuratelypredict intakes that will achieve normal long-term bonemineralization. For premature infants, regardless of birthweight, intrauterine bone growth may be approximatedby providing the recommended calcium and phosphorusintakes.59 The recommended molar ratio of calcium tophosphorus is 1.6 to 2.0. For infants fed preterm-mother'smilk, this intake can be achieved only through addingcalcium and phosphorus as individual salts or as a human-milk fortifier64 (Table 2). Some formulas designed forpreterm infants contain the amounts of calcium andphosphorus needed to achieve intrauterine accretion ofbone minerals; however, due to variations in absorption,adequate retention is not guaranteed in all infants. Therecommended postdischarge intake of calcium and phos-phorus is based on the current Canadian RNI for term in-fants during the first 6 months.65 Long-term studies sug-gest that the use of fortified formulas or preterm-mother'smilk is associated with improved bone-mineral con-tent,66,67 but further studies are required.

Magnesium

The magnesium requirement for premature infants is

estimated to be similar to that for term infants fed hu-man milk. Infants fed preterm-mother's milk, which con-tains 1.2 mmol/L of magnesium, fortified preterm-mother's milk, standard formula or formula for preterminfants retain magnesium at or just below the predictedintrauterine-retention rate (0.15 mmol/kg per day). 68,69High concentrations of calcium in formulas for preterminfants and fortified preterm-mother's milk may depressmagnesium absorption;j7 therefore, intakes from thesesources should contain higher amounts of magnesiumthan that found in unfortified preterm-mother's milk.

During the transition period, the infant's magnesiumintake should be adequate to maintain the normal serumconcentration of magnesium. If the infant is stable dur-ing the later part of the transition period, higher intakesmay be given with safety. During the stable-growing pe-riod, the intake needed to meet intrauterine accretion,regardless of birth weight, can be achieved with the useof preterm-mother's milk or formula." For premature-infant formulas that have a high calcium content the ra-tio of calcium to magnesium should be less than 11mmol of calcium to I mmol of magnesium in order tomaximize absorption of magnesium.70 The CanadianRNI for term infants6s is based on the content of magne-sium in human milk; this RNI is likely to be adequate forpremature infants during the postdischarge period.

Sodium, chloride and potassium

Premature infants generally require a higher sodium in-take than term infants and a higher intake than that sup-plied in human milk of mothers delivered at term (5 to 7mmoVL) or in formulas designed for term infants (8 to 9mmoVL).697172 The supply of chloride and potassium fromhuman milk, however, is generally adequate for preterminfants."

During the transition period, sodium and chlorideneeds are difficult to predict because of developmentaland clinical factors affecting homeostasis of these miner-als. The needs of each infant should be assessed to deter-mine if they are higher or lower than basal requirements,which can be met through feeding with preterm-mother's milk."'72 During the stable-growing period, hu-man milk may meet the recommended intake of sodiumand chloride if the infant is fed large volumes (185 to200 mLlkg per day).7' However, concentrations of thesenutrients in human milk decline after this period, so asupplement may be required. Serum levels of sodiumshould be monitored to determine the need for supple-mentation. Estimated potassium requirements can bemet through feeding with preterm-mother's milk, whichcontains 12.5 to 16 mmol/L of potassium. The concen-trations of sodium, chloride and potassium in formulasdesigned for premature infants may exceed the P-RNI;

CAN MED ASSOC J * JUNE 1, 1995; 152 (11) 1773

however, there are no reports of toxic effects associatedwith these levels. During the postdischarge period,sodium, chloride and potassium needs are likely similarto those of term infants.

Iron

The major reserve of iron for premature infants atbirth is the hemoglobin mass; there is little iron stored inthe liver or the spleen. Despite the low stores, iron defi-ciency is unlikely to play a role in the anemia of prema-turity during the first 2 months of life unless blood waslost during birth or as the result of phlebotomies to col-lect specimens for laboratory tests, and the lost bloodwas not replaced through an erythrocyte transfusion.7374In addition, erythrocyte synthesis is limited by very lowerythropoietic activity until 5 to 7 weeks after birth. Pro-phylactic use of iron supplements or iron-fortified for-mula during the first 2 months of life have no effect onthe fall in hemoglobin concentration during this pe-riod.7576 Once active erythropoiesis begins, however, allpremature infants require iron to maintain optimal he-moglobin production.7778

During the transition period, there is no need foriron. At the start of the stable-growing period, iron sup-plements are not recommended. However, starting 6 to8 weeks after birth, infants with birth weights of 1000 gor more should have their diet supplemented with iron(2 to 3 mg/kg per day) or be given formula containingiron (12 mg/L) to prevent iron-deficiency anemia.77 Theiron needs of infants with birth weights below 1000 gare likely greater. Therefore, for these infants, a total in-take of 3 to 4 mg/kg per day starting 6 to 8 weeks afterbirth is recommended.77 An oral iron supplement isneeded to achieve this intake. Iron supplementationshould be continued until the infant is 12 months cor-rected age (the infant's age had he or she been born atterm).78 At that time infant's hemoglobin and ferritin lev-els should be monitored to ensure adequate hematologicstatus.

RECOMMENDATIONS CONCERNING TRACE MINERALS

Nutritionally essential trace minerals include zinc,copper, selenium, chromium, manganese, molybdenumand iodine. Published reports of mineral deficienciesamong premature infants have involved only six of theseelements. However, infants born prematurely are at in-creased risk of trace-mineral deficiencies because of lowstores at birth, very rapid postnatal 'growth and variableintake.79,80 The trace-mineral content of human milk isthe gold standard for requirements for term infants, pro-vided that they ingest an adequate volume of milk.65However, for preterm infants there is no gold standard.

Instead, there are three acceptable objectives in settingintake amounts: prevention of trace-mineral deficiencies,replenishment of stores that would normally have beendeposited in the developing fetus during the last tri-mester, and the avoidance of excessive intakes, whichcould have toxic effects.

During the transition period, when the infant is likelyto be clinically unstable, intakes of trace minerals maynot be necessary, since deficiencies are unlikely to de-velop during such a short period. If trace minerals are in-cluded in the feeding regimen of infants during thisperiod, the intake should be adequate to prevent defi-ciency yet not enough to cause toxic effects. If par-enteral nutrition is given during the transition period,trace minerals, with the exception of zinc, need not beincluded. The recommended intakes for infants fed par-enterally are in keeping with the recent recommenda-tions by the Committee on Clinical Practice Issues ofthe American Society for Clinical Nutrition.63 Duringthe stable-growing period, when rapid growth resumes,trace minerals should be included in infants' diet at con-centrations that prevent deficiencies or at the higherconcentrations that also replace body stores. Higher in-takes should continue during the postdischarge periodwhen growth is rapid and the risk of trace-mineral defi-ciencies is high.

Zinc

The zinc content of human milk cannot be used as agold standard to establish dietary zinc requirements forpreterm infants. In fact, frank zinc deficiency developedin many breast-fed preterm infants.8'82 Although suchfrank deficiency is rare, many breast-fed premature in-fants may suffer from a zinc depletion without showingany signs of deficiency. Longitudinal studies of the zincstatus of premature infants during the first year of lifehave found that these infants have a hair zinc level sig-nificantly lower than that of term infants.8384 This evi-dence supports the suggestion that a zinc deficiency lim-its growth during the first year.No cases of acute zinc deficiency during the first

weeks after birth have been described. Therefore, duringthe transition period, the amount of zinc in human milkis likely adequate. For parenteral nutrition, a zinc intakeof 6.5 gmol/kg per day is recommended.85 During thestable-growing period, infants fed preterm-mother's milkhave not had a zinc deficiency. Our recommendation isbased on the zinc content of preterm-mother's milk, fedto infants in adequate amounts. Because of a postulateddepression of zinc absorption caused by other mineralsin human-milk fortifiers,59 fortified preterm-mother'smilk and high-calcium formulas should contain addi-tional zinc. During the postdischarge period, zinc intake

1774 CAN MED ASSOC J * le,JUIN 1995; 152 (11)

from human milk may be inadequate to meet the needsof a rapidly growing infant.882 An intake of 15 gimol/kgper day should meet these needs and can be achievedthrough the use of formulas designed for term orpreterm infants. Breast-fed infants would need a zinc-gluconate or zinc-sulfate supplement of 7.5 ,umol/kg perday to achieve this intake. However, the effect of zincsupplementation on breast-fed preterm infants has notbeen studied; thus, a definitive recommendation for zincsupplementation cannot be made.

Copper

Copper deficiency has been reported in preterm andterm infants fed primarily cow's milk, iron-fortified for-mula, pasteurized human milk or a total-parenteral-nutrition formulation that does not include copper.8989Deficiency has not occurred in infants fed current for-mulas or preterm-mother's milk. Although acute toxic ef-fects of copper are rare, long-term excessive intake or re-duced hepatic excretion can result in liver cirrhosis.9

During the transition period, copper intake should beequivalent to that provided by human milk. If short-termtotal parenteral nutrition is used, supplementation maynot be necessary.63 During the stable-growing and post-discharge periods, the intake of copper from human milkprevents deficiency. However, because copper absorp-tion may be depressed by the large of amounts of zinc9'found in some preterm formulas and human-milk forti-fiers, a copper intake of 1.6 to 3.2 gmol/kg per day isrecommended for infants, regardless of birth weight, fedfortified human milk or formula designed for preterm in-fants. For those fed parenterally, recommended intakesare 0.3 g.mol/kg per day.8563 Infants with cholestasisshould not receive copper parenterally, since biliary ex-cretion is the main excretory route.

Selenium

Although selenium deficiency in infants is rare, themineral is recognized as nutritionally essential.92 Infantsfed preterm-mother's milk (which contains 0.3 imol/L ofselenium), standard formula for premature infants (whichcontains 0.1 jImol/L) or formula for premature infantssupplemented with 0.4 gmol/L of selenium have beenshown to have similar erythrocyte selenium and glu-tathione-peroxidase concentrations. There is no evidenceof selenium deficiency among older preterm infants.

During the transition period, selenium intake shouldbe equivalent to that provided in human milk. Seleniummay be omitted from solutions used in total parenteralnutrition. During the stable-growing and postdischargeperiods, however, total parenteral nutrition should pro-vide 0.02 to 0.025 gmol/kg per day of selenium. Because

selenium is primarily excreted by the kidneys, theamount should be lowered if the renal output of the in-fant is decreased.63

Chromium

Chromium deficiency has been reported in threeadult patients receiving long-term total parenteral nutri-tion that did not contain chromium; however, such defi-ciency has not been reported in children.9344 Trivalentchromium has a very low order of toxic effects.95 Terminfants fed their preterm-mother's milk receive about 1.0to 1.9 nmol/kg per day of chromium.95 There is no infor-mation on the chromium content of the human milk ofmothers who have delivered preterm; however, sincepreterm infants fed their preterm-mother's milk have notdeveloped chromium deficiency, this intake is likely ade-quate. Similarly, since infants fed formula with higherconcentrations of chromium than those found in humanmilk have not suffered overt toxic effects, there is likelya wide range of safe intake.95

During the transition period, an intake equivalent to thatprovided in human milk is recommended,96 but chromiummay be omitted from solutions for total parenteral nutrition.The same amount is recommended during the stable-growing and postdischarge periods; however, total par-enteral nutrition should provide 3.8 nmol/kg per day. Be-cause chromium is excreted by the kidneys, the amountshould be lower if infants renal output is decreased.63

Manganese

Manganese deficiency in humans has not been con-clusively shown; however, the toxic effects of excessivemanganese in adults have been well described. Humanmilk contains about 0.1 gimol/L of manganese, and for-mulas contain higher concentrations. There is no evi-dence that the low intake of manganese in infants receiv-ing preterm-mother's milk is associated with deficiencyor that higher intakes in infants fed formulas are associ-ated with toxic effects.97

During the transition period, the manganese intakeshould be equivalent to that provided in human milk;manganese may be omitted from solutions for total par-enteral nutrition. This intake is also considered adequateduring the stable-growing and postdischarge periods.Total parenteral nutrition should provide 0.02 jmol/kgper day of manganese. Manganese should be omittedfrom total parenteral nutrition given to infants with hep-atic cholestasis.6398

Molybdenum

Only one case of molybdenum deficiency in an adult

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and none in infants has been reported.99 The molybdenumconcentration in the breast milk of mothers delivered atterm is about 2.0 nmol/L,' but that of mothers deliveredpreterm is unknown. During the transition period, an in-fant fed human milk receives 2.0 to 4.0 nmoVkg per day,which is also considered adequate during the stable-growing and postdischarge periods. Molybdenum supple-mentation of 2.6 nmollkg per day is recommended onlyfor infants needing long-term total parenteral nutrition.63

Iodine

In premature infants, the mechanisms that regulate io-dine levels are immature. Hence, if the infant's diet is de-ficient, the infant cannot compensate by retaining moreiodine and requires a higher iodine intake to maintain aeuthyroid state. Premature infants may experience tran-sient hypothyroidism when receiving iodine intakes of0.08 to 0.24 JmolVkg per day.'' If premature infants of agestational age of less than 34 weeks are exposed to highamounts of iodine (0.8 gmol per day or more) by cuta-neous administration of iodine solutions, a decreasedlevel of T4 (tetraiodothyronine) and an increased serumlevel of thyroid stimulating hormone may result.'02 Thecontent of iodine in human milk varies, depending on thedietary intake of the mother, between 1. 1 to 1.4 JmoVL.ILFormulas for preterm infants contain similar amounts.'03Thus, an average intake is about 0.2 jmol/kg per day.Since breast-fed infants receiving less than 0.24 imol/kgper day have a negative iodine balance'04 (assuming theydo not absorb iodine from iodine-containing skincleansers), supplementation is recommended.

During the transition period, an intake equivalent tothe amount in human milk is recommended. Iodine maybe omitted from solutions for total parenteral nutrition.During the stable-growing and postdischarge periods, ifa preterm infant is breast fed exclusively, an iodine sup-plement is needed to achieve the recommended intake.Neither breast-milk fortifiers nor commercially availablemineral-and-vitamin supplements contain iodine. Mostinfants receiving total parenteral nutrition are cleanedwith iodine-containing disinfectants or detergents, andone may assume that a significant amount of iodine isabsorbed through the skin. On the basis of this assump-tion, the recommended parenteral intake of iodine is 8nmol/kg per day.

RECOMMENDATIONS CONCERNING VITAMINS

Fat-soluble vitamins

Vitamin D

The main factor affecting the need for vitamin D in

early life is the infant's vitamin-D status at birth, which isrelated to maternal intake of vitamin D during preg-nancy. Human milk contains only small concentrationsof vitamin D (10 to 80 IUL), whereas the vitamin-D re-quirement of premature infants has been estimated at be-tween 400 and 5000 IU per day.'05-o07 Estimates vary sowidely because, in the populations studied, the vitamin-D status of mothers, and thus of infants at birth, differedgreatly. Premature infants of a gestational age of greaterthan 28 weeks appear to be able to hydroxylate vitamin-D metabolites adequately and to elicit a normal physio-logic response to hypocalcemia and hypophos-phatemial8 as well as to absorb an adequate amount offat-soluble vitamins. Little is known about the capacityof premature infants with a very low birth weight and agestational age of less than 28 weeks to absorb or hy-droxylate vitamin D.

During the transition period, the need to include vita-min D in formulations for total parenteral nutrition is un-known. Recommended total intake of the vitamin fromparenteral and enteral feeding is 40 to 120 IU per dayfor infants with a birth weight of less than 1000 g and 40to 260 IU per day for infants with a birth weight of 1000g or more.63 If the infant is stable during the latter part ofthe transition period, higher intakes of vitamin D maybe used with safety. During the stable-growing period,regardless of the infant's birth weight, a vitamin-D intakeof 400 IU per day is needed to achieve a normal serumconcentration of 25-OH vitamin D without increasingthe risk of toxic effects.06 If the infant is black or ofAsian descent or has a low plasma concentration of25-OH vitamin D (10 to 20 ng/mL), the recommendedvitamin-D intake is 800 IU per day. Formulas or human-milk fortifiers should contain 300 IU/417 kJ (300 IU/100kcal) of vitamin D to ensure that most infants receive ad-equate amounts. For small infants, vitamin D supple-ments are required to achieve these amounts. During thepostdischarge period, the vitamin-D intake recom-mended is 400 IU per day.65

Vitamin A

The retinol concentration of early milk of mothersdelivered preterm (from the 6th to the 37th day of lacta-tion) varies but is usually higher than that of mothers de-livered at term. Both retinol ester and total carotene con-centrations in human milk decrease during the course oflactation.15'"9 In addition, photodegradation of vitamin Amay occur in formula or human milk fed to infantsthrough plastic nasogastric tubes. Preterm infants havebeen shown to have low hepatic stores of retinol at birthand lower concentrations of plasma retinol and retinol-binding protein (RBP) than term newborns. Many in-fants have a plasma concentration of retinol of below

1776 CAN MED ASSOC J * ler JUIN 1995; 152 (11)

0.35 ,umol/L, which indicates a deficiency. Serum retinoland RBP concentrations are higher in infants receivingformulas designed for preterm infants than in those re-ceiving human milk; however, only infants fed formulasupplemented with 450 to 840 jig per day of retinolmaintain serum concentrations of retinol at prefeedinglevels.""' The lack of clinical and biochemical toxic ef-fects among infants given a vitamin-A supplement sug-gests that this supplement range (450 to 840 jig per day)is safe for preterm infants. Although several randomizedcontrolled studies have been conducted to determine theeffect of retinol supplementation on the incidence ofand outcomes from bronchopulmonary dysplasia (BPD),the results have been inconclusive.5,",2 Therefore, wecannot recommend giving a vitamin-A supplement to allinfants at risk of BPD.

During the transition period, infants generally receivenutrition both parenterally and enterally. The recom-mended amount of vitamin A to be included in parenteralnutrition is 500 ug/kg per day.63 No additional vitamin-Asupplements are recommended. Once parenteral nutri-tion is discontinued, and during the stable-growing pe-riod, the intake from human milk is below the estimatedintake needed to maintain normal serum concentrations.A total intake of 450 jig/kg per day is recommended forinfants with a birth weight of less than 1000 g birthweight and of 200 to 450 jig/kg per day for those with abirth weight between 1000 and 2000 g (higher amountsper kilogram should be supplied to lower-birth-weight in-fants and lower amounts to heavier infants). For infantsfed formula for preterm infants, the need for additionalvitamin A depends on the concentration of vitamin A inthe formula and the volume of formula ingested. Duringthe postdischarge period, it is recommended that infantsfed preterm-mother's milk receive a vitamin-A supple-ment until they have achieved a weight of 3.5 kg, whenthe supplement may be discontinued. Infants fed formulafor term infants at an adequate volume (150 mtlig perday or more) achieve the RNI."5

Vitamin E

Dietary vitamin-E requirements depend on the dietarycontent and interaction of vitamin E, polyunsaturatedfatty acids and iron. Vitamin E is found in low concentra-tions in the plasma and liver of infants born prematurely.' 3At least 10 trials of vitamin E supplementation have exam-ined its effects on the retinopathy of prematurity (ROP).A meta-analysis of the trials does not support supplemen-tation for the treatment or prevention of ROP.5' Althoughthere is no clear clinical benefit of vitamin-E supplementa-tion in premature infants, it seems prudent to maintainplasma vitamin-E concentrations in a range of 10 to 30mg/L, and a ratio of serum cx-tocopherol of I mg or more

to I g total lipids. Milk from mothers delivered pretermcontains greater concentrations of vitamin E (4.5 mg/L)than that from mothers delivered at term.'5 Hence,preterm infants fed their own mother's milk maintain ade-quate levels of vitamin E.'5

During the transition period, infants receive parenteralnutrition, which contains multivitamins including vitaminE; therefore, no additional vitamin E is recommended. Aparenteral intake of 2.8 mg/kg per day appears to be ade-quate.63 Once parenteral nutrition is discontinued, andduring the stable-growing period, the vitamin-E contentof adequate volumes of human milk should meet theneeds of most preterm infants with normal absorptive ca-pacity. For infants fed formula designed for preterm in-fants, the need for additional vitamin E depends on theconcentrations of polyunsaturated fatty acids and iron inthe formula. A vitamin-E intake from formula of 4 mg perday or more, with a ratio of 1.0 mg or more of vitamin Eto l g of linoleic and linolenic acids, results in normalplasma concentrations of vitamin E.

During the postdischarge period, no supplements arerecommended for breast-fed infants. Among those fedformula, the need for additional vitamin E depends onthe concentration of polyunsaturated fatty acids and ironin the formula.

Vitamin K

In 1988 the Fetus and Newborn Committee of theCanadian Paediatric Society"' recommended that allpreterm and ill infants receive a 1.0-mg intramuscular in-jection of vitamin K, within 6 hours after birth to preventhemorrhagic disease of the newborn. There is conflictingevidence concerning the efficacy of single or multipleoral doses of vitamin K in comparison with intramuscularinjection among term infants;'5,116 the effect of vitamin-Ksupplementation given orally among preterm infants hasnot been studied. In infants fed human milk exclusively,serum concentrations of phylloquinone and intake of vi-tamin K are very low;"' however, there is insufficient datato recommend supplementation in addition to the rec-ommended prophylactic dose. Infants breast fed exclu-sively after discharge who are given antibiotics for a pro-longed period or who have fat malabsorption may needvitamin-K supplements.We continue to recommend that all premature infants

receive a 1.0-mg intramuscular dose of vitamin K within6 hours of birth. For infants receiving parenteral nutri-tion, 2 to 100 jig/kg per day of vitamin K should be pro-vided until oral feeding is started.63

Water-soluble vitamins

There is little information available from well-

CAN MED ASSOC J * JUNE 1, 1995; 152 (11) 1777

designed clinical trials to support specific recommenda-tions for intakes of most water-soluble vitamins. There-fore, most of the current recommendations are based onobserved biochemical responses to variations in enteralor parenteral intake.,','-, To the best of current knowl-edge, these estimates are safe. Further research is neededto determine the optimal vitamin intakes.

For infants fed parenterally during the transition andstable-growing periods, we agree with the 1988 guide-lines of the Subcommittee on Pediatric Parenteral Nutri-ent Requirements of the American Society for ClinicalNutrition for the use of vitamins in total parenteral nutri-tion given to infants, including premature infants.63 Forinfants fed enterally, the P-RNIs for water-soluble vita-mins, the volumes of preterm-mother's milk and formularequired to meet these P-RNI during the stable-growingperiod and the recommended supplemental intakes areprovided in Tables 1 to 3.

FEEDING THE INFANT BORN PREMATURELY

The CPS Nutrition Committee recommends fortifiedpreterm-mother's milk or, alternatively, formula designedfor preterm infants as the feeding of choice for prematureinfants with a birth weight of less than 1800 g and possi-bly up to 2000 g or a gestational age of less than 34weeks and possibly up to 38 weeks (at this age the infantis often able to nurse effectively). The benefits of fortifiedpreterm-mother's milk and the need for a formula forpreterm infants become less apparent as the infant ap-proaches the weight and gestational age of a term infant,although an exact weight or gestational-age cut-off can-not be clearly defined. An exception should be made tothe recommendation for larger premature infants whosefluid intake is restricted or who grow poorly when fedunfortified preterm-mother's milk. For infants with a birthweight less than 1800 g, preterm-mothers milk, if avail-able, may be used without fortification until full feedinghas been established during the stable-growing period, atwhich point preterm-mother's milk should be fortifiedwith an additional source of nutrients. If preterm-mother'smilk is unavailable, formula for preterm infants is recom-mended from the beginning of enteral feeding.

PRETERM-MOTHER'S MILK

The use of human milk as a sole source of nutrientsfor preterm infants has been the subject of controversyand debate during recent years.'39 Early preterm-mother'smilk (from the first production of colostrum to 4 weeksafter birth) is more dense in nutrients than milk frommothers delivered at term and thus comes closer to pro-viding the nutrient requirements of preterm infants. Thisobservation supports the position that such milk should

be considered optimal primary nutrition for preterm in-fants. In addition to the nutritional properties of humanmilk, breast-feeding has psychologic benefits for themother and anti-infective benefits for the infant. Infantsfed their own mother's milk have a lower risk of necro-tizing enterocolitis,40 and even short-term use ofpreterm-mother's milk may be associated with long-termadvantages for intellectual development.29 41

However, preterm-mother's milk is not completely ade-quate as a sole source of nutrients, particularly protein,minerals and some vitamins, or to duplicate intrauterinegrowth (Table 2).'42 The use of human-milk "fortifiers" con-taining protein, minerals and vitamins ensures that infantsfed their preterm-mother's milk receive a nutrient intakethat meets estimated needs. Powdered or liquid fortifiersmay be added to preterm-mother's milk that is expressedand fed to the infant by tube or bottle. Since liquid hu-man-milk fortifiers, used in a 50:50 ratio with human milk,contribute a significant proportion of the infant's fluid in-take, they are designed to contain adequate quantities ofall essential nutrients. However, mixing preterm-mother'smilk with an equal volume of liquid fortifier dilutes theconstituents of the human milk, including the nutrients,growth factors and anti-infective properties.'43 Powderedfortifiers allow the feeding of undiluted preterm-mother'smilk. Like any powdered-milk product, powdered fortifiersare not guaranteed microbiologically sterile, '"4' althoughtheir use is not associated with increased rates of neonatalinfection. Because powdered fortifier is added to undilutedmilk, some nutrients (particularly protein and calcium)may be oversupplied, depending on the content of thesenutrients in the milk. In addition, because available pow-dered fortifiers may be insoluble in human milk, unless thefortifier-milk mixture is well shaken, the nutrients may notbe available for absorption.

There is limited evidence to support nutrient fortifica-tion of preterm-mother's milk.5369,4' However, for somenutrients the evidence shows that a deficiency may de-velop if premature infants are fed preterm-mother's milkalone and that their status improves if they are fed forti-fied milk. Therefore, fortification with these nutrientstotal energy, protein, calcium, phosphorus, sodium, vita-mins (riboflavin, vitamins A and D) and iron (during thepostdischarge period)- is definitely indicated (Table 2).For zinc, folate, iodine and magnesium, theoretic calcula-tions support the need for fortification; however, there isno evidence of nutrient deficiencies or responses to fortifi-cation. Therefore, fortification with these nutrients is onlyprovisionally recommended (Table 2). Supplementationmay also be indicated if elements contained in a human-milk fortifier reduce the bioavailability of another nutrient(e.g., zinc, magnesium and 'manganese) or increase the re-quirement for a metabolic cofactor (e.g., for vitamin B6 ina protein supplement).

1778 CAN MED ASSOC J * ler JUIN 1995; 152 (11)

Table 3: Intake volumes of formulas designed for preterm infants needed to meet P-RNIsduring the stable-growing period (see Table 1)

Formula; intake volume needed to meet P-RNI, mL/kg per dayexcept where indicated

Nutrient Similac Special Care*t EPF-Plus*t SMA Preemie*

Water 120-200 120-200 120-200

Macronutrients

Energy 130-167 130-167 130-167

Protein 160-182 145-167 175-200

Carbohydrate 110-180 109-178 110-180

Minerals

Calcium 122-182 122-182 214-3201F

Phosphorus 108-164 117-178 194-2951!

Magnesium 50-10091 81-16251 70-140$

Sodium 164-2631 180-287P 180-2871

Chloride 137-218i 129-206w! 167-2681Potassium 98-13711 122-170 130-182

Iron 750011 75001I 7500'

Zinc 42-671T 63-10091 63-1001T

Copper 34-60'1 73-125$ 100-1701T

Selenium 207-4141: NA** NA

Chromium NA NA NA

Manganese 4-3891 8-759 4-38

Molybdenum NA NA NA

Iodine 205-41011 500-10001i 360-7201!

Vitamins

Vitamin D, mL/d 800 725 833

Vitamin A 4801 42711 6251'

Vitamin E, mL/d 83-1 1 79 68-959 167-2331T

Vitamin C, mL/d 259 2591 10791

Vitamin B 20-259 20-259 50-6391

Vitamin B, 72-929 72-921T 277-35411

Vitamin B. 25-3091 25-309 100-12091

Vitamin B,, mL/d 3391 33T 751

Niacin 19-249 19-24T 120-154

Folate 167 167 500Gb

Biotin 591 509 839

Pantothenic acid 160-20711 160-20711 665-8601*Energy concentration of all formulas is assumed to be 3380 kJ/LLtAbbott Laboratories, Montreal.PMead Johnson, Ottawa.Wyeth-Ayerst, North York, Ont.This volume is above the recommended fluid intake (120 to 200 mLikg per day).liThis volume is below the recommended fluid intake (120 to 200 ml/kg per day).'-Not available.

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Although the long-term effects of fortification of hu-man milk have yet to be evaluated, randomized trialshave shown that infants given fortification have fasterrates of growth than those receiving unfortified preterm-mother's milk.6,69,47148 This increased growth rate maylead to shorter hospital stays, with economic and psy-chologic benefits for the hospital and the parents.

During the transition period, when growth is variableand infants are metabolically unstable, all infants, regard-less of birth weight, should receive a combination ofparenteral and enteral nutrition. Expressed preterm-mother's milk, without fortification, is the first choicefor enteral feeding during this period. During thestable-growing period, for all preterm infants regardlessof birth weight, feeding exclusively with preterm-mother's milk does not meet the P-RNIs. Supplements ofenergy, protein, calcium, phosphorus, sodium, vitaminsA and D and riboflavin are needed to achieve these rec-ommended intakes (Table 2). Supplementation with vi-tamin B6, folate, zinc, magnesium and iodine are provi-sionally indicated. In addition, an iron supplement isrecommended after 2 months. When an infant is able tonurse effectively (at a postnatal age of 34 to 38 weeksand a weight of 1800 to 2000 g), fortification may bestopped.

There are few data on the growth and developmentof premature infants breast-fed milk exclusively duringthe postdischarge period. Infants with illnesses and con-ditions requiring complicated and medical care are likelyto require more nutrients.3 This group may benefit fromprolonged feeding with human milk, accompanied byspecific nutrient supplements. Until further data areavailable, however, exclusive breast-feeding is recom-mended until the infant reaches 4 to 6 months correctedage, when solid food should be introduced. Iron supple-ments should be given beginning at 2 months andshould be continued throughout the first year of life(Table 1). Growth and development must be monitoredclosely. Although the effectiveness and timing of bio-chemical and hematologic monitoring has not been es-tablished, blood tests should be carried out at 4 to 5months corrected age to ensure that the infant does nothave a zinc deficiency, iron-deficiency anemia or earlyrickets.

FORMULA

There are many circumstances in which feeding aninfant preterm-mother's milk is impossible, and cow's-milk-based formulas for preterm infants should be used.When fed to infants in adequate volumes, these formulasprovide an intake of nutrients that promotes the duplica-tion of intrauterine growth without undue metabolicstress.7" 49'50 However, although growth rates may be

similar to estimates of intrauterine growth, the composi-tion of the new tissue may not be identical to intrauter-ine tissue composition. Formulas do not contain any ofthe biologically active immune substances, nor some ofthe enzymes, hormones or growth factors, found in hu-man milk. The long-term significance of the lack ofthese components has not been determined; however,recent studies suggest that mental and motor develop-ment are affected by the type of early feeding pro-vided.8, 41

Premature formulas available in Canada have energyconcentrations of 2796 or 3380 kJ/L, and the nutrientcomposition of each formula is slightly different, reflect-ing the uncertainty about premature infants' needs fornutrients, specifically protein-energy ratio, fat blend andamounts of calcium and phosphorus. In general, the for-mulas provide inadequate amounts of sodium, chloride,iodine and vitamins A and D, and excessive concentra-tions of trace minerals and water-soluble vitamins (Table3). Other types of specialized infant formulas, includingsoy-based, protein-hydrolysate, lactose-free, low-soluteand hypercaloric formulas,'5' were designed for term in-fants and should be used only for limited periods, if atall, to feed premature infants.

During the transition period, if preterm-mother's milkis not available, formula for preterm infants should beused; it may be used without supplementation. Manyclinicians advocate a gradual increase in the concentra-tion of energy in the formula to facilitate gastrointestinaltolerance; however, the benefit of this practice is un-proven."52'53 During the stable-growing period, ifpreterm-mother's milk is unavailable, formula for preterminfants is recommended. To meet the P-RNIs, the con-centration of energy in the formula should be 3380 kJ/L,and supplements of sodium and chloride, vitamins A andD and iodine may be needed. Formula for preterm in-fants is usually given until infants have attained a weightof 1800 to 2000 g, which corresponds to the usual timeof discharge from the NICU.'54'56 Preliminary evidenceshows that premature infants, especially those with abirth weight of less than 1000 g, who have illnesses orconditions necessitating complicated and medical caremay benefit from prolonged feeding with formulas witha higher nutrient concentration during the postdischargeperiod.3'.67 This applies as well to infants who remainbelow the 3rd percentile for growth or who have ill-nesses such as bronchopulmonary dysplasia. There havebeen few studies of the adequacy of standard formula de-signed for term infants in meeting vitamin, mineral andtrace-element needs of premature infants, and more re-search in this area is required. However, until moreevidence is available, we recommend the use of iron-fortified formulas designed for term infants beginning atdischarge until 12 months corrected age.

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