Archives of Disease in Childhood 1994; 70: F141-F146

A randomised multicentre study ofhuman milkversus formula and later development in preterminfants

A Lucas, R Morley, T J Cole, S M Gore

MRC Dunn NutritionUnit and UniversityDepartment ofPaediatrics,CambridgeA LucasR MorleyT J Cole

MRC BiostatisticsUnit, CambridgeS M Gore

Correspondence to:Dr A Lucas, MRC DunnNutrition Unit, DownhamsLane, Milton Road,Cambridge CB4 1XJ.

Accepted 1 October 1993

AbstractWhether breast milk influences laterneurodevelopment has been explored innon-randomised studies, potentiallyconfounded by social and demographicdifferences between feed groups. Here in astrictly randomised prospective multi-centre trial, Bayley psychomotor andmental development indices (PDI andMDI) were assessed at 18 months post-term in survivors of 502 preterm infantsassigned to receive, during their earlyweeks, mature donor breast milk or a

preterm formula. These diets were

compared as sole enteral feeds or as

supplements to the mother's expressedbreast milk. No differences in outcome at18 months were seen between the two dietgroups despite the low nutrient content ofdonor milk in relation to the pretermformula and to the estimated needs ofpreterm infants. These results contrastwith those reported from our parallel twocentre study that compared infantsrandomly assigned a standard termformula or the preterm formula duringtheir early weeks; those fed standardformula, now regarded as nutritionallyinsufficient for preterm infants, were

substantially disadvantaged in PDI andMDI at 18 months post-term. It is shownhere that infants from that study fed solelyon standard formula had significantly

Three centre study

Centres

No randomised

Neonatal diets assignedrandomly

TialA: Diets used as soleenteral feed (mother chosenot to provide her EBM)

Trial B: Diets used assupplements to mother'sEBM

Follow up periods9 Months post-term

18 Months post-term

7-5-8 years

Cambridge, Ipswich, King'sLynn

502

BBM v PTF

BBM v PTF(+EBM) (+EBM)

Pilot follow up completedDevelopmental outcome data

reported (3)Follow up completedDevelopmental outcome data

reported in this paper

Follow up complete by 1993(unpublished)

Two centre study

Norwich, Sheffield

424

TF v PTF

TF v PTF(+EBM) (+EBM)

No pilot follow up

Follow up completedDevelopmental outcome data

reported'. Data from trial Aincluded also in this paper forcomparison

Follow up complete by 1993(unpublished)

lower developmental scores at 18 monthsthan those fed on donor breast milk in thepresent study; yet the standard formulahad a higher nutrient content than thedonor milk. Thus, donor milk feeding wasassociated with advantages for laterdevelopment that may have offset anypotentially deleterious effects of its lownutrient content for preterm infants. Asthese outcome advantages were not con-founded by the social and educationalbiases usually associated with mothers'choice to breast feed, our data add signifi-cant support to the view that breast milkpromotes neurodevelopment.(Arch Dis Child 1994; 70: F141-FI46)

Recently we showed that the diet given topreterm infants for on average the first monthpostpartum had a major impact on develop-mental scores at 18 months corrected age.'That such a brief period of early dietarymanipulation had such profound effectsunderlined an unexpected sensitivity of theseinfants to their dietary management, withimportant implications for clinical practice. Inthat study, conducted in two of five centrestaking part in a larger five centre investigation2(table 1), infants were randomly assigned to a

standard 'term' formula or a nutrient enriched'preterm formula' as sole diets or supplementsto their mother's milk. Those fed the standardformula had a major disadvantage in develop-mental scores at 18 months compared withthose fed the preterm formula.

In the other three of our five centres, a

corresponding comparison was made betweeninfants randomly assigned to banked donatedbreast milk or preterm formula. We now reportthe main results on developmental outcome inthis three centre study for these babies at 18months post-term, the first formal follow upperiod.

Previous studies (see below) have indicatedthat human milk might have a favourable longterm effect on developmental status. Suchstudies, involving non-randomised compari-sons of breast milk and formula fed infants,may be highly confounded by the many socialand demographic differences reported betweenbreast compared with formula feedingmothers. We have used data from both thecurrent three centre study and our previoustwo centre study to explore this critical issuein circumstances where all the mothers hadchosen not to provide their breast milk thusavoiding the major differences normally

Table 1 Summary of the overall design of the multicentre feeding trials. Follow up periodsand summary ofpublications on developmental outcome

Randomised trial developmental outcome data for 7-5-8 years unreported, but epidemiological(non-randomised) developmental data on the first 300 children seen at 7-5-8 years wereanalysed according to whether mother provided her own expressed breast milk (EBM) or notand reported previously.'3BBM=banked (donated) breast milk; PTF=preterm formula; TF=standard term formula.

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found between breast and formula feedingmothers.

MethodsSTUDY DESIGN: AN OVERVIEWTable 1 summarises the overall design of ourparallel two and three centre randomiseddietary intervention studies, the follow upperiods, and the developmental outcome datapublished to date. The three centre studycompares children who were fed in their earlyweeks on banked (donated) breast milk versuspreterm formula as sole diets (trial A) or assupplements to mothers' expressed breast milk(trial B). The two centre study correspond-ingly compares children fed previously astandard term formula or preterm formula assole diets (trial A) or as supplements tomothers' milk (trial B).

In this paper, two aspects are included:firstly, the 18 month developmental outcomeresults for the three centre study (trials Aand B); and secondly, the non-randomisedcomparison of 18 month developmental scoresfrom babies fed solely on donor breast milk(trial A from the three centre study) with thosefed solely on term formula (trial A from thetwo centre study).

THE CURRENT STUDYA total of 502 infants weighing under 1850 g atbirth and admitted to the neonatal units inCambridge, Ipswich, and King's Lynnbetween January 1982 and April 1985, wereenrolled. Ethical approval for the study wasobtained in each centre, and parental consentalways sought; no parent refused. Only babieswith major congenital malformations known toimpair growth or development (for example,Down's syndrome) were ineligible.

Infants of mothers choosing not to expresstheir breast milk were randomly allocated topasteurised banked breast milk donated byunrelated lactating women to the milk bank ineach centre, or to a preterm formula (Farley'sOsterprem; Crookes Health Care) as theirsole diet (trial A). Those whose motherschose to provide their own breast milk wererandomly allocated to banked breast milk orpreterm formula as a supplement to mothers'milk (trial B). The intake of trial diet in trial Bdepended on the mother's success inproviding her own milk and varied from 100%down to 0%; the median intake of maternalmilk was 53% (lower and upper quartiles:17%, 91%), with no significant differencebetween babies supplemented with bankedbreast milk (median 50% or preterm formula(55%).

Trials A and B can be treated independentlyor combined to compare babies randomlyassigned banked breast milk (as sole diet orsupplement) with those fed preterm formula(as sole diet or supplement). Randomisation(designed by SMG), done in the first 48 hoursafter birth, was by use of opaque, sealed andnumbered envelopes, and was conductedindependently in each centre.1-3 Assignments

were based on permuted blocks of variablelength. Within each trial, randomisation wasstratified by birth weight (below 1200 g and1200 g or above) to increase the likelihood ofequal distribution of small, sick babies betweengroups.The banked breast milk contained a mean

protein content of 1-1 g/100 ml and a meanenergy content below 209-0 kJ (50 kcal)/100ml. The low energy content was due to the factthat donated breast milk collected in the early1980s in Britain was frequently drip breastmilk which, like foremilk, has a low fatcontent.4 5

This low energy density in the diet was off-set partly by the higher milk volume intakeof the donor milk fed group of up to 200ml/kg/day as opposed to a maximum 180ml/kg/day on the preterm formula (previouslywe reported that in the third week infants fedsolely on donor milk consumed on average15% more milk than those fed solely onpreterm formula).2 The preterm formula con-tained 2-0 g protein and 334-4 kJ (80kcal)/100 ml and, compared with donor milk(or standard formula), was also enriched insodium, calcium, phosphorus, copper, zinc,vitamins D, E, K, water soluble vitamins,camitine, and taurine. The standard termformula used in our previously reported twocentre study contained 1-45 g/100 ml proteinand 284-2 kJ (68 kcal)/100 ml.

Feeds were given by nasogastric tube. In all,90 babies required initial parenteral nutritionincluding amino acid (with or without lipid)infusion. The median number of days to fullenteral feeds in the whole study populationwas 7 (quartiles 6, 9). The trial diet was dis-continued when body weight was 2000 g or atdischarge from the unit, whichever wassooner.

Extensive demographic, social, clinical,anthropometric, and biochemical data werecollected on the infants. Social class was codedaccording to the registrar general's classifi-cation and mother's education according tocategories published previously.'Each surviving infant was invited by an

assessor blind to diet allocation (RM) forfollow up 18 months after expected date ofdelivery . A detailed history and physical exam-ination were undertaken and the Bayley scalesof infant development6 were administered toderive the mental development index (MDI)and psychomotor development index (PDI), ineach case corrected for prematurity.

Because developmental tests for children atthis age rely heavily on age appropriate finemotor skills, they are an inadequate measure ofa neurologically impaired child's cognitiveability. Children with such problems weretherefore excluded from most analyses, butincluded in a separate analysis for the mainresults to demonstrate whether their exclusioninfluenced the principal findings.

Results were analysed by Student's t test, x2test, and multiple regression. A sample size of380 was calculated at the outset as necessary todetect a 5 point difference in developmentalscores between feed groups (trials A and B

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A randomised multicentre study ofhuman milk versus formula and later development in preterm infants

Table 2 Characteristics ofsubjects followed to 18 months post-term and effect of diet on physical growth

TrialA TrialB(BBM or PTF as sole diet) (BBM or PTF as supplements) Combined trials A and B

BBM PTF BBM PTF BBM PTF

Total enrolled 83 76 170 173 253 249Deaths <18 months 7 9 13 16 20 25Follow up (% survivors) 72 (95) 64 (96) 149 (95) 153 (97) 221 (95) 217 (97)Cerebral palsy cases 4 8 13 11 17 19Boys 31 24 75 78 106 102Small for gestation (<1Oth centile) 27 22 38 52 65 74Apgar score <4 at 5 min) 2 2 4 6 6 8Social class ¢3 58 44 96 92 154 136Ventilated

>5 days 7 11 22 16 29 27>10 days 2 4 6 8 8 12

Mean (SE) gestation (weeks) 31-5 (0 4) 31-0 (0 4) 31-1 (0 2) 31-1 (0-2) 31 2 (0-2) 31-1 (0-2)Mean (SE) birth weight (g) 1414 (37) 1386 (40) 1385 (26) 1390 (24) 1394 (21) 1389 (20)Mean (SE) steady state weight gain

while on diet (g/kg/day) 12-6 (0 4) 17-2 (0 6)t 13-8 (0 3) 15-5 (0-3)t 13-4 (0 3) 16-0 (0 3)tMean (SE) head circumference gain

while on diet (mm/day) 1-28 (0 05) 1-49 (0-08)* 1-31 (0 04) 1-45 (0 05)* 1-30 (0 03) 1-46 (0 04)**Median days in study (quartiles) 31 (22, 47) 30 (20, 39) 31 (25, 50) 27 (18, 40) 31 (22, 49) 27 (18, 40)

*p=<0o03; **p=<O0O1; tp=<O0OOl. BBM=banked (donated) breast milk; PTF=preterm formula.

combined) at the 5% significance level with80% power (accounting for the larger standarddeviation of scores in infants born preterm).

ResultsMortality before 18 months was 9% (45/50 1)with no difference between feed groups (table1). The overall follow up rate in survivors was96% (438/457); the small loss of subjects wasprincipally due to emigration of families of USAir Force personnel. There were only fourrecorded refusals.

Babies fed the preterm formula gainedweight and head circumference significantlyfaster than those fed on banked breast milk,both when these diets were used alone or assupplements to maternal milk (table 2).

Table 3 MDI and PDI at 18 months by diet group. In trial A BBM or PTF was used asthe sole diet and in trial B as a supplement to mother's milk. Data are mean (SE)

DietDevelopmental Advantage for PTFtest BBM PTF (95% CI)

Trial A* n=62 n=52MDI 94-8 (2-1) 95-3 (2.7) 0-5 (-6-2 to 7-1)PDI 93-0 (1-8) 94-2 (2-2) 1-2 (-4-4 to 6 8)

Trial Bt n=134 n=139MDI 102-2 (1-7) 103-8 (1-7) 1-6 (-3-1 to 6 2)PDI 95-5 (1-3) 94-5 (1-4) -1.0 (-4-8 to 2 7)

Trials A plus B* n=196 n=191MDI 99-9 (1-3) 101-5 (1-4) 1-6 (-2-3 to 5-5)PDI 94-7 (1-1) 94-4 (1-2) -0-26 (-3-4 to 2-8)

All subjectst n=212 n=210MDI 98-6 (1-3) 100 1 (1-5) 1-5 (-2-4 to 5-4)PDI 92-2 (1-2) 90 9 (1-3) -1-25 (-4-8 to 2-3)

*Excluding cerebral palsy. tTrials A plus B including cerebral palsy. BBM=banked (donated)breast milk; PTF=preterm formula.

Table 4 Smallfor gestational age infants: MDI and PDI at 18 months by diet group. IntrialA BBM or PTF was used as the sole diet and in trial B as a supplement to mother'smilk. Data are mean (SE)

DietDevelopmental Advantage for PTFtest BBM PTF (95% CI)

All subjects* n=61 n=70MDI 98-2 (2-2) 102-4 (2 3) 4-2 (-2-1 to 10-6)PDI 93-7 (2-0) 96-7 (1-9) 3-0 (-2-5 to 8-5)

Trial A* n=23 n=19MDI 95-5 (3 2) 95-5 (4-5) 0 (-I i0 to 11 0)PDI 95-5 (2-8) 93.9 (4 3) -1-6 (-11-6 to 8 3)

Trial B n=38 n=51MDI 99-9 (3-0) 105-0 (2-5) 5-1(-2-7 to 13-0)PDI 92-6 (2-7) 97-7 (2-1) 5-1 (-1-7 to 11 9)

*Excluding cerebral palsy. BBM=banked (donated) breast milk; PTF=preterm formula.

Otherwise the infants followed up showed nosignificant differences in the clinical, social, ordemographic characteristics listed in table 2.Time spent in the study was similar in the twodiet groups.Median age at follow up was 81 weeks post-

term (quartiles: 80, 85 weeks). In 16 of the 438children followed up, the Bayley index couldnot be obtained either for medical reasons(severe deafness or blindness) or becausefollow up data were obtained by telephone forgeographical reasons.For the main trial comparisons (table 3), no

significant developmental differences betweendiet groups emerged in either trial A or B.

In babies born small for gestation (table 4),small advantages for preterm formula wereseen (5 1 points for both MDI and PDI intrial B), but these did not reach statisticalsignificance.

In our previous two centre study there was agreater effect of diet on development in boysthan girls.' Here this sex difference was lessmarked. Nevertheless, in trial A boys tendedto have higher PDI scores on the pretermformula than on banked milk: benefit 7-6points, 95°/O confidence interval (CI) -0 3 to15-5.

INTERSTUDY COMPARISONIn our previous two centre study, infants fedon a diet that did not meet the estimated nutri-ent needs for preterm infants (that is, standardterm formula), had a major deficit in develop-mental scores at 18 months corrected age,compared with those fed a specially designedpreterm formula. In this study, the surprisinglack of outcome disadvantage for donor breastmilk versus preterm formula, despite the verylow nutrient content of donor milk, raised thehypothesis that breast milk might conferadvantages for neurodevelopment that offsetpossible adverse effects of its poor nutrientcontent. To explore this further, we elected tocompare infants fed on donor milk in thisstudy with those fed a standard term formulain our previous one. In this comparison,macronutrient intakes were more similar thanthose of infants fed donor milk versus preterm

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Table 5 MDI* and PDI at 18 months in infants fed as sole diets BBM or PTF (threecentre study) compared with outcome in infants fed TF versus PTF (two centre study).Data are mean (SE)

Advantage forPTF (95% CI)

(A) All infantsMDIThree centre study BBM

n =6294-8 (2-1)

Two centre study TFn =5592-6 (2 7)

Advantage for BBM over TF (95% CI) 2-1 (-PDI

PTFn =5295-3 (2-7)PTFn =5998-6 (2-4)

-4 4 to 8-7)

Three centre study BBM PTFn=62 n=5293-0 (1-8) 94-2 (2 2)

Two centre study TF PTFn=55 n=5984-2 (2-1) 98-9 (2 2)

Advantage for BBM over TF (95% CI) 8-8 (3 3 to 14 3)§(B) Infants born smallfor gestational age

MDIThree centre study BBM PTF

_n

n =2395-5 (3-2)

Two centre study TFn =2190-1 (4-0)

Advantage for BBM over TF (95% CI) 5-4 (-PDI

n =1995-5 (4 5)PTFn =21101-6 (4-1)

-4-7 to 15 5)

Three centre study BBM PTFn=23 n=1995-5 (2 8) 93-9 (4 3)

Two centre study TF PTFn=21 n=2181-2 (3-7) 104-1 (2 3)

Advantage for BBM over TF (95% CI) 14-3** (5-2 to 23 4)

0-5 (-6-2to7-1)

6-0 (- 1-2 to 13-2)

1-2 (-4 4 to 6 8)

14-7 (8-7 to 20.7)t

0.0 (-10-7 to 10-7)

11-5** (0-1 to 229)

-1-6 (- 11-4 to 8 2)

22-9t (14-2 to 31-6)

§p<0-02, **p<001, tp<0 001. *Excluding cerebral palsy. BBM=banked (donated) breastmilk; PTF=preterm formula; TF=standard tenn formula.

formula; thus any outcome effects relating tothe unique properties of breast milk comparedto formula might emerge. Our analyses wereconfined to infants fed donor milk or termformula as sole diets (trial A) to avoid the con-founding effects of human milk usage in bothcomparison groups when donor milk orformula was used as a maternal milk supple-ment.

In table 5, infants fed banked milk versuspreterm formula as sole diets are contrastedwith those from our previous two centrestudy,' which compared term formula versuspreterm formula as sole diets. In the latter twocentre study there was a substantial (14-7point) advantage in psychomotor developmentfor preterm formula over term formula, and inthe small for gestational age subgroup theadvantages for preterm formula in MDI andPDI were 11-5 and 22-9 points. These highlysignificant differences in outcome between theterm and preterm formula fed groups contrastwith the relative lack of outcome differencesafter breast milk versus preterm formula feed-ing, as described above.

In the non-randomised comparison ofbanked milk (three centre study) and termformula (two centre study) there were signifi-cant advantages for the banked breast milk fedgroup in later motor development of 8-8 pointsoverall and of 14-4 points in the small forgestational age subgroup (table 5). The corres-ponding 2 1 and 5-4 advantages for donorbreast milk over term formula in mental devel-opment did not reach statistical significance,though detection of a 5 point difference inmental development between groups would

have required a substantially larger samplesize.

DiscussionIn a previous two centre study, we found thatpremature babies who were fed for an averageof one month on a standard term formula,showed a major reduction in developmentalattainment at 18 months post-term, comparedwith that in infants fed over the same periodon a preterm formula designed to meet thecalculated increased nutrient needs of thispopulation.' It was therefore surprising to findin the large prospective randomised studyreported here, that preterm babies fed duringtheir early weeks on unsupplemented bankdonated drip breast milk, a diet particularlylow in nutrient and energy content in relationto the needs of preterm infants, were notdisadvantaged in their Bayley developmen-tal indices at 18 months post-term whencompared with those fed the nutrient enrichedpreterm infant formula. These findings raisedthe hypothesis that breast milk might conferbenefits for later development that offset anypotentially deleterious effects of its lownutrient content. If so, these data would havepotentially important biological and clinicalimplications.

In order to test this hypothesis further, weelected to compare babies fed on bankeddonor breast milk in the current study withthose fed on a standard term formula from ourprevious two centre study. This comparisonis not a randomised one but is neverthelessjustified as the same preterm formula wasused in both studies, acting as an 'internalstandard'. The value of this comparison is thatbecause term formulas are modelled on breastmilk composition, the donor breast milk andterm formula should have relatively similarnutrient contents allowing any potentiallybeneficial non-nutrient or specific nutrienteffects unique to breast milk to emerge. Infact, the mature donated drip breast milk hadlower contents of a number of nutrients thanthose in the standard formula; for instance,protein and energy contents of the formulawere 1-45 g/100 ml and 284-2 kJ (68 kcal)/100ml compared with 1 1 g/100 ml and <209O0 kJ(50 kcal)/100 ml in the donor milk, the latterrepresenting an extreme that would now, inour view, be unacceptably low for currentpractice.7 Yet, despite this, infants fed solelyon unsupplemented donor breast milk ratherthan term formula, had significantly and sub-stantially higher psychomotor developmentalscores, with a 9 point advantage overall and a14 point advantage (nearly 1 SD) in thevulnerable subgroup of small for gestationalage infants. These data therefore support thehypothesis that breast milk promotes longterm neurodevelopment in children bornpreterm.

Furthermore the advantages we report fordonor breast milk over term formula are likelyto be an underestimate. Infants in our currentthree centre study (that include the donor milkfed group) had lower developmental scores in

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general than those in the previously reportedtwo centre study. This is apparent from theperformance of the preterm formula fed group(table 5), the internal standard for the tworandomised studies. Thus when this smallinterstudy difference is adjusted for, the overalladvantage in PDI rises to 14 (950/o CI 5 to 22)points and the trend to an advantage in MDIrises to 5 (-5 to 15) points. The more sub-stantial developmental advantages for breastmilk fed infants in the small for gestational agesubgroup reported here are, for the samereason, likely to be conservative.

During the early 1980s donated drip breastmilk was in widespread use in neonatal units inBritain. Drip breast milk, like foremilk, has avery low energy content. It is now recognisedthat such milk requires fortification withprotein, energy, and other nutrients to meetmodern recommendations for intake in pre-mature babies.7 The observation in this studythat babies fed unsupplemented banked milkfared so well developmentally could imply thatbanked milk has specific factors in it thatpromote neurodevelopment and ameliorateany detrimental effects of its low nutrient con-tent. Candidate factors in breast milk for suchan effect include long chain w-6 and w-3 fattyacids, for instance arachidonic and docosa-hexanoic acid, found in abundance in brainand retina,8 and the many hormones andgrowth factors in breast milk with hithertoundefined roles.9

In two previous publications we haveexplored the possibility that human milk couldindeed have a long term beneficial effect ondevelopment at 18 monthsl' and IQ at 7-5-8years' I in infants born preterm. In thesestudies we found that preterm infants fed ontheir own mother's milk had higher test scoresthan those who were not, even after adjustingfor a wide range of social and demographicfactors that could confound this comparison.Of critical importance, however, these previousstudies and those of other investigators26involve non-randomised comparisons betweenbreast milk and formula fed infants that may besignificantly flawed by the major sociobiologi-cal differences between these groups, notablythe higher socioeconomic status, higher educa-tional level, and more marked positive healthbehaviour in the population who choose tobreast feed. The major advantage of this studyis that these sociobiological differences do notapply here as the comparison of banked milkwith either preterm or term formula can bemade in infants whose mothers have all chosennot to provide breast milk.

In our nine month pilot follow up of thethree centre study cohort (table 1), we showedthat those fed in their early weeks on pretermformula rather than banked milk, had a signifi-cant benefit in adaptive, fine motor, languageand personal social skills, and in overall devel-opmental quotient.3 The lack of difference indevelopmental outcome between these samediet groups reported here at 18 months maywell represent recovery with time from theearly nutritional effects. We have shown pre-viously that the effects of early diet are most

seen in infants born small for gestational ageand in boys. ' 3 17 In this study there was a trendto a better outcome for motor development inboys fed preterm formula rather than bankedmilk: a difference of 8 points significant at the6% level. In small for gestational age infants,those fed preterm formula rather than donormilk also had a small, non-significantadvantage in developmental outcome. Perhapsthese results reflect a minor residual develop-mental disadvantage for donor milk at 18months in high risk groups, though it ispossible that these non-significant trends weredue to chance.

In summary, we show here that children fedunsupplemented donor milk are substantiallyadvantaged in their development at 18 monthscompared with those fed a standard termformula and were not disadvantaged comparedwith those fed a nutrient enriched pretermformula. The positive advantage we have seenpreviously' I in children who were fed their ownmother's expressed breast milk versus pretermformula, even after adjusting for social andeducational differences between groups, mightreflect residual sociobiological confounding or,alternatively, that mothers' own early pretermmilk has an even more beneficial effect ondevelopment than the donor milk we used onaccount of its higher nutrient content (forexample a mean protein and energy content of1-5 g/100 ml and 259-2 kJ (62 kcal)/100 mlcompared with 1 1 g/100 ml and 209X0 kJ(<50 kcal)/100 ml in donor milk).

Collectively, these findings suggest thathuman milk has a beneficial effect on develop-ment. However, they suggest that developmen-tal outcome benefit is also achieved by meetingthese infants special early nutrient needs, andthis is further emphasised by our previous twocentre randomised trial showing infants fed thestandard term formula performed substantiallyless well at 18 months than those fed thenutrient enriched preterm formula.Our findings have implications for the nutri-

tional care of preterm infants. If, as suggested,human milk and a nutrient enriched diet bothhave independent, perhaps additive, effects onlater development in infants born preterm, itwould be logical to combine both benefits byusing nutrient fortified human milk. Severalmultinutrient fortifiers have been designed tobe added to breast milk, and further work onthese products is warranted. Preterm formulaswill continue to have an important place wheninsufficient breast milk is available, whereasstandard term formulas neither provide theapparent benefits of breast milk nor thenutrient needs of preterm infants and areassociated with the worst developmental out-come of all the commonly available enteraldiets. This study also provides a new line ofevidence that strongly supports the moregeneral thesis that breast milk can exert afavourable effect on neurodevelopment, as ourdata are not subject to the inevitable socialand demographic biases found in mostepidemiological studies on preterm and fullterm infants that address this challengingbiological issue.

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We thank the staff of the neonatal units in Cambridge, IpswichKing's Lynn, Norwich, and Sheffield; Farley Health Products fortheir financial assistance, continuing collaboration, and supply oftrial diets; Dr Mark Gibberson, Dr Alison Hunter, and DrRosemary Edwards for their assistance with the follow up ofinfants in Sheffield; Penny Lucas for organising the neonatal datacollection and Evelyn Smith for preparation of the manuscript.

1 Lucas A, Morley R, Cole TJ, et al. Early diet in pretermbabies and developmental status at 18 months. Lancet1990; 335: 1477-81.

2 Lucas A, Gore SM, Cole TJ, et al. A multicentre trial onfeeding low birthweight infants: effects of diet on earlygrowth. Arch Dis Child 1984; 59: 722-30.

3 Lucas A, Morley R, Cole TJ, et al. Early diet in pretermbabies and developmental status in infancy. Arch Dis Child1989; 64: 1570-8.

4 Lucas A, Gibbs JH, Baum JD. The biology of drip breastmilk. Early Hum Dev 1978; 2/4: 351-61.

5 Lucas A, Gibbs JD, Baum JD. Human milk banking withdrip breast milk. In: Stern L, ed. Intensive care of the new-born II. New York: Masson, 1978: 369-79.

6 Bayley N. Bayley scales ofinfant development. New York: ThePsychological Corporation, 1969.

7 Lucas A. Feeding the preterm infant. In: Ballabriga A,Brunser 0, Dobbing J, et al, eds. Clinical nutnition of theyoung child. Vevey/New York: Nestec Ltd/Raven Press,1991: 317-36.

8 Carey EM. The biochemistry of fetal brain developmentand myelinisation. In: Jones CT, ed. The biochemical devel-opment of the fetus and neonate. New York: ElsevierBiomedical Press, 1982: 287-336.

9 Read LC. Milk growth factors. In: Cockburn F, ed.Fetal and neonatal growth. Chichester: Wiley, 1988:131-52.

10 Morley R, Cole TJ, Lucas PJ, et al. Mother's choice toprovide breast milk and developmental outcome. Arch DisChild 1988; 63: 1382-5.

11 Lucas A, Morley RM, Cole TJ, Lister G, Leeson-Payne C.Breast milk and subsequent intelligence quotient inchildren born preterm. Lancet 1992; 339: 261-4.

12 Hoefer C, Hardy MC. Later development of breast fed andartificially fed infants.3AMA 1929; 92: 615-9.

13 Rogerson BFC, Rogerson CH. Feeding in infancy and sub-sequent psychological difficulties. Jrournal of MentalScience 1939; 85: 1163-82.

14 Broad B. The effects of infant feeding on speech quality. NZMedJ7 1972; 76: 28-31.

15 Taylor B. Breast versus bottle feeding. NZ Med _7 1977; 85:235-8.

16 Rodgers B. Feeding in infancy and later ability and attain-ment: a longitudinal study. Dev Med Child Neurol 1978;20: 421-6.

17 Minowski A, Roux JM, Tordet-Caridroit C.Pathophysiologic changes in intrauterine malnutrition. In:Winick M, ed. Nutrition andfetal development. Vol 2. NewYork: Wiley, 1974: 45-55.

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