Early diet in preterm status infancy · regimens, and preterm formula composition have beenpublished elsewhere,'13 but briefly, the preterm formula contained 2 g protein, 0-335 MJ(80

Archives of Disease in Childhood, 1989, 64, 1570-1578

Early diet in preterm babies and developmentalstatus in infancyA LUCAS,* R MORLEY,* T J COLE,* S M GORE,t J A DAVIS,t M F M BAMFORD,§AND J F B DOSSETORII*MRC Dunn Nutrition Unit, and tBiostatistics Unit, Cambridge, and Departments of Paediatrics, *Universityof Cambridge, MHeath Road Hospital, Ipswich, and IlQueen Elizabeth Hospital, King's Lynn

SUMMARY Few data from randomised prospective studies address whether early diet influenceslater neurodevelopment in man. As part of a larger multicentre trial, 502 low birthweight infantswere assigned randomly, for a median of 30 days, to receive a preterm formula or unfortifieddonor breast milk as sole diets or as supplements to their mothers' expressed milk. Survivinginfants were assessed at nine months after their expected date of delivery without knowledge oftheir feeding regimen. The mean developmental quotient was 0*25 standard deviations lower inthose fed donor breast milk rather than preterm formula. In infants fed their mother's expressedmilk, however, the disadvantage of receiving banked milk compared with preterm formula as asupplement, was greater when the supplement was over half the total intake, and approached fivepoints, representing 0O5 standard deviations for developmental quotient. Infants fed donor breastmilk were at particular disadvantage following fetal growth retardation, with developmentalquotients 5.3 points lower.We suggest that the diet used for low birthweight babies over a brief, but perhaps critical,

postnatal period has developmental consequences that persist into infancy; infants who are smallfor gestational age are especially vulnerable to suboptimal postnatal nutrition.

Whether early diet influences later development is akey question in infant nutrition that has stimulatednumerous investigations in animals and man. Mostanimal studies have been in rats, whose young arevery immature at birth. In such experiments bothprenatal and early postnatal malnutrition may havesignificant neurological consequences including aserious loss of brain cells found at necropsy,l abrain-weight deficit that usually remains after nutri-tional rehabilitation,=5 and impaired performancein learning tasks and visual discrimination tests.6

In human infants who have died of severemalnutrition, the total number of brains cells hasbeen found to be reduced by 15-20%, and by 60%in those born weighing under 2000 g,7 which suggeststhat all low birthweight infants (whether or not theyare small for gestational age) are especially vulner-able to poor postnatal nutrition. Human studies onearly diet and later neurodevelopment, however,are difficult to interpret. Much work in humansconcerns the consequences of malnutrition in

developing countries, where poor diet is associatedwith medical and social problems that confound anyanalysis. Thus some workers report behavioural orintellectual benefits from dietary supplementaionfollowing malnutrition in infancy,8 9 whereas otherssuggest that stimulation was essential for thesebenefits.") Evidence indicating that early nutritionmay have lasting neurodevelopmental effects has,however, come from many other sources. Theseinclude studies on malnutrition associated withdisease (for instance, infantile hypertrophic pyloricstenosis, which has been associated with laterdeficits in attention and memory") and with theeffects of specific nutrient deficiencies (for example,iron'2).

Nevertheless it has been difficult to conductcontrolled randomised trials to test the hypothesisthat early diet is critical for later neurodevelopmentin humans. We considered that the preterm infant,born during a phase of rapid brain growth, would bean important model for such a study; currently used

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Early diet in preterm babies and developmental status in infancy 1571

diets differ greatly in composition and randomiseddietary assignment is practical. Furthermore a con-clusive outcome trial would have important implica-tions for clinical management.We have therefore conducted a prospective,

randomised five centre trial of the effect of diet onlong term neurodevelopment in infants weighingunder 1850 g at birth. The cohort will be followedinto adult life; the first formal follow up was 18months after their expected date of delivery, but inthree East Anglian centres we also examinedsurviving infants at nine months after their expecteddate of delivery. Our findings at nine months arereported here.

Patients and methods

All infants weighing less than 1850 g admitted to theneonatal units in Cambridge, Ipswich, or King'sLynn over the three year period 1982-4 wereentered into this study. Babies were excluded only ifthey had a major congenital abnormality known toimpair growth or development (for example,trisomy), or if they died before randomisation(within the first 48 hours). Approval was obtainedfor the study from the local ethics committee in eachof the trial centres. An important aspect of thisstudy is that after detailed explanation of the studyto the guardian(s), consent for the infant to takepart was never withheld, so that there was noselection bias in the cohort.

Each mother was asked whether or not she wishedto provide expressed breast milk for her infant. If amother chose not to provide her milk, the infant wasrandomly allocated either banked donor breast milkor preterm formula as the sole diet (trial 1). Infantswhose mothers elected to provide breast milk wererandomly allocated (trial 2) either banked donorbreast milk or preterm formula as a supplement tobe used when mothers were unable to providesufficient milk to meet their infants' enteral feedvolume requirements. The median intake of mater-nal milk in this 'supplement trial' was 53% of theinfants' feed volume during the study. Randomisa-tion, by permuted blocks of variable length, wasstratified by centre and birth weight; infants whosebirth weight was below 1200 g were randomisedseparately. Full details of the randomisation, feedingregimens, and preterm formula composition havebeen published elsewhere,'13 but briefly, the pretermformula contained 2 g protein, 0-335 MJ (80 kcal),35 mg phosphorus, 70 mg calcium, and 45 mgsodium 100 ml. Before the start of the study in 1982all infants in the three centres were fed on humanmilk (banked, or mothers' own, or a combination).

Extensive data were collected on obstetric, fetal,

and neonatal factors. The Registrar General's classi-fication was used to code social class'4; birth rank isthe infant's birth order in the living children of thefamily, infants from multiple births being assignedequal rank.The assigned diet was discontinued at the time of

discharge from the neonatal unit or when a weight of2000 g had been attained. After discharge from theneonatal unit mothers fed their infants as they andtheir local advisers chose.

Children were invited for follow up examinationnine months after their expected date of delivery.The median age at follow up was 40-4 weeks (lowerquartile 39-6, upper quartile 41.7). Full history andphysical examination were undertaken by RM inCambridge and King's Lynn, and by MB in Ipswich.Knobloch et al's developmental screening inven-

tory was given to each child to assess five fields ofbehaviour: adaptive, gross motor, fine motor, lan-guage, and personal-social. 15 For each field aquotient adjusting for prematurity was calculated asfollows: observed maturational age divided byattained age from expected date of delivery multi-plied by 100; an overall developmental quotient wascalculated as the mean of the five scores for eachsubject. It should be emphasised that the assessmentat this and subsequent periods was done with theassessor having no access to data on previous dietaryassignment.

In addition to developmental testing, the infantswere assessed neurologically by the same examinerwith the method described by Amiel-Tison andGrenier.'6 Infants were categorised as neurologic-ally normal, equivocal, or impaired. The tests layparticular emphasis on abnormalities in tone in thediagnosis of neurological impairment. Although 18month developmental data are not reported here,we have included the assessment of neurologicalimpairment that was made at 18 months with thesame tests.Developmental scores for neurologically impaired

infants can be a poor measure of their intellectualdevelopment, as many test items require manipula-tive skills appropriate for age. Results have there-fore been analysed separately for infants diagnosedas being impaired at nine months. Statistical analysiswas by Student's t test; results are also shown as95% confidence intervals. Tests for interaction wereperformed to determine whether the dietary effecton development differed significantly between con-trasting subgroups (for example, boys comparedwith girls, or small compared with appropriate sizefor gestational age). The significance of this inter-action was assessed by comparing the differences indietary effect between two subgroups, again byStudent's t test.



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1572 Lucas, Morley, Cole, Gore, Davis, Bamford, and Dossetor

Results

Altogether 502 infants were enrolled in this study.The mothers of 343 (68%) chose to provide theirbreast milk, those of 159 (32%) elected not to do so.Table 1 shows the mortality before nine monthsafter the expected date of delivery, and the demo-graphic and clinical details of surviving infants ineach group who were successfully followed up at thisage. Fifty nine surviving children were not seen;seven had moved overseas, nine refused follow up,and 43 were either untraced or unable to keep theirappointment (47 of these 59 were subsequently seenat 18 months, when 96% of survivors were seen).There were no significant differences between

feed groups in follow up rate, mean length ofgestation, birth weight, size for gestational age, sexdistribution, Apgar score at five minutes, theproportion of infants requiring mechanical ventila-tion for 24 hours or more. social class, mother'seducation, or the infant's birth rank (data for a

selection of these factors are shown in table 1). Themedian number of days (lower and upper quartile)to discontinuation of the assigned diet for infants feddonor milk (as sole diet or supplement) were 31 (22,49), and the corresponding values for infants fedpreterm formula were 28 (19, 40). There was nosignificant difference in the percentage of supple-ment received between infants fed formula or donormilk, 43-8% compared with 51-3%, respectively(SD 36%).The numbers of infants in each group diagnosed

as neurologically normal, equivocal, or impairedare shown in table 2. There are no significantdifferences in the incidence of neurological impair-ment.

Table 3 shows mean developmental scores for allfive fields of development and for overall develop-mental quotient in the randomised comparisons.These data do not include scores for neurologicallyimpaired infants, which are considered separately.When the two trials were combined the infants

Table 1 Comparisoni of preterm7 infants randomlY assignied to recei'e baniked breast milk or preterm formula as solediet or as supplemenits to their mnothers' milk

As sole diet

Baniked breast Preteonlmwilk fo nls7 (1

As sutpplemlentt to their mothers' milk

Ban,ked breast Pretermnmnilk fornula

No randomisedNo who died before the age of 9 months*No (%) seen nine months after the

expected date of delivervCharacteristics of infants seen at ninc months:Mean (SD) gestational age (weeks)Mean (SD) birth weight (g)No (%) weighing I dayMedian (quartiles) No of days to full feeds

837

66/76 (87)

312 (2X8)1392 (298)18 (27)24 (36)31 (47)14 (21)27 (41)6 (5.8)

769

17012

56/67 (84)

30S8 (2X8)1364 (300)17 (30)20 (36)26 (46)14 (25)27 (48)9 (6.16)

140/158 (89)

30(9 (2-7)1385 (297)36 (26)37 (26)75 (54)49 (35)51 (36)6 (5.9)

17315

138/158 (87)

30 9 (2-4)1386 (275)38 (28)49 (36)84 (61)54 (39)55 (40)8 (6.10)

*Fifteen of the 43 deaths occurred before enteral feeds had been started. ,birth weight less than 10th centile.

Table 2 Neurological status, at nine months and at 18 months after the expected date of delivery assessed withoutknowledge of the feeding regimen by the methods of Amnel-Tison and Grenier16

As sole diet As supplement to their mother's mnilk

Banked breast Pretermn Banked breast Pretermnmilk formula milk formnula

Total assessed for impairment 66 56 140 138At nine months:

Impaired 4 8 7 12Equivocal 0 1 8 3Total 4 9 15 15

Impaired at 18 months 4 7 11 10



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Table 3 Developmental scores at nine months after the expected date ofdelivery for infants born preterm who had beenrandomly assigned during the early weeks after birth to receive banked breast milk orpreterm formula as: sole diets orsupplements to mothers milk (trials 1 and 2 combined); as sole diets (trial 1); or as supplements to their mothers' milk(trial 2). Data include overall developmental quotient and scores forfive individual fields ofdevelopment, expressed asmean (SD) with 95% confidence intervals for benefit from preterm formula

Banked Preterm Difference-95%breast milk formula confidence interval

Trials 1 and 2 combined:No of infants 195 174Overall developmental quotient 97-9 (9-6) 100-4 (10-7) 0-4 to 4-6**Adaptive 101-3 (11-1) 104-0 (11-6) 0-4 to 5-1**Gross motor 99-9 (17-2) 102-3 (17-7) -1-2 to 5-9Fine motor 96-6 (12-2) 99-2 (13-5) 0-0 to 5 3*Language 93-3 (10-0) 95-6 (12-4) 0-0 to 4-6*Personal-social 98-0 (11-4) 100-6 (12-6) 0-2 to 5-1*

Trial 1-Banked milk compared with preterm formula as sole diets:No of infants 62 48Overall developmental quotient 97-2 (8-5) 98-2 (II 0) -2-7 to 4-8Adaptive 99-5 (10-2) 101-6 (10-5) -1-8 to 6-0Gross motor 98-9 (16-2) 98-7 (15.2) -6-2 to 5-6Fine motor 95-2 (11-0) 97-1 (14-5) -3-1 to 6-8Language 93-8 (11-0) 95-2 (15-0) -3-7 to 6-4Personal-social 98-5 (8.5) 98 5 (11-0) -4-7 to 4-6

Trial 2-Banked milk compared with preterm formula as supplements:No of infants 133 126Overall developmental quotient 98-2 (10.1) 101-2 (10-5) 0 5 to 5.6**Adaptive 102-1 (11-4) 105-0 (11-9) 0-0 to 5.7*Gross motor 100 4 (17.7) 103-7 (18-4) -1-2 to 7-7Fine motor 97-2 (12-8) 100-0 (13-1) -0-3 to 6-0Language 93-1 (9-6) 95 8 (11-3) 0-1 to 5.3*Personal-social 97-7 (11-6) 101-5 (12-2) 0-8 to 6.6**

Data from infants with neurological impairment are excluded here and reported separately in the text (*=p


infants. In this 'supplement trial', however, mothersprovided varying proportions of their infants' milkvolume requirements. When mothers provided mostof the infants' feed volume, the nature of therandomly assigned supplement could not be ex-pected to make a major difference to outcome. Thusany difference in outcome between donor milk andpreterm formula given as supplements to maternalmilk would be blunted. We planned in advancetherefore to analyse the results separately for infantsof mothers providing up to half of the enteralintake and those whose mothers provided more thanhalf. As expected, developmental advantages forinfants given preterm formula rather than bankedmilk were greater for those infants where thesupplement comprised more than half of their milkvolume requirement, with a 4 9 point advantage indevelopmental quotient for those receiving the for-mula rather than donor milk (101-4 (SD 10-5)compared with 96*5 (9.9), p


Size appropriate forgestational age

(n 1;33) rin 106)

I i

;irls

(rn 93) (n 77)

:95: C:z 1-6 to 4171lVentilated < 24 hours

(n --1 l 5) (n=99)

T

(95% Cl -0-8 to 4-3)

Banked Pretermbreast formulamilk

Small for gestational age

(rl 62) /n 68)

II(95% Cl 2.0 to 8-6)

Boys

(n 102) (n-97)

1 (95% Cl 0-4 to 6-1)

Ventilated B 24 hours

(n=80) (n=75)

31

(95% Cl 0-1 to 7-4)

Banked Pretermbreast formulamilk

Fig 2 Mean developmental quotient at nine months afterthe expected date ofdelivery in preterm infants randomlyassigned to receive either banked breast milk or pretermformula as sole diets or supplements to their mothers' milk.Values shown as mean (SEM) and 95% confidence intervals(CI) are given for the differences: (a) size appropriate forgestational age (left), and smallfor gestational age (right);(b) girls (left), and boys (right); and (c) ventilated


found that the diet assigned during the early weeksafter birth had a significant effect on developmentalstatus nine months after the expected date ofdelivery. Infants fed a special cows' milk basedpreterm formula, had a significantly higher overalldevelopmental quotient (when assessed by someonewho was unaware of the randomisation) than thosefed banked donor breast milk, when these dietswere used alone and in combination with mothers'expressed milk. Though preterm formula feedingwas associated with particular advantages in certainfields of development and subgroups of infants, inno specific instance was there any advantage fordonor breast milk. These data have importantbiological implications and are pertinent to the longstanding debate on whether unfortified maturehuman milk meets the nutritional requirements ofpremature babies.13The developmental screening inventory of Knob-

loch et al that was used in this study consists ofselected items from the Gesell developmentalschedules.16 When Gesell developmental quotientand Stanford-Binet intelligence quotient at schoolage are compared, the Pearson correlation coeffi-cient (r) is 0 70, rising to 0-84 after weighting forsocioeconomic state and incidence of convulsiveseizures.'6 We expect that the correlation betweenmean development quotient and later mean intelli-gence quotient in randomised groups may be evenbetter than correlations based on individuals. Thelonger term significance of our findings, however, isto be assessed at future follow up throughoutchildhood and beyond.

In trial 1, banked milk and preterm formula wereassigned randomly as sole diets; in trial 2, they weregiven as supplements to the mothers' expressedbreast milk (in volumes according to maternalsuccess in providing sufficient milk to meet theinfants' total feed volume requirement). Because inboth trials the dietary assignment was random,demographic and clinical factors other than dietwere equally represented between the two groups.Moreover, the combination of trials 1 and 2 was abalanced addition so that banked milk (as sole dietor supplement) compared with preterm formula (assole diet or supplement) was still a randomisedcomparison.We suggest that the observed significant differ-

ences in developmental scores between randomiseddiet groups are biologically important. Unlike in-telligence quotient, the overall standard deviationfor developmental quotient at nine months was only10 points. In the whole cohort the overall disadvan-tage in developmental quotient on donor milk was0-25 SD and in several major subgroups (see below)this disadvantage was 5 to 8 points (>0.5 SD).

Although other factors (such as very low gestationalage or severe respiratory disease) are associatedwith larger differences in developmental status atthis age, diet is one of the few potential influenceson development that can be manipulated in clinicalpractice.Given that donor breast milk conferred a later

developmental disadvantage overall, it was surpris-ing that no significant differences were found in thecomparison of banked donor breast milk or pretermformula as sole diets (trial 1). This was the smaller ofthe two trials, however, and the trend was generallytowards a reduced developmental quotient on donormilk. The randomised comparison between donormilk and preterm formula as supplement tomother's milk, based on a much larger sample,showed a significant developmental disadvantagefor the infants fed on donor breast milk. In infantswhose mothers provided their own milk, thedevelopmental disadvantage for those receivingdonor milk rather than preterm formula as asupplement was greater when the intake of supple-ment was more than half the feed volume require-ments. This 'dose response' association furthersupports the evidence for an early dietary effect ondevelopment.

In addition to effects of diet on overall develop-mental quotient, the randomised groups (trials 1plus 2) differed significantly in performance on fourof the five individual subscales (adaptive, finemotor, language, and personal-social skills) but notin gross motor skills. The standard deviation on thegross motor score, however, was large (table 3),suggesting that preterm infants are selectivelydamaged in this respect, and a large populationwould have been required to detect a diet relateddifference in this subscale. Nevertheless, grossmotor scores were significantly influenced by diet ininfants born with retarded growth.

Prenatal and neonatal malnutrition have eachbeen shown to be associated with a 15% reduction inthe total number of brain cells in rats; yet when'doubly deprived', with both prenatal and postnatalmalnutrition, they suffered a 60% reduction in thetotal number of brain cells by the time of weaning.'7Though such data have uncertain relevance to man,we speculate that the infants in this study who weresmall for gestational age could be regarded asdoubly deprived if, after intrauterine growth re-tardation, they were then fed an 'unfortified' dietsuch as banked breast milk (as a sole diet orsupplement to maternal milk). Our previousstudies'3 have indicated that human milk did notsupport intrauterine rates of somatic or head growthduring the neonatal period, even in infants ofnormal birth weight, and certainly did not provide



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adequate nutrition for catch up growth in mostof the infants born *after growth had beenretarded.The significant interaction between diet and fetal

growth retardation for developmental outcome indi-cates that infants in whom growth is retarded areespecially vulnerable to postnatal undernutrition.Preterm formula fed infants had similar develop-mental quotients whether they were small or ofappropriate size for gestational age, whereas infantsfed donor milk were at a significant disadvantage ifthey were in the small for gestational age subgroup(fig 2(a)). Thus our data indicate that even withmodern neonatal care, with emphasis on providingearly nutrition, some available dietary regimens(especially when fed to neonates who are small forgestational age) may not permit achievement of fulldevelopmental potential in infancy.

Smart points out that in animal studies onundernutrition the effects on subsequent growth andbehaviour are generally more pronounced in malesthan in females. '8 Interestingly, we showed agreater dietary association with development inmale children. Furthermore, sick infants who wereventilated for more than 24 hours showed a greaterdisadvantage on donor breast milk than thosereceiving minimal or no ventilatory assistance. Forthese differential effects on development to havemore than speculative importance it would benecessary to show significant interactions betweendiet and sex, or diet and ventilation. We identified ahighly significant interaction between diet andventilation for language development (sick ventilatedinfants on donor milk showed a 6-2 point disadvan-tage). For overall developmental quotient, how-ever, significant interactions with diet were notidentified for either sex or ventilation, though toexclude such effects would have required a muchlarger number. Nevertheless, the consistency of thedata with those in animals, together with the moreconvincing findings in infants whose growth wasretarded, supports the view that it is the 'vulnerable'male infant who is prenatally malnourished, or sick,who is most severely disadvantaged if fed on an'unfortified' diet.Our multicentre study should be viewed as a

group of 'management trials'. They were designedto answer the question: does the diet chosen for apreterm infant in the neonatal unit influence longterm outcome? No attempt has been made toinfluence dietary management in the time periodbetween discharge from the neonatal unit and thefollow up examination. As the groups were assignedrandomly, differences in feeding practice in thisintervening period should not have occurred unlesspart of the effect of the initial diet was to induce

some persistent change influencing the way the babywas subsequently fed.Viewed solely as a management trial our study

should not be expected to provide an explanationfor any benefit in outcome that emerged. We haveincluded a number of physiological and behaviouralstudies within these trials and our future analysesmay shed light on the mechanisms responsible forobserved outcomes. It seems plausible, however,that the developmental effects observed were adirect consequence of early nutrition, perhaps relat-ing to an important dietary influence on early head,and therefore brain, growth.'3 19 The explanationmight, however, have been entirely different; forinstance, the faster growth rate13 and hence earlierdischarge home in preterm formula fed infants couldhave influenced the mother's behaviour towards thechild, with consequent effects on development. Itshould be emphasised that donor milk and pretermformula differ both in nutrient and non-nutrientcontents; an overall advantage for preterm formulamay represent the sum of both benefits and dis-advantages. Whether breast milk would confer asignificant benefit over preterm formula if fortifiedto the same nutrient content is an importantquestion requiring a further outcome trial. Regard-less of the mechanism, it was surprising that a briefperiod of dietary manipulation (median 30 days)could have such prolonged consequences. It isunlikely that a comparable period of suboptimalnutrition in later childhood would have any lastingclinical significance. We suggest that the weeksimmediately after birth constitute a 'critical period'for nutritional management.The effects of early diet on later development

shown in these infants have important implicationsfor the dietary management of low birthweightinfants, and bear on the more general issue ofwhether early diet has persistent neurodevelopmentalconsequences in man. Clearly future planned followup of this cohort will permit us to examine thesignificance of our observations in terms of laterperformance.

We thank Dr R G Whitehead for help and encouragement, thestaff of the special care baby units at Cambridge, Ipswich, andKing's Lynn for their assistance and cooperation, and FarleyHealth Products for the manufacture of the preterm formula andfinancial and technical assistance.

References

Smart JL, Dobbing J, Adlard BPF, et al. Vulnerability ofdeveloping brain: relative effects of growth restriction duringthe fetal and suckling periods on behaviour and brain composi-tion of adult rats. J Nutr 1973;103:1327-38.



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1578 Lucas, Morley, Cole, Gore, Davis, Bamford, and Dossetor2 Stewart CA. Weights of various parts of the brain in normal andunderfed albino rats at different ages. J Comp Neurol 1918;29:511-28.

3 Siassi F, Siassi B. Differential effects of protein-calorie restric-tion and subsequent repletion on neuronal and nonneuronalcomponents of cerebral cortex in newborn rats. J Nutr 1973;103:1625-33.

4 Widdowson EM, McCance RA. Some effects of acceleratinggrowth. I. General somatic development. Proc R Soc Lond1960;152: 188-206.

5 Bedi KS, Thomas YM, Davies CA, Dobbing J. Synapse-to-neuron ratios of the frontal and cerebellar cortex of 30-day-oldand adult rats undernourished during early postnatal life.J Comp Neurol 1980;193:49-56.

6 Smart JL. Early life malnutrition and later learning ability: acritical analysis. In: Oliverio A, ed. Genetics, environment andintelligence. Amsterdam: Elsevier, 1977:215-35.

7 Winick M. Malnutrition and brain development. Oxford: OxfordUniversity Press, 1976:115.

8 Chavez A, Martinez C. Neurological maturation and perfor-mance on mental tests. Quoted in: Early nutrition and laterachievement. London: Academic Press, 1987:138-9.

9 Freeman HE, Klein RE, Townsend JW, et al. Nutrition andcognitive development among rural Guatemalan children. Am JPublic Health 1980;70:1277-85.

"O Sinisterra L. Studies on poverts, human growth and develop-ment: the Cali experience. In: Dobbing J, ed. Early nutritionand later development. London: Academic Press, 1987:208-33.Klein PS, Forbes GB, Nadar PR. Effects of starvation in infancy(pyloric stenosis) on subsequent learning abilities. J Pediatr1975;87:8-15.

12 Ankett MA, Parks YA, Scott PH, Wharton BA. Treatment withiron increases weight gain and psychomotor development. ArchDis Child 1986;61:849-57.

13 Lucas A, Gore SM, Cole TJ, et al. Multicentre trial on feedinglow birthweight infants: effects of diet on early growth. Arch DisChild 1984;59:722-30.

14 Office of Population Censuses and Surveys. Classification ofoccupations 1980. London: HMSO, 1980.

15 Knobloch H, Pasamanick B, Sherard ES. A developmentalscreening inventory for infants. Pediatrics 1966;38:1095-108.

6 Ameil-Tison C, Grenier G. Neurological assessment during thefirst year of life. Oxford: Oxford University Press, 1986.

17 Minkowski A, Roux J-M, Tordet-Caridroit C. Pathophysiologicchanges in intrauterine malnutrition. In: Winick M, ed. Nutri-tion and fetal development. Vol 2. New York: John Wiley,1974:45-55.

18 Smart JL. Undernutrition, learning and memory: review ofexperimental studies. In: Taylor TG, Jenkins NK, eds. Proceed-ings of Xlii International Congress of Nutrition. London:Libbey, 1986:74-8.

19 Cooke RWI, Lucas A, Yudkin PLN, Pryse-Davies J. Headcircumference as an index of brain weight in the fetus andnewborn. Early Hum Dev 1977;1:145-9.

Correspondence to Dr A Lucas, Dunn Nutritional Laboratory,Downham's Lane, Milton Road, Cambridge CB4 IXJ.

Accepted 1 June 1989



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Early diet in preterm status infancy · regimens, and preterm formula composition have beenpublished elsewhere,'13 but briefly, the preterm formula contained 2 g protein, 0-335 MJ(80