In this prospective, blinded, randomised outcome trial, with follow up of 98% of survivors still in Britain, the diet assigned to a premature baby for an average of just 4 weeks after birth had a significant effect on IQ—notably verbal IQ in boys—7½-8 years later when IQ scores are highly predictive of subsequent ones.14
Our findings suggest that suboptimal early nutrition in preterm infants can have a permanent effect on their cognitive function, emphasising the potential importance of dietary management decisions in this population. In biological terms our findings now provide “experimental” evidence in humans to support the long debated hypothesis that nutrition during critical or vulnerable periods of brain growth may have lasting consequences for cognition.5,10
Apart from its broader biological purpose, this study examined the practical question of whether early diet influences outcome in a typical, unselected, and heterogeneous preterm population in a neonatal unit. We did not study whether the perinatal sensitivity to nutrition identified extended beyond full term. While many other investigators have approached this1–6
there is still a paucity of formal randomised studies.8
The only strictly randomised study of post-term nutrition on long term outcome is that by Grantham-McGregor et al on 127 subjects. They showed a small increase in cognitive function at follow up in nutritionally supplemented stunted children in a developing country.20
Our data also show (tables and ) the higher IQ in children whose early diet included their own mother’s milk (trial B) versus those fed solely on formula (trial A). This non-randomised comparison has been published elsewhere19
and does not confound the present study, which considers the randomised comparison of standard infant formula versus nutrient enriched preterm formula used either as sole diets (trial A), as supplements to mother’s milk (trial B), or in the balanced addition of trials A and B which preserves randomisation.
Sex differences in the effect of diet
Previously and in another cohort (comparing preterm formula with banked donor breast milk) we found that effects on development induced by early diet were most prominent for language development.21
Again at 7½-8 years verbal or language based skills were predominantly affected. Lack of dietary effect on performance skills, however, might reflect our choice of only two performance subscales (block design and object assembly) in this abbreviated form of the Weschler intelligence scale for children (revised). This issue will be resolved at future planned follow up.
In animal studies long term consequences of early malnutrition on learning and behaviour are seen predominantly in males.22
Also, in the study by Fitzhardinge and Steven on full term infants who are small for gestational age only boys had later cognitive deficits.23
Our analysis according to sex was the principal preplanned subgroup analysis and was further justified by the significant interaction between sex and diet (significantly different impact of diet on development). Interestingly, the observed dietary effects on cognitive scores were significant only in boys. Also, although an effect of diet on the proportion of children with “poor outcome” was seen in both boys and girls, again the dominant effect was in boys. There was no cognitive disadvantage for boys versus girls when a nutrient enriched preterm formula was used (fig ); only when boys were fed suboptimally (on standard formula) was there a major loss of cognitive potential. Why the male brain should be so vulnerable to early nutritional insults is an unresolved biological issue. We found no sex difference in mean gestation or birth weight. Boys, however, as expected, were sicker with 25% (42/168) requiring ventilation for more than 7 days compared with 16% (30/190) in girls. This could in part explain the sex effect if diet had more impact on later cognitive development in sicker individuals; indeed, a previous analysis provided some evidence for this.21
Figure 2 Mean (SE) verbal intelligence quotient (IQ) and overall IQ in boys and girls fed standard versus preterm formula as their sole diet. Dietary comparison is made for all boys and also for those receiving highest intakes of trial diets (see text).*P<0.05; (more ...)
As the principal effects were seen in boys and in trial A our data may reflect a chance finding in a subpopulation of our cohort. Several factors, however, argue against this. As trial B reflected a comparison of trial diets substantially blunted by use of human milk in both groups it is not surprising that the effects of diet are seen in trial A. Furthermore, when we selected subjects for the highest intakes of the trial formulas (given for at least 2 weeks and, in trial B, at least 50% of enteral intake as formula) dietary effects were more distinct (for instance, boys selected in this way and fed solely on term rather than preterm formula had a major disadvantage of around 10 points in overall IQ versus 6 points in non-selected boys). This relation between the effect size and amount of trial diets consumed favours a causal relation. We also found an advantage of preterm formula over banked donated breast milk at a 9 month follow up in an entirely different though parallel cohort; this study also showed an effect predominantly in boys, as in the numerous animal and human studies cited above.
Diet and cerebral palsy
Unexpectedly, among infants fed the standard rather than preterm formula cerebral palsy was significantly more common, and we explored whether the lower cognitive scores seen in those fed standard formula were due to this imbalance. This proved not to be the case; even with specific analysis of data from children with cerebral palsy, low verbal scores (<85; over 1 SD below the mean) were seen over twice as commonly in both boys and girls previously fed the term rather than preterm formula and over three times as commonly in boys (45% v 13%).
The association between diet and cerebral palsy (largely spastic diplegia) was a post hoc finding but raises a clinically important hypothesis for formal testing. There is evidence from newborn rats and preterm monkeys that the brain may reorganise to achieve complete functional compensation if cortical damage occurs sufficiently early.24
It is plausible that, although cerebral palsy in prematurely born children might originate prenatally or at least before enteral feeding has commenced, whether the brain can subsequently achieve functional compensation at a time of rapid brain growth and development might depend on the provision of adequate nutrient substrates. Indeed, in the average period on the trial diets (4 weeks) the preterm infant’s brain should increase by 50% in weight at “in utero” rates.25
We showed here a major deficit in head12
and therefore brain25
growth during the neonatal period in those fed the term formula. Further studies are needed, however, to investigate the issues here.
The two trial formulas (table ) differed in their contents of protein, energy, calcium, phosphorus, iron, zinc, copper, and several other micronutrients, though not in quality of protein or fat. Our trial was not designed to explore which nutrients influenced neurodevelopment. Broadly our findings support the generic hypothesis that failure to meet overall nutrient needs during this critical period of brain growth has significant consequences for cognitive development. While standard “term” formulas, widely used when our cohort was recruited, are now infrequently fed to very low birthweight preterm infants, poor nutritional status remains common in these babies; our findings therefore have contemporary relevance in emphasising the importance of avoiding this.
In conclusion, we have shown that brief early dietary manipulation in preterm infants has major effects on later cognitive function. The study provides further support for our more general thesis26
that early nutrition during critical windows in early life may have “programming” effects on long term outcomes and provides some of the first evidence from a strictly randomised, blinded, and long term trial with near complete follow up that early nutrition may have persistent effects on the human brain.