Discussion

In this prospective cohort study, a significant increase in protein intake in the first month after birth did not alter Bayley-III scores at 2 years’ CA, despite improved early growth. We also did not find any difference in cerebral palsy or sensory deficits between the two groups, consistent with other reports in the literature.20 ,21 High protein nutrition and its effect on neurodevelopment remains a controversial issue and the literature is not homogeneous in its findings. An observational study by Stephens et al22 of 148 ELBW infants found an independent positive correlation between protein intake in the first week after birth and Bayley II Mental Development Index (MDI) score at 18 months’ CA. In Stephens’ study, the majority of energy and protein intakes during the first week after birth were intravenous and it should be noted that some babies received very low protein intakes, in contrast to the babies we report here. This also is true for other papers reporting the relationship between neurodevelopment outcome and intravenous protein intakes.20–22 Blanco et al21 reported a lower Bayley II MDI score at 18 months’ CA in infants who received 2 g/kg/day intravenous protein in the first week increasing to 4 g/kg/day compared with their counterparts who received 0.5 g/kg/day increasing to a maximum of 3.5 g/kg/day. This difference was no longer found at the age of 2 years. Of note is the fact that the higher amino acid group actually had poorer growth; thus, although this study appears to contradict the hypothesis that greater protein intakes in early life improve neurodevelopmental outcome, it is consistent with the hypotheses that in extremely preterm babies, protein intakes are probably inadequate for optimal growth23 and that early growth and neurodevelopmental outcomes in this population are linked. In contrast, a study comparing Bayley II MDI score at 18 months’ CA between ELBW infants who received at least 3 g/kg/day of protein in the first 5 days after birth and those who received <3 g/kg/day found no differences between the two groups.20 In this study, enteral nutrition contributed to approximately 5% of the total energy intake by day 7. In our study, approximately 25% of week 1 energy intake was from enteral nutrition in both cohorts. Early enteral nutrition also is advocated to improve outcomes24 ,25 and this factor must be considered when interpreting studies in which enteral nutrition was either restricted to minimal enteral feeds or significantly delayed. We found a significant correlation between motor scores and enteral intakes during week 1 after birth, but only in the ‘before’ cohort. One explanation might be that healthier infants are more likely to receive more enteral nutrition and these infants would be expected to have a greater likelihood of better Bayley-III scores. However, this association remained after adjusting for variables such as birthweight z-score and duration of ventilation and a similar relationship was not found in the ‘after’ cohort, despite enteral intakes not being different between the two cohorts during the first week after birth.12 An alternative explanation might be that in babies in whom total protein intake is insufficient, improving enteral intake improves outcome whereas once total protein intake is sufficient this is no longer the case.

Extremely preterm babies frequently suffer both fetal and postnatal growth restriction4 ,26–28 with faltering postnatal growth being very common4 ,29 due to the difficulties in providing nutrition sufficient to support the very rapid rate of growth that fetuses of equivalent gestational age undergo in utero.4 ,30 Both fetal growth restriction and postnatal faltering growth are associated with adverse neurodevelopmental outcome.5 ,31 Thus, it seems likely that suboptimal nutrition contributes to both the faltering postnatal growth and the impaired neurodevelopmental outcomes that are seen commonly in ELBW babies.23 ,32 Faltering growth in preterm babies is different from the classical faltering growth of poorly nourished term infants where weight is affected first followed by length with sparing of head growth until severe malnutrition is present. In preterm babies, length and head growth appear to be affected much more quickly with z-scores falling by 1–2 SDs for all measures of growth during the first month of postnatal life.12 ,33 This early effect on head growth likely reflects the extremely rapid brain growth that occurs at the gestational ages ELBW babies are receiving suboptimal nutrition as head circumference correlates with brain volume.34 There is an increase in total brain tissue volume of 22 mL each week from 29 to 41 weeks’ gestation,35 resulting in a fourfold increase in cerebral cortical volume between 28 and 40 weeks35–37 and a >30-fold increase in cerebellar cortex surface area between 24 weeks and term.38 ,39 This very rapid development may also result in greater vulnerability to damage from less than optimal nutrition. Indeed, in adolescents born preterm, performance in final school examinations and IQ score is best predicted by the total volume of white matter in the brain detected on MRI scans at a mean age of 16 years, irrespective of the presence or severity of other brain abnormalities.8 However, despite our data demonstrating improved head growth in the ‘after’ cohort, consistent with the results of a recent randomised controlled trial which demonstrated that protein intakes equivalent to those in our ‘before’ group resulted in improved head circumference at 28 days compared with the control group that received lower protein intakes,40 we did not find improved neurodevelopmental outcomes as assessed by Bayley-III scores. This could be due to the observational, cohort nature of the study or because there is no beneficial effect for neurodevelopment of increasing protein intake in extremely preterm babies above a certain threshold and, perhaps, protein intakes in both the ‘before’ and ‘after’ groups were above this threshold. Finally, 2-year outcomes are quite early in the context of extremely preterm birth; it may be possible that any beneficial effects are not manifest until older ages. Limitations of this study are the potential bias inherent in non-randomised studies, as well as the non-contemporaneous nature of the two cohorts, meaning that other changes in management practices over the duration of the study that we have not identified could also affect outcomes. The outcome data reported here were collected retrospectively and some data, such as the need for special intervention, were provided by the parents. Thus, these data need to be interpreted with caution and further studies should be performed to confirm the relationship between the need for an early intervention teacher and early nutritional intakes in ELBW babies.

We acknowledge that this follow-up study is underpowered to detect a clinically meaningful difference in Bayley-III score. Thus, although we have not found an effect of increased protein intake on Bayley-III scores at the age of 2 years in this cohort study, this does not mean that there is no effect. For example, to detect a five-point Bayley-III score difference with 90% power at a 5% level of significance would require 190 babies per group with a total of 380 subjects. A more meaningful difference in neurodevelopmental outcome may be survival free of disability at 2 years’ CA. To detect an absolute difference of 15% in survival free of disability between the two groups at 2 years’ CA requires a total of 430 babies (n=215 in each group) with 85% power and a 5% level of significance (two-sided), taking into account a 10% loss to follow-up rate and a rate of 50% in the control group.

A randomised controlled trial of increased protein intakes in early life with neurodevelopmental outcome as the primary outcome is required to answer definitively whether increased protein intakes in the first weeks after birth in extremely preterm babies improves survival free from neurodisability. Such a trial (the ProVIDe study) is now recruiting (ACTRN126 12001084875).