Activity Transcript

Atul Singhal, MD: Hello. I'm Atul Singhal, professor of pediatric nutrition at the UCL Great Ormond Street Institute of Child Health in London. Welcome to this program titled “The Interplay Between Infant Nutrition, Early Milestones and Long-Term Outcomes”. Joining me today are Cristina Campoy, who's full professor at the Department of Pediatrics, University of Granada in Spain, and John Colombo, who's professor of psychology and director of the Schiefelbusch Institute for Life Span Studies at the University of Kansas in Lawrence in the US.

Why is it so important to talk about this? Well, we know that early nutrition has a major impact in neurodevelopment. We know that breastfeeding is associated with improved neurodevelopment outcomes. But the real challenge is how do we communicate the importance of early nutrition from parents to carers, so that we can improve these health outcomes?

Now, in the past, we've always focused on nutrition as a role of meeting nutritional requirements. But we've now begun to recognize that infant nutrition has a role beyond that of meeting nutritional requirements and really matters for long-term health. And this is based on the concept of programming, the process by which the stimulus end result, breastfeeding, has a long-lasting and permanent effect on the structure and function of an organism, your brain function many years later. The brain is particularly sensitive to programming effects because of its large size. If you look at log brain weight against log body weight, you'll see that all animals lie on a straight line. Fortunately, for us, a baby's brain is much bigger relative to its size than all other animals. One of the reasons we can have such a large brain and still be born safely is that much of our brain development occurs after birth. This means that the brain is extremely sensitive to early environment and, particularly, nutrition. Many of these environmental factors can influence brain development but importantly, a controllable early life, including nutrition, reduction of toxic stress and environmental enrichment.

Now, in poorer countries, malnutrition is the major cause of poor cognitive development, but in richer countries, we've been trying to answer the question does human milk influence future brain development? Well, there are at least 6 systematic reviews that show that breastfeeding is associated with better cognitive outcomes with an effect size of about 3 to 8 IQ points. These effects are independent of potential confounding factors. The effect is even there after adjusting from maternal IQ. In this study by Belfort, each extra month of breastfeeding increased verbal and nonverbal IQ by about 0.3 points. The effect is there in richer countries. It's been there in poorer countries such as Brazil, Chile and Philippines. Interestingly, it's not been seen in Sub-Saharan Africa. The effect there is in adults and children for cognitive behavior and motor outcomes, different ethnic groups, and mothers with a low and high levels of education.

The problem is these are observational studies, so there may be unmeasured confounding factors which influence both her decision to breastfeed and long-term cognitive outcomes. The lack of experimental design means it's hard to prove a causal link between breastfeeding and future neurodevelopment. Well, there are 3 possible solutions to these confounding [variables]. We can use a dose response association, greater breast milk, better cognitive outcomes. We can look at selected populations where the confounding is the other way around. For example, in the west, breastfeeding is associated with a high socioeconomic status, but in poorer countries, associated with low social class. And finally, we can do a randomized controlled trial. But clearly, randomizing babies to breast milk or formula is unethical and difficult to do. Well in fact, all 3 things have been done to show that breastfeeding can improve neurodevelopment in young infants. For example, for dose response in preterm infants where you feed them by nasogastric tube, so you can measure the exact amount of human milk, you put down that nasogastric tube, we showed that more breast milk intake was associated with greater IQ and brain volume in adolescence. And this has been confirmed in healthy term infants and longer duration of breastfeeding is associated with white matter development in adolescence. In selected populations in Brazil, breastfeeding is associated with low socioeconomic status, but higher IQ up to 30 years later and even 30% increase in income later in life. And finally, we have a randomized control trial.

This is the Belarus [PROBIT] study. And what they did in this study was not [to] randomize individuals, but different centers to a control or to a breastfeeding promotion intervention. The intervention works, so 43% of babies were exclusively breastfed in the intervention group compared with only 6% in the control group. When they followed these babies up at 6.5 years, IQ was higher in the intervention group. Strong evidence suggests that breastfeeding improves cognitive outcomes. Interestingly, the effect disappeared at 16, but breastfed babies still had better verbal abilities. And in fact, regulatory bodies such as the scientific advisory committee in nutrition in the UK have now said that there is evidence of not breastfeeding maybe also be associated with disadvantages for certain neurodevelopmental outcomes.

If we accept that breastfeeding can improve cognitive outcomes, what are the mechanisms involved? Maybe they are confounding? I don't think that's the case because of the evidence I've shown you, there may be better bonding between the mother and the baby. We don't have a lot of evidence to support that. And there may be nutritional differences between breast milk and formula. And this is a key area of research, particularly long chain polyunsaturated fatty acids and the milk fat globulin membrane. The key questions are what are the mechanisms involved and how do we communicate the importance of early nutrition to parents? John, what can you tell us about developmental milestones and key neurodevelopmental outcomes?

John Colombo, BA, MA, PhD: Well, thank you, Dr Singhal. As you've referred to, the first years of development are likely very critical for lifelong outcomes, in particular with respect to learning and development. Historically, clinicians have used these developmental milestones to assist with the early identification of developmental delay, typically because the milestones follow predictable courses in particular with infants, very young infants and young children. One of the things that our research has shown over and over again is that the interpretation of milestones is nuanced and complex. They're very important in that they are indicators of early delay, but the response of milestones to nutrients is interesting and mixed. For example, nutrients may or may not have effects on the traditional or common milestones that have been traditionally assessed by clinicians. For example, in gross motor or fine motor ability. In our experience, cognitively based assessments represent a more sensitive approach to measuring the effects of these nutrients.

I'll give you a couple of examples. One, the long chain polyunsaturated fatty acid (LCPUFA) is that we found typically don't affect the early milestones on, for example, the Bayley Scales. But they do affect, for example, early measures of attention and early measures of vision. And then later on, measures of executive function, which are critical to more complex types of cognition. That said, we have found, for example, that milk fat globule membrane (MFGM) does affect early motor and early cognitive abilities.

And so, one of the things that we impress on practitioners is that the milestones are not necessarily the only way to measure the effects of these nutrients. In fact, what we often see, and you refer to it and in some of your introductory materials, is that we will see an effect of a nutrient on a particular outcome early, which then disappears later on. A really good example of this is the effects of LCPUFA on early visual acuity. There's a clear effect in the first year, but then that goes away later on. What is important to think about with respect to telling parents about these outcomes is that that early advantage in one domain of these milestones may then give the child an advantage or an accelerated path to show advanced development in other domains when the difference in the original domain disappears. And so, it's really complicated and while the milestones are important for all sorts of reasons, they're not necessarily the only way that we want to evaluate the effects of these nutrients.

Dr Singhal: Thank you. I think that's a very, very important point. Milestones are important, but they're not the only thing that is related to cognitive outcomes. Thank you. That's very interesting. How useful are these milestones in terms of relating to long-term neurodevelopment of outcomes? I think you've answered that.

Dr Colombo: The milestones are related to later outcomes in a couple of important ways. One, as we all expect when we start to measure these milestones, that there would be a direct path between a milestone that's measured at one point and a milestone that's measured at another point, that there would be a direct path between them. That may occur but in fact, most infants and children attain these milestones at some point as they move through their developmental course. It's also the case that an advantage in one milestone in one domain may affect a different domain whatsoever, but later on. And so, you will get these effects in what we would call in the discipline, a developmental cascade, where effects seen here have effects later on, but not necessarily in a direct or straightforward fashion that those effects are mediated by other underlying processes in development.

Dr Singhal: Well, clearly, I think you've highlighted the importance of nutrition for development milestones and your development. But I'm going to ask Christina, what evidence do we have on the impact of breast milk substitutes and achieving some of these developmental outcomes and milestones?

Cristina Campoy, MD, PhD: Okay. Thank you very much, Dr Singhal, because your excellent talk, and also to introduce me. In fact, it is really very important that early nutrition impacts on the neurodevelopmental outcomes, and we have several samples and studies showing that this effect is maintained over time, and it continues even many years later. So, we have a study, for example, it was shown how milk fat globule membrane supplementation in infant formula has an effect on the cognitive scores, which were higher in infants who were supplemented with the infant formula, supplemented with the milk fat globule membrane, than those infants who were fed a standard infant formula. So, there were not significant differences in motor or verbal domains, but still, these cognitive scores were higher. Then we see also that the breastfed infants in this study performed better in verbal domains than in the formula-fed groups, performed also significantly better in the cognitive domains than the standard formula group, and not when we compare with the infants fed with the formula supplemented with the milk fat globule membrane. And we have also positive effects of breastfeeding on cognition, which may be due probably to all the bioactive compounds who have human milk, such as milk fat globule membrane.

There are also other studies. One is the COGNIS study. It was a randomized clinical trial performed in 170 infants who received an infant formula containing milk fat globule membrane components, synbiotics, LCPUFAs, gangliosides, sialic acid, and nucleotides, or there were also infants fed a standard formula up to 18 months. And we have also a breastfed group. What we saw here, it is that we assessed the visual function. And what we saw here, as you can see in the slide, it is that the babies who were breastfed, or who fed the experimental formula, the new one, the percentage of infants who responded at seven and a half minutes of arc in the visual recording, it was a cortical visual of evoked potential recording, we saw that they have more infants who arrive to this very low differences in the minutes of arc. So that means they have better visual acuity. And this, it was really different in front of the standard formula group. As you can see here, the breastfed group was significantly higher, the number of infants with higher visual acuity, than the standard formula. But there were no differences between the breastfed group and the experimental formula. So that means that visual acuity, also it's a part of the brain maturation. In this case, the brain maturation was improved in infants who were fed with the experimental formula compared with those who receive only the standard formula. So that means that when we add these components, these active components already present in the human milk, functionally we aim to mimic, really, the result obtained in breastfed infants.

There are also some other data from the COGNIS group, and we also performed an analysis of the gut microbiota, and we tried to see if there were some kind of differences between the babies fed with the standard formula, the experimental formula, or the breastfed. What we saw is that there were differences in the maturation of the gut microbiota, and these kinds of differences, we found some patterns, because the breastfed group matured slower, [in terms of] the gut microbiota, than the formula-fed groups. And when we analyze the pattern or the velocity of this maturation, we saw that those babies who matured slowly have the same cognitive scores and language scores than the breastfed group. And the question is here that those babies who matured faster, they showed lower scores, especially in [the] language development domain. So that means that we found that the experimental formula promoted slower maturation, more children with a slower maturation of the gut, similar to breastfed infants. And this was associated with better language development, that, as you know, it's a domain which is also associated with a better cognitive score. So, what we can say is that the neurodevelopmental outcomes were similar between experimental formula-fed infants with the slow trajectories and breastfed infants at 12 months of age.

We also explored between 18 months and 2.5 years of age with the 70 children with a standard formula, or experimental formula, and also 33 breastfed children, as referring to participating in this cognitive study. We explored the behavioral problems evaluated by using the child behavioral checklist, at 18 months and 2.5 years. And the result, again, seemed to suggest a similar score increase between experimental formula children and breastfed children.

Dr Singhal: Thank you, Christina, what can you tell us about the impact of infant nutrition on neurodevelopment outcomes in the long term? Mothers are obviously very interested in milestones in early life, but clearly, they want to know whether how they feed their babies affect neurodevelopment many, many years later.

Dr Campoy: Thank you very much, Dr Singhal, because your question, it is true, there are in fact long-term neurodevelopmental outcomes from formula supplementation, because we demonstrated in the COGNIS study as well that for delay and need to improve more, the percentage of children with this problem, were much higher, significantly higher in those who were fed with the standard formula, regarding those fed with the experimental formula or were breastfed. And we have more children with the normal use of language when they were fed with the experimental formula or were breastfed, vs those who received the standard formula. With another test, a total oral language test of Navarra (PLON), it was exactly the same. We saw, again, that there were more children who need to improve or were delayed in the use of language, yes, in the standard formula group. And there were no differences between the experimental formula group and the breastfeeding group. And the same, there were more children with normal use of language or normal language domain when they were fed with experimental formula or breastfeeding.

Also, at 6 years we noticed that there were still some differences, statistical differences between the experimental group and the children fed with the standard formula. As you can see here, in this slide, the experimental formula group show better vocabulary, and also higher IQ vs those children who were fed with the standard formula. And also, with the PLON-R, this test, the score continues to show at 6 years, [that] those children who were fed with experimental formula, have higher or better use of oral expression of language, with the direct score we see here, than those who were fed with the standard formula.

But it is not only with the neuropsychological testing. We have now very interesting data regarding the brain. The opportunity with these new technologies, with the fMRI technologies, offer us an opportunity to study the effects of nutritional intervention during early life, on the structural changes in the brain, and also the functionality of the brain regarding this intervention. And we saw after adjusting for many, many different factors, confounding factors, that there are differences in the brain volume and the cortical fitness between children fed with the experimental formula or the standard formula, at 6 years of life. This, it was really amazing. From my perspective, it's the first time we find such kind of important data. You have to know that functional MRI, it is a very objective analysis, or a very objective assessment. And really, these changes are important. So, what we found, it is that children fed with experimental formula have better verbal IQ, comprehension, memory, and semantic fluency, greater volumes of parietal regions related to memory, language, information processing, lower cortical fitness in frontal regions commonly associated with better cognitive development. This is, for example, associated with better memory, executive function, or language, and IQ. And also, we have the experimental formula and the breastfed children showed also lower functional connectivity in key brain ranges, involved in processing salience stimuli, eating motivation, and atonic drive and desire to consume food, when we compare with the standard formula-fed children.

So, the question is that these results reinforce the positive effect of breast components such as milk fat globular membrane on the brain development, but also associated with other biotic compounds like LCPUFAs, or synbiotics, or other components already present in the human milk. So as much as we mimic human milk with the different components, biotic components available, we improve the infant formula.

And the results are here. This study, the COGNIS study is interesting because it has been designed to demonstrate the synergistic effect of these biotic compounds on brain development. This is another study which is really important to be mentioned. For many years we have been working with the LCPUFAs supplementation in infant formula and trying to demonstrate the effects and the long-term effects on neural development. This is the DIAMOND study, which was, from my perspective, the most important one, or one of the most important ones in the world regarding the effect of the different amount of LCPUFAs and the long term, very long-term effects. So, they also explored the effects of this supplementation with fMRI in children at 9 years old. And as you can see here, especially this is perhaps the most realistic issue, it is that the functional connectivity, for example, depending on the percentage of amount of LCPUFAs supplemented in the formula, the better one, it was when you supplemented 0.64% of the LC-PUFAs in form of DHA. So, that means that [the] attention system is modulated by long-term effects of LCPUFA supplementation in the babies. We have also different white matter volume. And it was also observed that there were less in the groups of 0.32% or 0.64% of supplementation of DHA, docosahexaenoic acid. And also, we have the functional test activation. And again, here it was the signal changing. So, the question is that the children who were fed with the formula supplemented with different amounts of DHA work better in this test activation of the attention system than those who were not supplemented with the LCPUFAs.

And the same here regarding an inhibition system. And again, they show the same with the metabolism and neurochemical metabolism of the brain. So, that means that we have these long-term effects from very, very early in life, up to 9 years old. And we can demonstrate this effect clearly with the introduction of these new technologies. So here, we can conclude the importance to breastfeed the babies. Breastfeeding, it's the way to achieve the optimal neurodevelopmental outcomes. And if this is not possible, infant formula supplemented with all the available biotic compounds for infant formula should be given to all children.

Dr Singhal: Well, thank you very much, John and Christina. I think you've highlighted the importance of nutrition for neurodevelopment. But as I mentioned right at the beginning, one of the key challenges we have is how do we communicate some of these messages to parents and caregivers? And I think the messages that we really need to get across are the importance of optimal nutrition for long-term health and the different nutritional approaches that we can use to try and achieve these benefits.

I think we need to emphasize that the brain structure and capacities formed relatively early before the age of 3, and failure to optimize brain development at this important stage can have long-term consequences for education, for work potential, and for mental health. And some of the nutrients that we know are important in neurodevelopment include the polyunsaturated fatty acids, linoleic acid, α-Linolenic acid, docosahexaenoic acid, and arachidonic acid, and obviously, milk fat globular membrane.

These are just some of the lipids that are important for neuro development, but lipids aren't the only thing that we know that are important for brain development. Probably top of the list is iron, which are the most common nutritional deficiency around the world. And it's been shown to be associated with cognitive development, particularly motor function. In poorer countries, zinc deficiency is important because zinc intake is related to protein intake. And iodine in deficiency in early life clearly has adverse effects. And particularly in countries where they have a low intake of iodide salt. Many, many vitamins are important, particularly B12 in areas where there's low protein intake, particularly in vegetarian populations, but also vitamin A. And certain amino acids may influence cognitive outcomes such as tyrosine and tryptophan. And more recently, we've begun to understand that there's an interplay between the brain and the gut, the so-called gut-brain axis. And this means that certain prebiotics and probiotics may also have an effect on neurodevelopment in early life. And clearly all of these different nutritional aspects are going to be important for the development of the baby. It's not just due to one individual nutrient.

When it comes to communicating [with] mothers, we need to emphasize that breastfeeding is the best forms of nutrition for the newborn. Now, [if] we can't breastfeed, pumped human milk is the next best thing. And for preterm infants, we often use pasteurized donor milk. And for moms who choose not to or can't breastfeed for some reason, then there are many different infant formulas available such as cow's milk-based protein, soya-based formulas, and hydrolyzed formulas. And each of these has their own different advantages and uses.

And I'm just going to wrap up here. And I hope we've convinced you that the answer to the question, does early nutrition improve long-term brain development is clearly yes. There's strong evidence that breastfeeding improved neurodevelopmental outcomes. Breast milk has many key nutrients, including MFGM and lipids. And all of these, they're going to be important for optimizing nutrition in the newborn. I'd just like to thank Cristina and John for this great discussion and for you for participating in this activity. Please continue to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.