This presentation was delivered by Dr. Steve Wu, MD, Director of Evidence Generation and Clinical Research, Reckitt Mead Johnson Nutrition.  Narrator:

We now introduce Doctor Steve Wu. Doctor Wu graduated from Columbia University with a degree in medicine and then completed his pediatric residency and gastroenterology fellowship training at the University of California, Los Angeles. He is board certified in pediatric gastroenterology and serves as volunteer Associate Professor of Pediatrics at the Indiana University School of Medicine. Doctor Wu's clinical interests include functional GI disease, food allergy and intolerance, feeding disorders, and obesity, as well as general childhood nutrition.

He is currently the Director of Global Clinical Affairs at Reckitt Mead Johnson Nutrition, overseeing clinical research and innovation both within Mead Johnson Nutrition and in collaboration with researchers from around the world. Please welcome Doctor Wu.

Doctor Steve Wu:

Hello, everybody, and good morning. Salaam alaikum. Dan Selamat pagi. Selamat siang. For all our Mexican colleagues – who’s from Mexico? Raise your hand. So many of you (Mexicans) – well for all our Mexican friends, good morning and I hope you slept well – it’s difficult I know. Thank you very much for everybody. For that. Welcome. I'm very, very happy to be able to, speak with you today and, share the stage with my esteemed colleagues.

So we've heard many things so far this morning. We've heard about the, central importance of understanding nutrition and malnutrition. We've heard about the, essential role of nutrients in human milk, for, for health, as well as for brain development. Doctor Gishan has, shared with us the information about milk fat globule membrane, or MFGM in particular, an essential nutrient in, in human milk as well as now in, in some formulas and its benefits for, clinical outcomes as well as what Doctor Deoni just showed its benefits for, neurodevelopment. So what I'd like to talk to you about and these next few minutes, is we know that there's, an effect of feeding, MFGM, and MFGM components in infancy, but does it last?

There are benefits in in infancy. But are there also benefits later on? Here's my disclaimer. Okay, so, if MFGM is beneficial for neurodevelopment in infants, and we have heard evidence that it is, what is the evidence for lasting neurocognitive effects? Later on, a few years later, in young childhood. So, this is one of the studies that Doctor Gishan, described to you. This is a study that, my colleagues, including Doctor John Colombo, who you saw in the video and other colleagues in China did a number of years ago. And we looked at the effects of infant formula with added MFGM as well as added lactoferrin. The objective was to, first of all, I just, review something that you heard earlier to evaluate the impact of MFGM and lactoferrin in cognitive development, in health, in infants. We enrolled healthy term infants from China, and we fed them up to 12 months of age and continued follow up to 18 months of age. So the outcomes included growth and tolerance, which we always look at in growing infants, as well as markers of neurodevelopment and adverse health events. The study arms included a control formula, 228 infants and investigational formula containing DHA, an area as well as supplemented with MFGM. and Lactoferrin 223 infants and I say supplemented because MFGM. components are in all milk. So even a control formula, it does contain small amounts of MFGM  components, not very high, not as much as in human milk. But there is some. And at the bottom, you see the, the several, neurocognitive measures that we measured over the 18 months of age. Okay. And here are the results from that study.

Most importantly, we found that if you look at, the graph on the right side, which is, Bayley-III cognitive scores at 12 months of age, there was a very significant increase in, the cognitive, the language and the motor sub scores of the Bayley at 12 months of age in the children who were supplemented with MFGM and lactoferrin, there was no difference in social emotional score on the Bayley and there was no significant difference in general adaptive score. What else did we look at? Also, the group that got MFGM and lactoferrin for the first 12 months had higher mean scores in the Ages and Stages questionnaire. This is a developmental screening questionnaire that was, administered between 4 and 9 months of age. They had longer sustained attention at 12 months. They were they were able to, play with the toy and focus their attention for longer without being distracted. And they had higher scores on three categories on, the MacArthur-Bates Index, which is a measure of, language development and early life, including sentence complexity. So they, the children who got additional MFGM, they didn't have more vocabulary words, but they were able to put them together into more complex sentences.

So, conclusions from this study, formula supplemented with MFGM and lactoferrin was associated with improved scores in cognitive, language and motor development and sustained attention at 12 months, improvements in some language measures at 18 months of age. And the study adds to the body of evidence supporting that there are, neurocognitive benefits brain benefits associated with receiving adequate MFGM in infancy. Okay. This sets up our first question in this study. Which of the following outcomes were found at 12 months in infants who received added MFGM and lactoferrin A higher mean Bayley cognitive, language and motor scores. B longer mean sustained attention C improved social emotional score D both A and B.

Okay. And. Oh, congratulations. Great. Give yourselves a hand. The answer is both A and B higher. Mean Bayley scores and longer, mean sustained attention, but not social emotional score. Okay, next slide. Okay. So, like I said, this adds to body of evidence supporting MFGM. But what happens to the neurodevelopmental progress of these children later on?

We thought it would be great to be able to follow them up, and fortunately, we were able to do so. So what I'm going to report to you today is a new study was just published, by Doctor Colombo and some of our other colleagues this year in Journal Pediatrics. And it looks at it reports improved brain outcomes at five and a half to six years of age.

And these children. So the objective of this study was to follow up from the previous study, to ask what happens later? The study population was 116 of 292 eligible participants. So 40% of the children who were originally in the first study were re-enrolled in the second study. I'm describing I'll briefly describe the outcome measures, but in the next few slides I'll go into more detail about what they are. So we used the, Wechsler Preschool and Primary Scale Intelligence, abbreviated WIPPSI-IV for short. So this is a, a validated and standardized, measure of, brain development or were, neurocognitive function, with a number of different subscales. We also, used with the with the collaboration of, of doctor, Doctor John Colombo, who is an expert in in child development, the dimensional change card sort test task, or DCCS and the Stroop task. Both of those are, measures of executive function or higher brain function. And we also looked at the child behavior checklist, which is a brief parentally reported measure, used to detect behavioral and emotional problems. Okay. So at, we followed up these children five and a half to six years later, as I, as I said, we had about, 40% follow up. The control group was and it was evenly split, 59, 57 in each group, the control versus the MFGM. And lactoferrin group, we found that, because we, we looked at health outcomes and growth outcomes as well. There were no group differences in height or weight or, body, body mass index at follow up.

And we looked at demographic and socioeconomic variables as well, just to make sure that in the population that followed up, there weren't big differences, between the, the two groups, there was a group difference only on family income, which was a little bit higher in the MFGM lactoferrin group. But we used, statistical methods to adjust for that, that difference in that between the variables.

So, these are the results that we found on the, on the left side of the screen is the, unadjusted on the right side of the screen is, is the, adjusted for the, the sociodemographic variables, but essentially, we said we found that there were very, very striking effects. This is after feeding MFGM. And lactoferrin versus not up to 12 months of age.

When we went back and we, and we tested on the WIPPSI, many years later, we found that there were significant differences in the full scale IQ, which is a summary of all of the other categories. In processing speed, processing speed, makes a lot of sense. We've heard so much about, myelination and the role of MFGM components and particularly sphingomyelin, but, other components as well in myelination, which, which improves, the processing of brain signals makes it more efficient so that that really, fits together very nicely. There was a significant, improvement in visual spatial, function as well. However, for working memory, fluid reasoning and verbal comprehension, we did not see a difference. Now, I'll tell you about the dimensional change card sort test. Again, this is a test of, executive function, and this is how it's done. So a child and you saw this in the video a little bit is presented with a card that is either red or blue. And, in the example here, it either has a boat or it has a rabbit. And in the first phase, the pre switch phase, the child is told that you have to match color. So you match blue to blue, you match red to red. And they found that, the two groups were equally able to do that. The second phase, the post switch phase, they changed the rules. So now the children are told if you see a boat, you match it to the boat. If you see a rabbit, you match it to the rabbit. So you're matching the shape to the shape. And again it was found that the in the post switch phase, there was no difference. However, it gets more complicated than that. The most complicated phase is the border phase. So here the children are told when there is a box around the picture, then they match it to the same color. When there's not a box around the picture, they match it to the same shape. That's very complicated. I have trouble doing it myself. I've tried it, but very interesting. They found that there was a significant difference, a significant improvement, and the children who got MFGM and lactoferrin in infancy, they were they scored higher. They were better able to do the border phase test. The Stroop test is another, test of executive function. And in this case, the children are told they have to inhibit their natural response.

So, for instance, if they're shown a picture of the sun, they have to say night. If they're showing a picture of the moon and stars, they have to say day. So they have to inhibit what they normally would say and do the opposite. It's a measure of executive function, an ability to learn rules. And we found here that, again, the group that had MFGM and lactoferrin showed an improved ability to do this task improved in, in executive function. And there were no significant group differences However, in the child behavior checklist. Okay. So a few things to mention about this study. It, the conclusion it showed a persistence of this cognitive effect, from feeding in the first year to an effect still present at five and a half to six years of life when kids are starting preschool or maybe about to go into preschool.

Some limitations. The follow up, population was 40%. We wish it were higher, but it's hard to, to get people to get the subjects back after so many years. There were two nutrients tested, MFGM and lactoferrin. However, as, as Doctor Gishan noted, there's growing evidence. There's a lot of evidence that, that that we talked about showing brain benefits of MFGM. Whereas lactoferrin, we know has effects on, the microbiome and on health and on iron, but it is not shown to be, effective, by itself for brain outcomes. So this these data are consistent with, evidence of a link between MFGM components and, and myelination, as Doctor Deoni showed you. Okay.

So I'll go a little quickly through this. I think we've talked about this, okay. Go on and question two. So, get ready to answer this question, please. The Columbia 2023 study reports a follow up of infants who had consumed MFGM and lactoferrin and the Li 2019 study. At what ages? A two years of age. B three and a half to four years of age, C five and a half to six years of age and D 9 to 10 years of age.

And this one, I hope, is easy. Yes. And, majority of people got that right. So thank you for listening. Okay. Next slide. Okay, so, I have two more studies that, I'd like to, to, speak with you a little more, briefly before we finish. And this study is, was presented at ESPGHAN, a few years ago. It's the long term impact of bovine MFGM supplementation during infancy on executive function at 14 years of age. So this is the longest, follow up of, of any study in the literature, that relates to, supplementation of MFGM so, this was, presented by, Doctor Lazarte and at  ESPGHAN, she is, she's a doctor from, Peru. And the objective was to follow up, study of adolescents who participated earlier in an MFGM feeding trial in infancy. The original study looked like this. There were 550 infants who were enrolled, a little bit older, in infancy, between 6 and 12 months of age. They were fed, a complementary food that either had MFGM or placebo skim milk powder for six months. And the results of that study were showed that there was a lower incidence of diarrhea and bloody diarrhea in the group that was supplemented with MFGM. So, that actually shows that MFGM components do have, an effect on, on, on gut health. But unfortunately in that study, it was not designed to look at brain outcomes at the time. However, what was amazing was that even after all these years, the investigators were able to follow up so many of these, these children. So the original study cohort of nearly 500, an incredible, 78% of them were still able to be located for follow up.

Divided, as you see there. So the cognitive results, at this 14 year old follow up, they looked at the Wechsler intelligence scales for for children. Which had four different scores. None of those showed significant differences in, a subscale score or in full scale IQ. So overall for IQ, there was not a difference after 14 years.

Probably not that surprising because if you if you think about just getting something for six months during your first year of life and then sure that that's going to have an impact, but then the next 13 or 14 years, there are so many other influences on on intelligence, the family demographic characteristics and school achievement were not different between the groups.

However, there was one additional thing that was done and, the kids were tested with, CANTAB Cognitive Function Test. I'll show you a little more about that. In in a minute. So these are, electronic tablet based, tests of certain cognitive functions. Okay. So, here are the four categories cognitive flexibility, spatial memory span, inhibitory control, and spatial working memory.

So, just to give you an idea of how these were tested, these children were given a, an electronic touch pad, sort of like it, like an iPad, programed with the software to test them, for these different, categories of function, including, things like reaction speed, reaction time and, spatial working memory and, I have two slides showing the results. This shows the results by according to gender. And, the results that were different between, boys and girls are circled by red. Surprisingly to me, because my, my, my working assumption generally is that girls are smarter than boys, but, which may be, may be true in other measures. And these reaction time test, there was a difference in favor of the boys, in many of those functions. But if you look at the bottom two, working memory between errors, fewer errors is better. And the bottom one, working memory strategy, a lower score, is better. And in, in, in both of those categories, there also was, a difference found, based on gender between boys and girls.

Why that is, it's, it's very it's very unclear. There are certainly a lot of, dietary and environmental and social influences. That could have happened in the, in the previous, 12 to 13 years. But also I'll, I'll remind you that in overall test of intelligence, there were no differences between boys or girls.

And moving on. And here were the results, by formula group. So when we when we analyzed compared to who had received the GM in infancy and who had not, there were no significant differences for most of these functions. The reaction time, for span length, stop signal, reaction time, or the working memory between errors.

But there was one difference, one significant difference. And it's, circled in red on the bottom. And working memory strategy. There was a significant difference, in favor of the MFGM group. So the MFGM group, not only had made fewer errors in working memory, but had, an improved working memory strategy for its, a small difference, but, but again, it was a difference found 13 years after the feeding intervention.

So the conclusions of this study, supplementation of the diet with MFGM in infancy was associated with most outcomes being very similar, including overall IQ. Boys performed significantly better than girls in several executive function measures. And although there were not significant differences based on on feeding in most of the measures for working memory strategy, there were fewer errors in the group that received, MFGM during infancy.

So what does what does that mean? I think it's, it also look at with the, the previous study and with other studies in the literature, it does show that about feeding of MFMG or MFGM components in infancy may have some lasting effects on neurocognitive function, even though the effect here is small. And admittedly, it's relatively small, I think it's quite remarkable to be able to detect any difference between two groups based on, feeding during infancy and looking 12 years later.

To my knowledge, that hasn't been reported for for any other nutrient.

Okay. Last question, last question. This study, found measurable differences. And which of the following findings after follow up at age 14? In children, A general IQ score, two working memory strategy, three growth and D and D reaction time.

Okay. And very, very good. The answer is working memory strategy. So, that means that all of you passed. That means I passed as well. Okay. Next slide please. Okay. So the last study I will mention, this is not a study that I participated, at, at all, but this is a study from, doctor Nieto-Ruiz in Spain and, and colleagues, they looked at, function at six years after, an intervention with a formula that, included MFGM.

Long chain polyunsaturated fatty acids, like the DHA, ARA and Symbiotics in infancy. So what Doctor Nieto-Ruiz and colleagues did was, feed children with, a control formula or this, supplemented formula up to 18 months of age. And also, compared to a breastfed reference group, the outcomes included brain MRI and a neurocognitive test, follow up to age six years.

So the results they found were that the experimental formula group was associated with greater volume in parietal regions and greater cortical thickness on brain scanning, higher vocabulary scores and IQ, and better performance in a test of attention. So, in conclusion, the authors, said that the formula with MFGM and other components now there were a number of other components as well, is associated with effects on neurocognitive development and brain structure at six years of age. So, so this is very much in line with the data that, that, that we saw in the Colombo study, and in the, in the Lazarte study, which is, which has not yet been published, but it will be. I think that I will note about here is the effect seen in this study is likely to be multifactorial because the control and the experimental formulas differed in MFGM components, but they also differed in DHA, and they also differed in, in in particularly added sphingomyelin.

So we know we know that multiple things are important for for neurodevelopment. And the the difference in DHA content also likely had an effect. Okay. So that, I always like to end by showing pictures. On top you see a beautiful picture from Bali, Indonesia, on the bottom. I hope you think that's a beautiful picture as well.

That is Evansville, Indiana, and the Ohio River, which is, where I live and where the Mead Johnson, global R&D center is. So, if you're ever there, I hope you visit. And thank you very much for listening.