The articles reviewed in this week's episode can be found below:
Immediate “Kangaroo Mother Care” and Survival of Infants with Low Birth Weight https://www.nejm.org/doi/10.1056/NEJMoa2026486 Influence of different breast expression techniques on human colostrum macronutrient concentrations. https://www.nature.com/articles/s41372-021-00989-9 Migration of cyclohexanone and 3,3,5-trimethylcyclohexanone from a neonatal enteral feeding system into human milk. https://www.nature.com/articles/s41372-021-01036-3 Changes in macronutrients of human milk after bolus feeding: a simulation study. https://www.nature.com/articles/s41372-020-00899-2 Maternal dietary fat intake during pregnancy and newborn body composition. https://www.nature.com/articles/s41372-021-00922-0 Body adiposity and oral feeding outcomes in infants: a pilot study. https://www.nature.com/articles/s41372-021-00975-1 Breastfeeding and growth trajectory from birth to 5 years among children exposed and unexposed to gestational diabetes mellitus in utero. https://www.nature.com/articles/s41372-021-00932-y The effects of probiotic supplementation on the gene expressions of immune cell surface markers and levels of antibodies and pro-inflammatory cytokines in human milk. https://www.nature.com/articles/s41372-020-00875-w Comparison of standard versus high-dose ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus in preterm infants. https://www.nature.com/articles/s41372-021-01046-1 Patent ductus arteriosus shunt elimination results in a reduction in adverse outcomes: a post hoc analysis of the PDA RCT cohort. https://www.nature.com/articles/s41372-021-01002-z Temporal and seasonal variations in incidence of stage II and III NEC—a 28-year epidemiologic study from tertiary NICUs in Connecticut, USA. https://www.nature.com/articles/s41372-021-00961-7 Invasive mechanical ventilation at 36 weeks post-menstrual age, adverse outcomes with a comparison of recent definitions of bronchopulmonary dysplasia. https://www.nature.com/articles/s41372-021-01102-w High CPAP vs. NIPPV in preterm neonates — A physiological cross-over study. https://www.nature.com/articles/s41372-021-01122-6
The transcript of today's episode can be found below:
babies, pda, paper, milk, nicu, article, infants, looked, probiotic, interesting, group, feeding, study, care, outcomes, kangaroo, moms, thought, cpap, gestational diabetes
Okay, welcome to journal club. Daphna. How are you?
I'm doing great. I didn't have quite the busy week that you did. And I am thrilled. It's a good month for learning about kangaroo care in the in, in papers. So I'm thrilled, you know, it's
right into it. You're not wasting any time.
Well, I'm excited. Okay.
Okay. Well, I want to open the podcast by again, thanking all the people who are listening and downloading, we're getting tremendous feedback. It's, it's really great to see your community building around the podcast, we're very thankful. And, yes, thank you for all the support. So without further ado, I'm going to start right away with with this article that came out the New England Journal of Medicine. This this paper that Daphna referred to called immediate kangaroo mother care and survival of infants with low birth weight. It was, it was published on May 27 of this year, obviously, in the New England. And it was done. I mean, the it was a study group called the WHO immediate kangaroo mother care study group. And basically, the, the basics of the article are that the group had tried to evaluate the safety and efficacy of continuous kangaroo mother care initiated immediately after birth, in infants with birth weight, one to 1.8 kilos. And this included five tertiary level hospitals in Africa, in Ghana, sorry, India, Malawi, Nigeria, and Tanzania. And basically, they looked at several outcomes, mortality from enrollment to 28 days and mortality from enrollment to 72 hours. And the long list of secondary outcomes. The main findings of the articles are that for these infants who were born between one and 1.8 kilos, who received immediate kangaroo care, they had lower mortality at 28 days, then those who received conventional care with kangaroo mother care initiated after civilization. And and so that was, and so they wrote that the between group differences favoring immediate kangaroo care mother or mother care at 72 hours was not really significant. So a 20 days when he was when they found some significant outcomes. And I thought that was huge. So definitely, what did you tell us a little bit about the paper and what your thoughts were on that study?
Well, I think it's great news for this, especially for resource poor communities, definitely. But I think it would be remiss to say that we can't take more from this paper here, you know, in the United States in well developed resorts, rich units, either. Obviously, these aren't our smallest babies, right? One, one to 1.8 kilos. But those are babies who, in general, even the United States are not getting a lot of kangaroo care. And so I think that we can learn a lot from this learn a lot about, you know, the safety. And what was really interesting I want to bring your attention to is that so the control group was about one and a half hours a day, but the median daily duration in the, in the kangaroo care group was about 17 hours. So an average of 13 to 19 hours. And that is just tremendous. And I don't think I've ever seen that here in the States. So, you know, obviously, our societal constructs are a little bit different. mommies are having to go back to work, they can't spend, you know, 1720 hours in the unit every day. But the fact of the matter is, that kangaroo care is safe. And that I think it will continue we will continue to learn that it's going to change outcomes that we haven't even been been looking at and so it's, you know, just like the medications we study, we really have to give it its due diligence and, and, and teach parents about the benefits and let let them decide how much they're able to do or not to do. But we definitely have to be offering.
Yeah, this was this was a very interesting paper, I think you said a lot of interesting things about number one, the babies were not particularly small. I mean, they were the median. The median gestational age was 33 weeks. And again, if you look at practically speaking the numbers, obviously, this is published in the New England. So obviously, the numbers are perfect. There's like 1600 babies in the intervention arm 1600 babies in the control arm. And but when you look at the outcomes, obviously you say, well, that doesn't really translate into at least what we're seeing in the US. Or you would say maybe in Europe, where the rates of of mortality for sepsis are like 15% 20%. And these are high numbers. But then like you said, this is not really meant to portray outcomes in high resources setting but in low resource environments, and you see that kangaroo care, did make a difference in reducing mortality at 28 days. The big question is, what do we take away from this paper? And I've been scouring the the article saying, so what do I take away from this article? To the bedside? And how do we apply this in? In the US, this is where we practice. So let's just let's just call it what it is. And there's different things that I wanted to get your opinion on? Because number one, I don't know if you picked up on that in the article. But in the procedures section of the article, they mentioned how they got consent, right? And they spoke to those mothers about kangaroo care prenatally. And I thought that was like, Oh, that's interesting. I did so many prenatal consults. I have never mentioned about how we're going to do kangaroo care if the baby is born, never never thought about that. And
you know, I love the prenatal consult. It's one of my favorite parts of the job. And you know that I love kangaroo care. But I have never spoken about kangaroo care, in the prenatal consult. And you know, it, I'm always reminded because almost no matter what is happening with the baby after delivery, a parent's first question, or the question that they want to ask us, and they don't ask us is, when do I get to hold my baby? And they're waiting for us? To tell them? And so this is just a great reminder, especially for, I think people who, you know, poopoo, the utility of kangaroo care?
No. And, and I think, number one, this is something that is going to have to be like, I think this paper is bringing this to the forefront. This is a major issue. It needs to be brought up very early on before delivery. Number two, you're going to face the usual delayed cord clamping cord milking situation where it's like, is it my job? Is it the how are we going to communicate with our obstetricians to make sure that this can happen? Well, the link here is the mother, if the mother tells their OB is I'm expecting to do kangaroo care, right after delivery, then they can effectuate change, I think in the delivery suite so that this can be done. And so to me, I think bringing that up at the at the prenatal consult is potentially is a game changer.
Yeah, we had another article, you know, just last month, six weeks ago about and I don't have it here, we can maybe link at some other, you know, in the show notes, but about father's doing kangaroo care in the delivery room, and how that changed the kind of short term outcomes. And so we just, I'm hoping that the the community will be asking for it because it's something that we can't ignore anymore.
Yeah, and the other thing that was very interesting to me is that neonatology sometimes has some very wishy washy papers, right? About, this is better for the baby, and you're like, I don't really know. But this paper somehow was able to take a practice, which feels very ancient and very authentic, and show objectively, the medical benefits of it. I thought that was fascinating to objectively put in concrete term, yes, mortality is going down. If you increase the time exposure to kangaroo care, and you look at these numbers, they're pretty impressive. In their primary outcome, death between enrollment and 28 days, there was in the kangaroo care group 12% mortality versus 16% in the control group with a P value difference of point 001. And even at 72 hours, even though they didn't really mention it as a as a statistically significant difference because it is not, but it was still pretty much lower 4.6% versus 5.8% with a P value of point oh nine. So I mean, this is this is if this had if this had this is what I was, this is how I interpret this paper. I almost replaced in my head kangaroo care with medication X. And you think if this was medication X that they said, Hey, mortality rates have gone down by 5% between the two groups, we would all been using it. I mean, look at vitamin A, and all that stuff. And I am I am hopeful that people will take this as seriously as they would if it was a medication that they could just order in the computer.
Yeah, and the interesting thing, right about studying kangaroo care is can we ethically withhold it anymore? And in fact, this study their Data and Safety Monitoring, shut down the study because of the reduced mortality. And they they said, we can't, we can't randomize babies to not get kangaroo care. So I think the studies ethically we'll have to, you know, be observational, but I think there's still plenty of of data we can collect. I do also think this is not a political podcast. But, you know, if we are really serious about integrating kangaroo care into neonatal care, then, you know, we've got to support moms, and there are a number of ways that we can we could do that, that we, you know, as neonatologist have to advocate for because I think it changes outcomes in babies.
Yeah, and, and you and then I think it's also the issue with with neonatology sometimes is that we tend to think of all deliveries as being the same. And this article by being a bit selective in the population that they were using made a very interesting point, because I do I don't think that even for babies that are born at 30 weeks or below, doing immediate kangaroo care, is it? Is it feasible? Probably not, if you have to just intervene, but it opens the door to, I would say, I was thinking in my head backwards, I was saying, all right, let me see full term, I could expect the baby to be doing kangaroo care immediately after birth. And I started going back week by week, and thinking, at what point do I say no, I kind of want to assess this baby first. And I was able to go at least philosophically to like 32 weeks, I would say, You know what, up to 32 weeks, I can let the baby be on the mother. And if if I can visually see that the baby is breathing, okay, and that I can put a pulse ox on the baby, make sure that the heart rate and the oxygen saturation is good. This is very, very feasible. And so like you said, I think it's it's putting a little bit of a, an incentive on the clinicians as to what is your argument for not doing it? And so I think this was this was this article is a big deal.
While the other thing that they didn't discuss in this study is so what happened the rest of the 28 days, right? Were those moms doing more kangaroo care during that time period. And so I think we're gonna find that immediately is beneficial, but even if it's not immediate, then we just we have to work on on getting getting babies to do skin to skin whenever we have the opportunity. So I loved it. Okay.
Yeah, it was good. It was one of these articles that you get the feed that it's, it's published and it blows you away that Oh, my God, this, this is really significant. Let's move on to know that
kangaroo care certainly helps with breast milk production, and we have no shortage of breast milk articles.
That's right. So let's go to the journal apparently otology. And this month, this month's edition is interesting. It has a lot of different niche and different pockets of topics that they're that they're dealing with. So, what what are called you want to start with
I Liked this article influence of different breast expression techniques on human colostrum macro new macro nutrient concentrations. Lead, Arthur Camila Barros, Mo Gaco, DaSilva, probably butchered that. But they looked at a convenient sample of mothers that delivered greater than 36 weeks and two separate hospitals in Rio de Janeiro, Brazil. And they collected paired samples of milk. And so moms have a right breast and the left breast for for the most part. And so they were randomly allocated to one breast with a electric pump and one breast with hand expression. And then they evaluated these paired samples. And so they had almost 100 mothers each providing two of the samples and they showed that the concentrations of protein and carbohydrate did not vary between samples, but that there was a statistically significant increase in lipid and caloric content in samples collected by manual expression. And so, you know, this was a, this was a small study. The changes are small, but but the lipid concentration was point five grams per deciliter. And so when we think about how often we are adding additional additives to breast milk in the in the NICU You, I think there, we really have to think about how we can optimize the milk that we're already getting in the lacto, you know, engineering that we can do to milk to optimize it without having to add stuff that's not coming from human moms. So I thought it was interesting. I think that this is going to open up, I'm hopeful that it will open up more studies, looking, looking at things like this.
Yeah, I mean, I don't know what to make of this, because it's very interesting in the context of the other articles that we're going to talk about when, in terms of the use of different equipment, and it's the relationship between human milk and, and plastics and all that stuff. But I mean, is it? Is it practical to compare hand expression versus electric pump? And how I'm wondering how do we how do we take that to the bedside?
Well, so I don't have all the literature in front of me. But we know that manual expression is much more effective and efficient in the first few days of life. And I think that's something we can readily bring to the bedside. And you know, the first thing they will into mommy's rooms or handpumps, I mean, our electric pumps. And so that's something we can do right out the gate is optimized colostrum by teaching hand expression, which is more work takes a little bit more hand holding for lack of a better term, breast breast holding sometimes, and and it's hard, right? It's a lot of work. It's a burden on our mother, baby nurses. But the moms who are really dedicated to providing milk, we can teach them to do this, we can show them the videos online to do it, and they can do it. And we know that it especially in the preterm, the extremely preterm baby, that lipid exposure and the or lack of lipid exposure in the first few days, takes him a long time to catch up. And so, for me, I think that's something I can be more forceful about, and expression, especially in the first few days when I know that it's going to optimize milk output to begin with. Okay,
I Yeah, absolutely. I think, no, because I mean, it makes it sound like, so does that mean that I'm going to have to head Express for the, for six months?
We can't, I mean, there, there's a rare mom who can do exclusively hand expression and just exclusive pumping is, is a task in and of itself, but I think in those first few days, and again, I hope it's going to open the floodgates to more literature about how we can optimize the milk we give.
So following up there was is it okay if we continue on these two articles? Okay. So, the first one still in the Journal of parasitology is called migration of cyclo hexa non and 335 tri methyl cyclohexane non from a neonatal enteral feeding system into human milk and first author. Listen, it almost scared me away. And I was very happy that I had to read it. So I read it and and I even wrote next to it. Wow. Because I it's just I think to me, that was a very important paper. First author is preta Prasad. And this is from a group out of Chicago. And basically, what they're talking about and the introduction is a bit long, I think because it's it's it's needed to be long it talks about the VOCs, the volatile organic organic compounds. And in the introduction, they talk about some of the the noxious effects that VOCs have and how the the Environmental Protection Agency has identified them as public health concerns due to their liquidity and how exposure to volatile organic compounds have been during pregnancy associated with reduced birth weights, postnatal growth, and that children who are exposed to higher concentration of VOCs are at high risk of developing asthma, atopic dermatitis. So, I mean, I am not very well versed into the negative effects of VOCs. But I had heard of them. And in this study, what they did is that they took unfortified human milk samples, and they were infused through an enteral feeding system with varying duration of infusions, incubator temperature and pre infusion to priming. And they were and they had sort of an analyzer that was used to identify the VOC profile of the milk pre and post infusion, and they looked at two of those volatile compounds. One of them is cyclohexane. Nan, and the other one is 335 trimethyl cyclohexane Nan, and they found that it accumulated significantly in milk samples post infusion drill ration of infusion had a significant effect on the OC accumulation and accumulation patterns of cyclohexane Nan and 335. TMC differed significantly based on milk type. So they looked at the different milk type, they looked at donor milk versus mother's human milk. And then they looked at the duration of infusion. And they found that even in, in maternal milk, there was a significant accumulation. They did it in three phases, they looked at baseline 30 minutes and four hours. For donor milk, it accumulated almost on a dose sort of incrementally with time, and for maternal milk, they found a really a big spike at 30 minutes, and it was still elevated at four hours, but not as much. So that was fascinating to me that we could we could potentially, like the pump, and the and the, and the tubing is not something I had ever thought of as potentially being harmful to the babies. And this gave me pause for thought. Should I should we go into this? Or should I just talk about the other article that's on the same topic?
No, I think I think you're right. I think it's super interesting. And like you said, we have another article to discuss about timing. But I think it should give us pause, I think we should work to find what is the optimal timing for, you know, duration of feeds. Because it, it does matter. It's not a one time thing. It's it's like, you know, how many X rays does one baby get? And so every feed is an exposure. And so I think that's how we have to have to think about it. The other thing that I'll take away, and I think we should all take away is that I loved how the study compared mom's own milk and donor milk. And I'm not, I'm not sure why they're different here. I'm really not, but they are. And it's just a good reminder that we can't, you know, offer donor milk as an equivalent to mom's own milk, you know, we really have to appreciate and thank moms for the milk that they bring, we have to encourage them that that their milk is superior to donor milk, and if we can get it, and if we can support Mommies to bring in their own milk that, you know, it makes a difference. Yeah,
I think I think as donor milk becomes more and more available, you tend to put him on the same footing as mother's milk. And and they really aren't, I mean, they're processed, and does that create a bit more stickiness for these sorts of organic compounds to be sort of grabbed and attached to the milk? I'm not sure. The other article, which talks about something similar is called changes in micro and macro nutrients of human milk after bolus feeding a simulation study. The first author is involved Zoomer friend from the University of Tel Aviv. And what they did is that they were trying to evaluate possible changes in macronutrients and energy content of human milk after transfer through a feeding tube by means of simulation of human milk delivery through an NG tube. What that means is that they took samples of human milk, and they measured the levels and concentrations of macronutrients, but another portion of it was put through the pump and was analyzed after going through the pump to see if there were any changes from same sample in terms of protein, fat, and so on. And they follow the pretty standard protocol where the milk was sort of collected thawed, frozen thawed and just a bit like what we do to to milk in the NICU, they were able to perform at measurements. And what they found was was quite was quite striking, striking, the main fat concentration decreased by 2.1%. After being infused with the pump, the main carbohydrate concentration decreased by about 3%. And the total energy content decreased by about 1.5%. The protein content remained relatively stable. And so that was another article that is looking at some things from a different angle. The other article from Chicago looked at the effects of the pump and the equipment on the milk itself. And this looked at how the milk is being changed by going through the pump. So I thought they were so complimentary. And and yeah, I'm curious to see what what what do you think about that one as well?
Yeah, I mean, that's something we know right? We know that some nutrients get lost gets stuck in in the in the tubing, but it's nice to know how much and you can imagine over time that that is impactful. And the I would have liked to have seen them vary the time frame. That's what I would have liked to see. And I hope we see that so that way That way, maybe we can pick an optimal measurement and it may not work at an optimal time for feeding. And it may not work for every I mean, we know the physiologic timeframes. But that's not always possible, right? In our especially our extremely low birth weight babies, it's not always possible in our hypoglycemic babies. And so we may not be able to do it every time. But it's it's nice to have the data and we can at least target an optimal timeframe.
It made me think of what we spoke about with Matt shuba. Last week, where we talked about loss aversion, and I connected with that idea of sometimes you have a baby that is feeding ng or OG. And it's time to start oral assessments, oral feeds, and we may be lost, we have some loss aversion of saying I don't want to mess this thing up this baby is has is PICC line is out. TPN is off and tolerating enteral feeds, I don't want to start pushing this baby to feed by mouth quickly, and then cause some intestinal intolerance, and then have to put the baby and Po, you're afraid of these things. And you tolerate them going slower on the advancement of oral feeds, because you feel safe, that being being fed through ng over the pump is very, very safe. But these articles are now showing you not only are you losing some of the nutritive aspects of your milk, but you may also be delivering toxic compounds to the baby, because you're still using the pump. So like you said, I think the pump is necessary and you use it when you have to. But I guess it's it's now it's it's going to be we're going to start treating them like central lines, you know, saying well, do we need that tubing today?
That's when really it makes you think about duodenal feedings totally differently, and, you know, shortening our trials of, of do animal feeds.
So and this is and this is plastic in the NICU. So it's it's sort of my mind exploded a little bit because I'm like, What about the PICC? Lines? What about the umbilical lines? What about all the other things that we expose babies to? It just felt very overwhelming. And, I mean, I think the escalation of medical care has to be taken extremely seriously. And we have to do it as fast as possible. Because again, there's it's not 100% safe to have central lines as we know, but all these all these foreign material have have their take, they take they take their toll on the baby.
Definitely. We have some other breastfeeding papers here also maternal Perinatology. Let's see there, we have this maternal dietary fat intake during pregnancy and newborn body composition. Lead author, Natalie, a demon, they looked at 185 dyads, of mothers of singleton pregnancies, and they really looked at what was mom eating during pregnancy, um, and the postnatal, obviously birth weight percent body fat abdominal circumference and the ponderable index. So that was interesting, because I think that we're not, we're not using a lot of markers in neonates that we might use an older children or adults. In terms of kind of body composition. We don't have really good normative values for those things either. But it's interesting to evaluate, especially since we now we're learning that so much about our neonatal body composition, food intake, nutrition impacts are out or adult body. And so they looked at these groups of moms. And they wanted to see did the maternal fat intake during pregnancy correlate with newborn body fat, and they anticipated that it would. Just for reference, the moms had a pre pregnancy BMI on average of about 27 gestational diabetes rates of about 9% So you can see if that fits your your population, and the maternal fat intake did demonstrate significant correlation with newborn percent body fat. When stratas stratified by sex, it actually held true for males but not for females. And then they actually looked at when was when we're, when was the fat exposure, so to speak, so the second trimester saturated fat and unsaturated fat intake correlated significantly with infant adiposity. And so they're just highlight stating that there's a probably a, you know, a sensitivity to maternal fat intake during the whole pregnancy, but particularly in the second trimester.
And that's I thought that's what it was going to be picked up by some type. I thought some newspaper was going to pick up on that and say, you know, you can eat fat as much as you want during the first trimester, just watch second trimester, third trimester.
Well, you know, I can't imagine asking moms to do any more things differently during pregnancy, you know, there's really a lot to think about during pregnancy. And that can sometimes be overwhelming. But it's interesting to think about when we look at, you know, childhood disease. And so I heard that we have to optimize maternal nutrition, you know, during pregnancy, really, especially for our little babies.
And for the for the young neonatologist who are listening to us. This is, to me, this was very reminiscent of the Barker hypothesis, right? I mean, the study of the feminine the Dutch famine, and seeing that mothers who were starving because of the famine had babies with lower birth weights. And this idea of the, the infant origin of adult childhood origins of adult disease starts here. And having a baby that has a higher BMI or higher fat composition has long term ramification on the baby. And so to me, it was almost a mirror image of the Barker hypothesis on the other side, which is interesting, because the Barker hypothesis came, I don't know, I think he published that in the, in the 50s 60s, when mothers were, were starving. And thankfully, now we live in an era where we have ample resources and ample amount of food. And now the and now we're seeing the other side. So that two I thought that was very poetic that in 2020, this is this is now how we look at it, how do we manage the BMI of babies based on maternal diet during the pregnancy? And, and it was interesting to see that it holds true that if maternal intake is low, then you'll have lower birth weights. And with higher fat intake, especially during second and third trimester, you can have very high Z scores.
Yeah. So something certainly for our OB colleagues, but I think that we something still interesting for us, you know, we know that moms are going to have recurrent pregnancies. Frequently, that happens. And so I think there is sometimes some counseling that we can do in the NICU.
And what was interesting is that in the same journal, that's that's why I think journals are doing a good job these days of bundling articles. But there was this other article called called body adiposity. And oral feeding outcomes in infants. A pilot study by Srikant was phonathon, from the University of Central Florida, not too far from where we are. And basically what they looked at. It was a retrospective study of infants who were born at more than 37 week placements of infants who were born at more than 37 weeks postmenstrual age and they looked at the effects on tube feedings compared to birth, gestation and matched infants on for oral feeds. Actually, you know what, even though I want to add the author's affiliation, said Orlando, but the study took place at a level four NICU at Nationwide Children's Hospital in Columbus, Ohio. So I just want to clarify that because it could be a bit misleading. But basically, what they looked at was, what is the effect of the body composition of children and their and the effect that it has on their ability to orally feed. And it was a small study, it was 16 cases versus 16 controls. But they do found that they did find that higher body adiposity worsens the feeding outcomes of babies. And so you see, with two articles in the same journal, the direct link between maternal maternal behavior during the pregnancy and direct medical effects after birth.
Yeah, when we actually have a third paper that speaks to that, but I thought that this pilot study was interesting, because we've all had that experience, you know, a bit a big baby, maybe gestational diabetes, maybe not. And you know, they're a late preterm or they're approximating term gestation, and they just don't, they just don't eat well. And so I thought that this was an interesting place to look, especially in that late preterm group, you know, is it because is it because of late preterm? Or is it because of other other factors that that we're learning about? But I think we should speak about this other study that is similar breastfeeding and growth trajectory from birth to five years among children exposed and unexposed to just gestational diabetes. malladus in utero lead author, Camille do gas. So this looked at Mother infant dyads. from Quebec, they had 103 infants exposed to gestational diabetes and 63 children unexposed to gestational diabetes, and because of the health record, and they were able to follow a weight and weight increases, and Z score trajectories over time, some of the children they were even able to follow up to five years. And basically, what they found is that children who were exposed to gestational diabetes had higher weights. At six months, at four years, and at five years of age, they did adjust for things like maternal age, income and education. And so that individual age, weight, actually, that effect went away. But when they still looked at the z score trajectories, it was increased, basically across childhood, for the babies who had been exposed to gestational diabetes in utero.
Yeah, they mentioned something like that, that at six months, I think the curves separated a little bit. So they did see a significant difference. And then they sort of got closer to each other. And then it's at around four and five years that they really you can see that that sort of crossing that happens. And that was very impressive.
Yeah, very interesting. And obviously, we know that there are environmental factors, right, that do predispose to gestational diabetes. And that may continue even postpartum and then early childhood feeding. But that's not true for all cases of gestational diabetes. So I thought that was interesting. I think it's, it's something that we have to be thinking about, especially given the degree of kind of childhood obesity. I also liked that they looked at feeding. So they looked at formula fed infants in breast fed infants. And interestingly, there was there were no differences. I thought there might be, but there weren't. So I thought that was interesting, as well.
We're blazing through today.
Well, we got a lot of ground to cover.
Yeah, there's, you know, the apparent ontology is always always packed with with interesting articles. And, and again, I think it's for the listeners, I think sometimes what's interesting, and where I think we can provide some benefits to the audience is that you may be able to read one paper, but having the opportunity to go through the entire journal, sometimes you can see the connection points between the different papers and papers that may on their own ground, not provide may provide X amount of information in combination with other papers suddenly become so augmented, and your understanding of the problem becomes so much more complex. So that's, that's actually really nice. Did you have a paper you wanted to go to next? Or should I go ahead?
Um, I mean, we can mention this probiotic paper.
Go ahead. I will give us the honors. I will read the I will read the title, I think, oh, no, no, I want to read the title so that I can sound smart. And because I was smart. No, but this one, hold on. Where's the so this is, again, in general of peanut allergy, the effects of probiotic supplementation on the gene expression of immune cell surface markers and levels of antibodies and pro inflammatory cytokines in human milk. And this paper was from Veronique de Mayo mature from where were they from? It looks like from from from Boulder, Boulder City in Nevada, USA. Alright, so you tell us about this study.
So So I think that probiotics are hot topic. Perry, Natalie, let's just say and, and beyond. I think they're just a hot topic. So what I found interesting about this study is that the probiotic in discussion was Greek yogurt. So I thought it was worth mentioning. So it was a very, very small study, they looked at 15 women who take quote, unquote, daily probiotics, but for 11 of the women, it was just Greek yogurt daily, like yogurt intake. And then for for the moms Greek yogurt and some sort of probiotic capsule, which we know there's a range of probiotic options and they offer a bunch of different things. So they're not all equivalent. And they looked, they have their control group of 12 women who do not consume probiotics, and they they looked at some pretty I think impressive markers. So they were even looking at CD 28, CD 19 and CD 38 as well concentrations of immunoglobulins and pro inflammatory cytokines, il six TGF alpha and interferon gamma. And so they looked at a very few characteristics, they're kind of baseline characteristics between the group of mothers, I would have liked to have a little bit more data about that. But from what they gave us, there was no major differences between mommies, we didn't get a lot. We didn't get any baseline data on the infants, presumably, the, obviously, it's harder to get that data. So we we didn't get that. And, you know, I don't know what to make of it. But they showed that CDA CD 28 was higher in the probiotic group, there was not a change in immunoglobulins. And that il six was higher in the probiotic group, I would have liked to have seen some analysis, even though it's very, very small, but between the just yogurt group and make yogurt plus probiotic group, I think that moms care about their intake, they care about their health, they will, you know, they'll try to
in the NICU, how many times have you been asked by a mother? What can I do?
Exactly, that's right. And, and all the time is what I'm eating affecting the milk, especially when we say oh, we have to fortify your milk, or we have to, we got to add more stuff. And the moms say, Well, maybe my milk is deficient. And so, you know, I if we can give mommies things they can do if we can work on lacto, engineering, milk, just like we talked about in the other study, I think it's something we we owe to these mommies who are spending time pumping to give to get them more information. And
this, this paper has an important place, I think in the current discussion, number one, because the AP came out recently with a recommendation that that they do not recommend the use of probiotics in preterm babies. So that was, that was a big deal. And there's a lot of politics around this. And many people have discussed it, I invite everybody listening to go read the statement from the AP looking at the current evidence and and that's the recommendation, it was followed almost immediately in JAMA peds by a retort from, from Abdul Razak, one of our friends from Twitter, who basically showed that with the evidence that we currently have right now, even if new trials were being published, it wouldn't change the outcome that we're seeing, which are positive and reducing NEC. So regardless of where you stand, you can clearly see that there's there's a big hot debate going on. And it's difficult for clinicians who are not involved in this debate to decide what to do. If you're a clinician, and I'm going to be, I'm going to be speaking for myself here. I am not an expert on nutrition or probiotics. But it's difficult because you you take care of patients at the bedside and you say, well, the AAP is saying don't do it. And then I see pretty good evidence that it is beneficial. I get reports from other clinicians that are saying that it's beneficial. So what am I supposed to do? Well, this paper from the Journal of parasitology, this month says, Well, you know, you could actually get the benefits from probiotics indirectly, by just feeding it to the mother. That's I think is an interesting is an interesting way of doing of looking at it and still capitalizing on the effects of probiotics.
Yeah, and again, I don't know what to make with this data, you know, il six was increased, and that's a pro, you know, inflammatory marker. So I don't, you know, it'd be nice. It would we don't have any neonatal outcome data, but but the
ahead. No, I
was saying the CD 28 and the nd and it's in the cell. The T cell markers were interesting. Yeah, that that's what they looked at. How does that help you? How does that help the babies fight off infections? I don't know.
Well, I just think it adds, it adds to the debate. And if if we we've looked at a lot of things, giving moms vitamin D, giving moms, the iron supplementation, you know, are there ways that we can avoid having to give more things to neonates and give it through their mommies instead? So the debate continues, I guess, Oh, yeah.
Man, we're still we're running out of time, and there's still so many more papers. It's okay. What do you want to go through to what do you want to go to next?
I thought this was interesting. It's come up a few times. Recently for us in clinical practice the comparison of standard versus high dose ibuprofen for the treatment of hemodynamically, significant PDA and preterm infants.
Yeah, this was I pulled up the wrong paper, but this was published again this month. Last author is souvik Mitra, which we mentioned in our interview with Michael narvi, who is a super great follow on Twitter. He is a brilliant researcher. And I think you know, when Michael narvi was mentioning the fact that on Twitter, he's able to interact with world leading researchers. I think this is the type of people he was talking about. This is somebody who has been putting out great research on PDAs. And who talks about this issue in a very clear manner. So it was a great paper, it looks at the effectiveness and safety of standard versus high dose ibuprofen for the treatment of hemodynamically, significant PDA. And hemodynamically, significant PDA was defined as moderate to large in size. And that was about 1.5 millimeters or greater, with documentation of a left over dilated left atrium. And for that, for people who are interested, that means left atrium to aortic root ratio of 1.5 or greater. They retrospectively looked at preterm infants to either receive the standard dose 10 Five, five milligrams per kilo per day over three days, or a high dose where basically they would divide it into different sort of segments, you would have the 123, where they would get 10, five, five, but then they three to five, they would get 15 7.5 7.5, and then more than five days where they would get 2010 and 10. And so they were able to look at 60 preterm infants, mean birth weight was 898 grams mean gestational ages 26 weeks. And high dose ibuprofen was associated with a 21% Absolute reduction in PDA ligation, compared to standard dose ibuprofen. And then when they did their adjusted analysis, the receipt of standard dose ibuprofen, independently predicted increased PDA ligation risk, and there was no difference in a lot of the different outcomes that they looked at oliguria, neck VPD and so on. Right. So their conclusion was at Hydrocyanic profund may significantly reduce PDA ligations. And it was it was an interesting study. I mean, what do you make of it?
Well, in first they did, they did have babies who got oral or IV, which I thought was interesting, because that's been a part of the discussion in the past. And obviously, this is an ongoing debate in neonatology about the role of PDAs and closing PDAs. But if you're going to close a PDA, then, you know, it's nice to know what you think will be most effective. And I actually thought I want just to spend some time on their kind of dose escalation, because that's not something that I have done. Admittedly, in the in the past, I've either thought, well, I'll use either low dose or high dose, depending on an array of clinical scenarios.
Well, sometimes we've done it, where we do the standard dose, repeat an echo and then follow up with a second dose after the echo shows that it may be a smaller PDA smaller.
Sure, and you know, their group had done some, some pharma pharmacokinetic work, and they were comfortable with this dose escalation based on postnatal age, which I thought was, was interesting, especially because the one to three days is still you know, 10, five, five, just like their their standard dosing regimen. So I would have liked to have seen a matched control group, just to have that data. But I, I liked that there kind of safety outcomes were not worse in the in the group. And so I think that's what people are most concerned about.
And just to mention them, these were NEC VPD, oliguria, ROP gi bleeds, ivh and all cause mortality, and they found no difference. So yeah.
Yeah, I think that was useful.
Talking about PDAs, my God, the PDA PDA is just, we're not going to we're not going to avoid the PA guess. But there was another very interesting article that was published this month. And the last author is f. L. Koufax. We've mentioned before on the show, who is also a great twitter follow, and the article is called pitting ductus arteriosus shunt elimination results in a reduction in adverse outcome, a post hoc analysis of the PDA RCT control. And this was a postdoc appraisal of the PDA RCT to assess the relationship between early PDA shunt elimination and chronic lung disease or death. And I guess the reason I want to mention this article is that they looked at preterm infants less than 29 weeks who are at high risk of developing BPD or death. And they looked at if their PDA score was five or more obtained using echocardiography, between about one and a half days to two days of life, what would be the outcome of closure on their long term outcome. And for the people who are not familiar, this group had published a paper in the Journal of in the Journal of Pediatrics, which they refer to obviously in this article as the PDA or city where they looked at this PDA risk score, which is a pretty long formula it has its available there. It's gestation in weeks minus some factor plus the PDA diameter times another factor plus the left ventricular outflow tracts in mL per kilo times another factor, and so on and so forth. And you can come up with a with a risk score that ranges between zero and 13. Right. And so they use this score to define five as a sort of cut off and see if for patients who had a high PDA score, which was five and above, compared to patients who had a low PDA score, and when. And so what they did is that they they looked at the babies who had successful intervention, intervention, failure, and placebo. And then they had a third group, which was defined as low risk, which, which I forgot. I forgot how they define the low risk group, darn it.
Here, low risk infants who are not enrolled into the trial, but followed until discharge the low risk groups, basically a control
group. And so what they, what they found in their primary outcome was BPD, or death, and then BPD, and survivors and death. And what they found was BPD, or death, their comparison was the rates of it were 29% Is that 29%? Yes, 29% in the intervention success group 85% in the intervention failure group, 60%, in the placebo, 8% in the 8%, in the low risk group. And so what what this demonstrates is that the score, when they were able to successfully treat the PDA, in these babies with the high score, they were able to significantly impact BPD, or death and BPD. And survivors, just to give you that other data points, BPD, and survivors went down from 54% in the placebo group to 14%. In the intervention group that was successful, the intervention group that had a failure had a BPD, rate of 75%, which is completely nuts, death, and finally death. placebo group was 13%, intervention, failure 39% intervention, success. 18%. Another one not really significant, but point 06 on the P value. So okay, I'm gonna let you talk. Tell me what you think.
Well, I just don't know what to make about this intervention failure group. We don't we don't know. Were they smaller? Were they larger? Are we knows that they weren't closed? And maybe that speaks to the clinical illness severity of these babies, that we weren't able to close the PDA? I don't know. But I thought that was particularly interesting. I'm avoiding the answering your question about does interphase intervention success versus placebo? This is with intervention failure group,
this is another one where both articles actually complement each other. This PDA score is something I'm going to try to create a an Excel calculator out of, and I want to start using it because it's very comprehensive. And the Journal of Pediatrics article is really good. And you can see that intervention success is important. And then it to what length, are you going to go to reach intervention success, right? Because sometimes I think we give a single course of medication, we echo sometimes and we say, oh, it's got smaller, alright, that we're going to call it a day. Because we're not going to pursue more aggressive treatment. But maybe we should, when you look at this data, where, again, these are, I'm going to preface this by saying this was a small study, intervention success was 17. Babies intervention failure was 13 babies. So they add up to about 30 babies for the intervention group, the placebo was 30 babies, and the low risk was 13. Infants. So it's, it's small numbers, but reduction from 60% in the placebo groups 85% in the intervention, failure to 29% of BPD, or death, in the intervention success really makes you think about I should really make an effort to close a PDA. It should,
it should be noted that the groups were a little bit different, though, you know, to the baseline characteristics. So the intervention success group, the babies were slightly older and they were bigger. So it's just and same thing in the placebo group. So the intervention failure group had the smallest youngest babies and so it's just something
intervention, the intervention failure group human Correct.
Their average gestation was 25.3 weeks in the intervention success group 26.6 in the placebo group 26.3 And the intervention failure group, average birth weight was 695 versus nine 932 in the intervention success group, and the placebo group 969. So you they'll have note that those babies were younger and smaller. And maybe, maybe both why they were harder to close. And, and you know, the outcomes were different. So
yeah, and that's that goes again with some of the papers that we discussed two weeks ago, where we looked at the fact that babies for less than 26 weeks really need to have their PDAs closed compared to babies who are a bit older, and that this non intervention on PDA doesn't apply. It should not apply to every baby, irrespective of their gestational age. Now, I think you take that into account plus this PDA score plus the potential use of high dose ibuprofen, it feels like we're getting more and more tools to address this issue without having to do crazy things. You know what I'm saying? Not not not some very difficult procedure, that you may not have the services available in your hospital. So I think that that's,
I mean, the question is changing, right, not from Should we close the PDA or not, but which PDA should be close?
Exactly, exactly. And so that the PDA score was interesting. The the use of Hydrocyanic profund is also something that can be potentially used. Very interesting stuff, you know?
Yeah, I agree. Speaking of outcomes related to PDAs, we do have a paper on neck, which we can at least touch on, it was an observational study. That at that was at least interesting to note. So temporal and seasonal variations and incidence of stage two and three neck a 28 year epidemic epidemiologic study from tertiary NICUs in Connecticut, lead author Darius, Jim Govt. They looked at two units in Connecticut between the years of 1990 and 2018. They included almost 17,000 infants in the analysis. And I'll give you their their neck rates. So overall, about 2% of NICU admissions 3% in the low birth weight to less than 2500 gram, infants 6% In the very low birth weight less than 1500 grams, and almost 9% in the ELB W so less than 1000 grams. You can see how that fits with your population. Sip was diagnosed, they also looked at sip. So SIP was diagnosed 1.6% of all NICU admissions and in their VLBW W's point eight in their ELD W's 1.6. So not surprisingly, which we kind of know about neck significantly associated with lower birth weight and lower gestational age of birth. Sip was more common in infants of lower birth weights and gestational age at birth. And they found that SIP seemed more common in their male group. And both neck and sip significantly higher in multiple births, in black infants on univariate analysis, but after adjusting for birth weight and gestational age, and this was not seen in neck, but there was still an association with multiple births and black race babies after adjusting for birth weight and gestational age at birth. So that's just some of their baseline data. But what was was interesting is that their incidence of neck overall had not changed significantly. And that they found that birth months birth in April and May were independently associated with stage two or three neck even after adjusting for a lot of confounding factors, and that they saw this kind of multimodal distribution with spikes every 10 years. So, you know, the the team's hypothesis is that, you know, could this be related to some sort of environmental factors? This is different than the South Korea paper that showed a significant decrease in neck for their their meta timeframe. What did you think?
I thought that was interesting. I mean, this in the discussion, they do go into details about this bimodal relationship between the incidence of neck and that technically, there should be some hot seasons for neck like May June and October, November. And I have no idea if this is if this is evidence that is true or not, but we are in June and I'm gonna make sure wonder. And so I'm wondering if this is I'm what I don't know. I don't know what to make this. And I am sure somehow intrinsically I am sure that there's something that temporal association between atmospheric pressure there must be some role and Our mental role that always plays a role is are they able to pick up on that signal in the study? And at conclusively say that May, June and October, November are the hot season? I don't know. I think it's just interesting to have a paper that highlights those two times of the year as potential high risk for neck.
Yeah, something something to think about. And, you know, it's it's always good to have data that confirms, you know, things we already know, right? We know, it's the smallest babies, the lowest gestational age, and we know that there are some racial disparities in the NICU. And it holds true for NEC. And that's something that we just can't, can't ignore.
So and just so people know, I mean, this was a 28 year retrospective study, so so the idea that there's a sick site cyclicity to every 10 years, there may be a hard season, it's difficult to get from this study, because they only cover two of those timespans. But on a month to month basis, I mean, they had they had a significant number of data. So something something that's that was interesting, for sure.
Well, we have a lot more papers still in the Journal of Perinatology. You do you want to review some of those or
I have two papers that I want to mention. One of them is more of a shout out to our friends at the BPD collaborative. It's called invasive mechanical ventilation that 36 weeks postmenstrual Age adverse outcome with a comparison of recent definitions of bronchopulmonary dysplasia, Blanca cuivre government is the lead author Leif Nealon is the senior author. And basically, they looked at the dependence on mechanical ventilation, both invasive and non invasive at 36 weeks. And they looked at how does that translate into higher risk for complications and mortality. Beyond that point, and obviously, invasive makeup, mechanical ventilation was worse. But they also looked at the different definitions of BPD and saw how they were able to identify the highest group, the highest risk population with these new definitions, which we've spoken about, I think, on the first episode about a paper that had looked at that as well. And they were able to show that obviously, the Jensen and or the neonatal Research Network definition was a bit better in detecting these grade three patients. And even the NI CHD definition from 2016 did a better job than the typical one of how much oxygen that you wanted 36 weeks. So I thought that was interesting. And I think the BPD collaborative does tremendous work. And it's I was just wanting to recognize them. The other paper on respiratory outcomes that I was interested in was this one called high CPAP versus and IPPV and preterm neonates, a physiological cross cross over study. first author is Amit Mukherjee and last author's Jennifer Beck, from Ontario, Canada, I think, from Canada, from McMaster University. What What was interesting was they were trying to so they took basically, the gist of it is that they had babies who were on nasal CPAP babies who were on an IPTV and they switch them, they switch the babies who are in IPPV, to high CPAP. And babies who were on CPAP, to an IPP and switch them back and basically looked at, at the outcomes. So babies who were either what they call the high CPAP was the people of nine to 14, and other babies were on an IPP, and they had to meet obviously, they had to be they had strict criteria, they had to be more than two weeks old, they had to be at least 28 weeks, they had to be between one and 2.5 kilos, they had to be on less than 60%. And obviously they had to have parental consent. And what they looked at was when they swapped those patients from an IPP to CPAP, they did echocardiograms, and they looked at right ventricular outflow and left ventricular outflow, and they found that there was no difference. And so sometimes, what, what, what was very interesting is that sometimes we can leave babies and then IPPV, and a lot of that pressure can be, especially the minute we pressure maybe a bit higher, and they may get a lot of, of transmitted pressure to the abdomen, and that may impact fees and so on. And so you see that by actually not being so keep adverse, and using CPAP, two levels of 910 1112 1314. Even, you're not really going to impact negatively the outflow tract of the heart. Obviously, we have to be cautious with this data because it's small, it involved only 15 subjects. But I think this is very valuable data because this is a question you always have about how high can I go on the CPAP? And, and I thought that was I thought that was very interesting that they were able to look at that. They they even looked at you know the using Z Nava catheters looking at EDI, and they found no difference in terms of the peak EDI versus the minimal EDI is between an IPPV and CPAP. So I really liked that paper. I tend to do that sometimes even as a trial basis on a lot of the babies just try them on higher CPAP to take them off and IMV and I found that to be quite successful. So I'm happy to see that so and people are also publishing on a topic.
Yeah. And you know, we love we like Nava, so it was nice to see how they use the catheter feedback, you know, feed out data to, to kind of verify what they were finding in the in the trial. But for me, this is a reminder that I, I could probably use higher peeps than I have and I have been comfortable with in the past. So
and this was something that Dr. Sherman that Joe DiMaggio always, always sort of mentioned, right? Even if you're taking a baby off Nava, just straight CPAP leave the catheter and see what your eyes are doing, see how the work, get a sense of their work of breathing on CPAP to make clinical decision as to how they're tolerating that. So So I think that was really good. Yeah,
a little more objective data. So very neat. I mean, I think we should mention that there was a lot of kind of observational studies, survey data about how the COVID 19 pandemic has impacted and NICU care. NICU stays parental engagement. I'm not sure that we'll have the time to read through all of them. But I think certainly, there's some papers there to see. For review on that topic.
I think it was it was important to mark the moment of saying this is we went through something traumatic. And and I think, is this something that we're gonna have to deal with? Again, hopefully not, but we're going to need to better prepare our staff for these types of events, obviously.
Well, and I do think for the NICU, specifically some of the papers, discussed parental, obviously visitation and changes in things like parental handling of babies holding kangaroo care, things like that. And I think we have yet to see what impact that will have developmentally on on some this kind of cohort of babies this this year. But hopefully, hopefully, we'll be able to relax some of those restrictions.
In the coming I wanted to, I wanted, we spoke about this, but I wanted to maybe highlight a little bit some of the of the feedback that we're getting for the podcast and really just, you know, highlight some of the comments we're getting. And is it is it okay with you? If we go through at least one of the ones that we received on Apple podcast?
Is it okay with you? You You tell us that people have enjoyed the podcast? No, please go.
I want to believe that if we get negative feedback, well, we'll read them out on the air. But But please don't send us negative feedback. This is from er h three, I think I'm not exactly sure. And and this is a comment that was left a few days ago saying thanks to the incubator for a great interview with Dr. narvi. I think Twitter and podcast will make new and intelligence better physicians, I look forward to more episodes. So I think that was really nice. Because when the audience is able to appreciate some of the work we're doing specifically, when it comes to connecting different worlds of neonatology. It's It feels like we're being validated, because that was the whole point of Michael's interview, really, to communicate the need for social media and connections between the people within the community. So thank you.
But yeah, we appreciate all the feedback. It makes us want to keep, keep doing what we're doing. So we appreciate it, we're happy to receive constructive criticism as well. And we want to, we want to keep making this better for you. So just, you know, give us give us that feedback. So we can keep improving.
Yeah, and and we're going to continue reviewing the journals that we're reviewing. I also wanted to mention on the air, the fact that we're not really reviewing articles from the archives of disease and childhood. And this is a conscious decision because they have their own podcast where they talk about some of the highlights of their of their articles. And so we I highly recommend that you follow the ADC podcast for a summary of those of those articles. But yeah, leave us some feedback. Tell us what you want to hear about. And we have some great episodes. I think the next week, we have Betsy Pilon, who is who is the Executive co founder of the hope for HIV foundation in Michigan. And she has a lot of interesting things to talk to us about. And her her path and her experience with with HIV. So stay tuned for that one.
I guess that's all we have time for.
Thank you Daphna. I'll see you around soon enough.
All right, everybody have a good one be well,
thanks. Thank you. See you next week. Thank you for listening to this week's episode of the incubator. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you so feel free to send us questions, comments or suggestions to our email address you queue firstname.lastname@example.org You can also message the show on Instagram or Twitter, at NICU podcast. Personally, I am on Twitter at Dr. Nikhil spelled Dr. NICU, and Daphna is at Dr. Duffner MD. Thanks again for listening and see you next time. This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns, please see your primary care practitioner. Thank you