Hello Friends 👋

Despite a busy week, we are happy to present a new episode of Journal Club. Articles mentioned this week in the episode are listed below.

The articles covered on today’s episode of the podcast can be found here 👇

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, Juul SE; HEAL Consortium.N Engl J Med. 2022 Jul 14;387(2):148-159. doi: 10.1056/NEJMoa2119660.

Antibiotic exposure prevents acquisition of beneficial metabolic functions in the preterm infant gut microbiome. Xu Y, Milburn O, Beiersdorfer T, Du L, Akinbi H, Haslam DB.Microbiome. 2022 Jul 7;10(1):103. doi: 10.1186/s40168-022-01300-4.

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts. Welch BM, Keil AP, Buckley JP, Calafat AM, Christenbury KE, Engel SM, O'Brien KM, Rosen EM, James-Todd T, Zota AR, Ferguson KK; Pooled Phthalate Exposure and Preterm Birth Study Group; Alshawabkeh AN, Cordero JF, Meeker JD, Barrett ES, Bush NR, Nguyen RHN, Sathyanarayana S, Swan SH, Cantonwine DE, McElrath TF, Aalborg J, Dabelea D, Starling AP, Hauser R, Messerlian C, Zhang Y, Bradman A, Eskenazi B, Harley KG, Holland N, Bloom MS, Newman RB, Wenzel AG, Braun JM, Lanphear BP, Yolton K, Factor-Litvak P, Herbstman JB, Rauh VA, Drobnis EZ, Sparks AE, Redmon JB, Wang C, Binder AM, Michels KB, Baird DD, Jukic AMZ, Weinberg CR, Wilcox AJ, Rich DQ, Weinberger B, Padmanabhan V, Watkins DJ, Hertz-Picciotto I, Schmidt RJ.JAMA Pediatr. 2022 Sep 1;176(9):895-905. doi: 10.1001/jamapediatrics.2022.2252.

Associations of Maternal Milk Feeding With Neurodevelopmental Outcomes at 7 Years of Age in Former Preterm Infants.Belfort MB, Knight E, Chandarana S, Ikem E, Gould JF, Collins CT, Makrides M, Gibson RA, Anderson PJ, Simmer K, Tiemeier H, Rumbold A.JAMA Netw Open. 2022 Jul 1;5(7):e2221608. doi: 10.1001/jamanetworkopen.2022.21608.

Bronchodilator responsiveness and dysanapsis in bronchopulmonary dysplasia. Nelin LD, Kielt MJ, Jebbia M, Jadcherla S, Shepherd EG.ERJ Open Res. 2022 Jul 4;8(3):00682-2021. doi: 10.1183/23120541.00682-2021. eCollection 2022 Jul.

Policy Statement: Breastfeeding and the Use of Human Milk. Meek JY, Noble L; Section on Breastfeeding.Pediatrics. 2022 Jul 1;150(1):e2022057988. doi: 10.1542/peds.2022-057988.

Physiologically based cord clamping for infants ≥32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants ≥35+0 weeks gestation. Badurdeen S, Davis PG, Hooper SB, Donath S, Santomartino GA, Heng A, Zannino D, Hoq M, Omar F Kamlin C, Kane SC, Woodward A, Roberts CT, Polglase GR, Blank DA; Baby Directed Umbilical Cord Clamping (BabyDUCC) collaborative group.PLoS Med. 2022 Jun 23;19(6):e1004029. doi: 10.1371/journal.pmed.1004029. eCollection 2022 Jun.

The Hardest Thing. Viswanathan VB.JAMA. 2021 Dec 14;326(22):2263-2264. doi: 10.1001/jama.2021.21545.

The transcript of today's episode can be found below 👇

Ben 0:46

Hello, everyone. Welcome back to the podcast. It's Sunday. We have another week of journal club today. This is fun. How are you? Definitely.

Daphna 0:57

I'm holding up buddy. No. I'm feeling like you're you've had a long week on service.

Ben 1:04

Yeah, it's been. It's been a long week, we've been procrastinating the board review episodes, which means that we've been pretty much we've been pretty much recording, like every day after work. I mean, after after sign out. And but it's, it's, it was kind of neat. We hit the milestone of like, 100 board review episodes. That was kind of cool. And

Daphna 1:28

now this was like, this was kind of like, one of those ideas we had that were like, Well, surely this won't work. But let's do it. Because it was a need that like, I had the need personally. So yeah, we started in January. And that was that.

Ben 1:46

And here it is. I mean, we are publishing at a very brisk pace. So that explains the the 100 episodes reach very quickly. But you know, this was great. And thanks to Dr. Martin and Dr. Brodsky for supporting that and helping us in making this happen. And thank you to the audience for keeping us going. But yeah, it's been a busy busy week. And yeah, some some updates and stuff that we don't really need to talk about on the podcast. But yeah. Yeah, I mean, I was very excited that we were working on releasing my app to the main date app to the iOS store, which finally happened. So yeah, we'll talk to you guys more about that at some later point. We have to probably break break break down a little bit. What we're trying to do with this app does, etc, etc. But it's cool. It's all very cool. Is there anything else that we needed to talk about? No, not really.

Daphna 2:40

I think that's it.

Ben 2:45

Yeah, yep. Yep. Okay, then let's not waste any more time. Who should I start?

Daphna 2:51

You should start.

Ben 2:52

I feel like I could start. So the first paper that I wanted to talk about today is the anticipated publication of the healed trial in the New England Journal of Medicine. A title. Yeah, that was that was a long you add

Daphna 3:13

in a drumroll? Can you?

Ben 3:15

Could I do drumroll probably.

Daphna 3:23

Oh, yeah, you gotta keep that one on hand for more often use.

Ben 3:31

So yeah, so the title of the paper is trial of erythropoietin for hypoxic ischemic encephalopathy in newborns. The first author is Yvonne Wu, who is from California. It's a it's a large collaboration of investigators, obviously. And Dr. Wu had was the first author on the most recent evidence looking at HIV and EBO, but I didn't know she was a neurologist. I thought she was a neonatologist. So now, you know, now I know. Anyway, it's great. So anyway, the background information is pretty straightforward. Obviously, I'm always fascinated by this statistics, hypoxic ischemic encephalopathy, affects more than 10,000 infants each year in the US, one to three per 1000 births, and accounts for 22% of neonatal deaths worldwide. It's like,

Daphna 4:31

it's extraordinary. So we're just looking for every little thing to augment therapeutic hypothermia.

Ben 4:37

Right in the background, obviously. dimensioned Dr. Wu's paper where they looked at a face they did a phase two trial that looked at using 1000 units per kilo EBO versus placebo and looking at MRI and we reviewed actually that paper on the neonatology review podcast when we did the not too long ago or the week on ESS so the question In the heal trial was trying to answer it was. It was it was a double blind randomized placebo controlled trial to determine the safety and efficacy of high dose erythropoietin in conjunction with therapeutic hypothermia for Neuro protection in newborn infants with HIV. But the study included babies who were born at 36 weeks or more that had one or more signs of perinatal depressions, perinatal depression. This included an Apgar score of less than five at 10 minutes. cardiopulmonary resuscitation received beyond 10 minutes of age, a pH of less than seven or obese deficits superior to 15, moderate or severe encephalopathy according to a Sarnat criteria present at one to six hours of age. And then the receipt, obviously, of passive or active of passive or active therapeutic hypothermia, that was started within six hours after birth, and was continued for a duration of 72 hours. The exclusion criteria were pretty straightforward birth weight less than 1800 grams head circumference less than 30 centimeters. So some microcephaly, genetic or congenital condition affecting neurodevelopment, a hematocrit of more than 65%. That's actually a great board review question. If you're if you're a fellow try to figure out why they excluded these babies. Yeah, I'm not gonna say more parents considering redirection to palliative care, and several apathy attributed to a post natal event. So not something that was around the time of delivery garden with diminished cognitive capacity, I think that was very nice to mention that and a surviving twin undergoing therapeutic hypothermia, and that the anticipation that the child would not be available at two years of age. The intervention was the receipt of erythropoietin at a dose of 1000 units per kilo, or an equal volume of selling for the placebo group. And this was given IV before 26 hours of age at at within the first one to six hours and at two days, three days, four days and seven days. So a total of five doses. The primary outcome of the study was death or neurodevelopmental impairment of any severity at 22 to 36 months of age, neurodevelopmental impairment was defined as either having cerebral palsy, or gross motor function classification system level of at least one and a cognitive score on the belly of less than 90, I was so happy to see that. Because my mentor and I Dr. Charlie Bauer, we were always so frustrated with the fact that the you get like the belly three is very generous, right? Like, kids score much higher on the belly three than they used to on the belly to. And by using. By using certain cut offs, you can you can always find that there's cognitive outcomes that are very, very good. So by using a cognitive score of less than 90 to be defined as, as cognitive impairment was interesting, because they set the bar pretty high. secondary outcomes included deaths, cerebral palsy, GMF GFGMFC, s level, cognitive and language score in the valley three, and then they had a four level ordinal outcome consisting of death, moderate or severe and other mental impairment, math impairment or no impairment. They reported the parents are reports of seizure vision impairment and hearing loss, behavioral abnormalities and obviously MRI findings that were done at about four to six days after birth when possible. The study finally one more piece of information was they were based on a modified intention to treat approach, once randomized, always analyzed, but in this case, the babies had to have received at least one dose of people. And then they were analyzed. So randomization plus one dose of people. Any questions definitely so far about the methods.

Daphna 9:12

Now, so far, so good. Okay.

Ben 9:15

So the results were as follows 500 infants were included in this modified intention to treat analysis 257 in the in the erythropoietin group 243. In the placebo group, the evaluation of efficacy at 22 to 36 months of age, included 93.4% of the hippo group, and 91.4% of the placebo group. I think the COVID sort of threw a monkey wrench into the whole thing, so they had to extend their original window, but nonetheless, they captured most of these babies. Okay, let's look in the results. So the primary outcome death or neurodevelopmental impairment are 22 to 36 months of age occurred in 52.5%. In the EPO group compared to 49.5% in the placebo group with a relative risk of 1.03 and a confidence interval of point eight six to 1.24 P value point seven for no significant difference in the primary outcome. Yeah, yes, ma'am. death occurred in 14% 14.4% of the EPO group versus 11.5% of the placebo group. That two was not significantly different. neurodevelopmental impairment occurred in 43.8% in the EBO group 42.3% in the placebo group, also not statistically significant. The results of the four level or no outcome measure ie death, moderate or severe mental impairment, mod impairment or no impairment did not differ materially according to the trial groups, the percentage of children with a high externalizing behavior score was 7.2% in the equal group 1.5% in the plus in the placebo group. And that was statistically significant. There were no appreciable difference between there were no appreciable between group differences in brain injury score on MRI, the severity of brain injury, or the pattern of brain injury. And so the trial concludes by saying that multiple high doses of erythropoietin administered during the first week of age to newborns undergoing therapeutic hypothermia for moderate or severe hypoxic ischemic encephalopathy did not result in a lower risk of death or no other mental impairment than placebo, basically, shooting down a little bit the hopes that we had based on the preliminary data that people could be of value to these babies in terms of this primary outcome. So an unfortunate event, an unfortunate result for the HIV community that is seeing one more potential agent fade, but a very good study that helps us narrow the medications and the interventions we're giving babies, especially since it's not really shown to be too much of a benefit.

Daphna 12:13

Yeah, I you know, we're, we're still pretty early in our careers, right, admittedly, but it really felt like this collective community. sigh of disappointment, right when this came out just a few just just a week ago. So

Ben 12:29

yeah, it is what it is. But that's the healed trial. A long awaited

Daphna 12:35

long. Okay, well, thanks for reviewing that buddy. And I am going to take us in a little bit of a different route here. And talk about this article antibiotic exposure prevents acquisition of beneficial metabolic functions in the preterm infant, gut microbiome. Nice long title for us this this evening. Lead author shoe and in the journal microbiome, good for you for finding this in microbiome.

Ben 13:12

I think you're the one who found it.

Daphna 13:13

I found it Oh, good for me. And this was done in collaboration with Cincinnati Children's Hospital. So what they wanted to look at was, specifically postnatal antibiotic and administration, did it affect the microbiome, both in diversity of flora and in the metabolic function. So this was a prospective cohort study. The inclusion criteria were babies less than 36 weeks postmenstrual age with a birth weight of less than 2000 grams. And the intervention was obtaining samples at one week and three weeks of age from babies in a variety of sites. So they looked at the skin in the axilla. And they looked at the growing skin and then the gut flora, they looked at stool samples. So the baseline characteristics, they had 133 stool samples, and 253 skin samples, collected again, between for 68 infants born at less than 36 weeks postmenstrual age and a birth weight less than 2000 grams, and they collected these samples at one week and at three weeks of age. The median birth weight was 1384 grams and the median gestational age was 30.5x. The other things to note 86.8% of these babies received maternal antibiotics within 72 hours prior to birth 32.4 receive these post natal antibiotics. So these are antibiotic exposed group. I thought that was pretty good 32% and 46 or 46 infants 67.6% did not receive any postnatal antibiotics in the first two weeks. The differences for the baseline groups the antibiotic naive group was statistically significantly a little bit older, mean gestational age of 31 in five weeks compared to 28 and five weeks. Otherwise, there's no difference in the categories collected birth weight race, rates of C section, diet, meaning where they breastfed maternal antibiotic exposure, and specimen collection time in days. Most infants in this study were fed human milk during the study period 97% Isn't that great. So then, they were looking again at the primary outcome to really look at the diversity of the flora. So the team found that all three body sites examined that in in the antibiotic naive group, so didn't get postnatal antibiotics, but may have gotten maternal antibiotic exposure. The number and diversity of genera increased from week one to week three. And so they describe this as the maturing of the gut flora by increasing diversity. Similarly, a comparison of samples at week one and week three postnatal age received revealed maturation and differentiation at all three body sites. And at week, one, samples from the three body sites were more closely clustered together, so they looked more similar. By week three, the microbial composition had become more distinct across the three sites. And the composition of growing skin microbiome was much more similar to gut microbiome than was the auxiliary skin microbiome, which is a good reminder that the skin around the diaper area has a lot of those bacteria around it. And then the composition at each body site at week three was distinct from composition at week one. So a lot of changes happening. And then they wanted to look specifically about which types of bacteria so among the genera that significantly changed from week one to week three, Clostridium demonstrated the most significance in abundance and Week Three after accounting for potential confounders, gestational age, maternal antibiotics, route of delivery and infant diet. Several other general Klebsiella Sunraysia and E. coli were also significantly increased. Conversely, the staff species demonstrated the greatest decrease in abundance from week one to week,

Ben 17:59

you said staff species.

Daphna 18:01

Yes. That was your question.

Ben 18:07

Yeah, that was my question that thought I miss her. So just wanted to make sure the steps of our caucus species. Okay, that's right.

Daphna 18:14

And then they wanted to look at specifically the contribution of gestational age to these differences in microbiome at week one and week three, in these antibiotic naive infants. So remember, we're still talking about babies who did not have any postnatal antibiotic exposure.

Ben 18:30

Can I clarify that then? Because I wanted to ask you this question. So my understanding of the methods that you described are that they compare two groups of infants, some one of them that was quote unquote, naive, meaning they didn't receive antibiotics, right. And another one where the babies were exposed to antibiotics, postnatal antibiotics,

Daphna 18:47

but some babies in each group got maternal antibodies,

Ben 18:52

and they could exactly right. That's the one thing I wanted to clarify, they did not have control over the maternal antibiotic administration. Correct. And then the last

Daphna 19:01

question, theoretically, they didn't have control over any antibiotic gets ministration. But what I would have liked to have seen is a separate group that had no antibiotic. Right? Group

Ben 19:14

and the antibiotic naive group didn't get antibiotics all the way through because they looked at it at week one and week three, you said, Right, correct. So even at week three, they were still naive. Correct. Okay. Okay. Thank you.

Daphna 19:30

Yeah, that was that's what I was looking for was I wanted to see the babies who got no antibiotic exposure, because that's something we were discussing this week with board review, about more maternal antibiotic.

Ben 19:43

Like if you could have stratified the data even further into subgroups. Yeah, fair enough.

Daphna 19:49

And they did have that information because they did. They did say like in this small analysis Really looking at the, the different types of bacteria that they did account for maternal antibiotics when they looked at the type of bacteria. Okay,

Ben 20:11

thank you for clarifying. Okay.

Daphna 20:16

So going back to what was the effective gestational age, so they found diversity, and overall composition of the microbiome was not significantly different between infants born at the 28 to 32 weeks compared with 33 to 36 weeks gestational age, whereas postnatal age had a more significant impact on the microbiome composition than just the overall gestational age. Okay. And then they did look at gender differences. And they found that only one time point, with a significant difference based on gender was the groin at one week, so not a lot of difference there. And then they wanted to look at the antibiotic exposed group. So again, these are babies who got postnatal antibiotics. Fortunately, the duration and intensity was generally short to they say, quote, unquote, indeed, the 22 infants that received antibiotics 72% received less than 48 hours of impingement, and predominantly during the first three days of age. So I thought that was actually pretty good antibiotic stewardship. But they still saw a difference. So stool samples showed a decrease in diversity during the first and third weeks, and skin samples from the groin demonstrated decreased diversity by the third week. There were no significant differences in the diversity of microbiota from the axilla. from week one to week three. Overall, there was decreased differentiation of the gut microbial composition in the antibiotic exposed infants compared to the antibiotic naive infants. So basically, that antibiotic treatment showed a shift in the microbial composition, basically in the complete opposite direction relative to changes seen with the typical maturation that accompanies postnatal age. So I thought that was really interesting. I love these microbiome papers because they show you those colorful images of the bacteria and how they change over time and in different sites. So definitely something to take a look at. They also looked at the genera that differed between the microbial composition of these antibiotic exposed infants and again accounted for gestational age antibiotics, breast milk and delivery mode. And then stool samples they had a different types of bacteria they had sphingomonas acidic borax and Canada were significantly enriched in the antibiotic exposed group, whereas bacteria like glowshift, streptococcus, Enterococcus, and the staphylococcus were significantly more abundant in the antibiotic naive infants in the first week after birth. at week three, no genus was significantly higher in abundance in the antibiotic exposed infants. While several Clostridium class Droidekas, streptococcus staphylococcus and Blau show were significantly increased in the antibiotic, naive infants at three weeks after birth. So basically, antibiotic exposure really decreased the diversity resulted in a DOM they call the domination of the gut microbiome by a small number of bacteria, general both at one week and week three. And in these antibiotic treated babies, E. coli and Klebsiella were the dominant bacteria at all time points. They also looked at these metabolic pathways. And basically the data is similar, there was a significant change in the distribution of metabolic pathways in the preterm infant between week one and week three and those antibiotic naive infants, which showed this kind of maturation and increasing metabolic capacity in postnatal age when they didn't get antibiotics. But the change from week one to week three, and these antibiotic exposed infants was not significant. So they did not demonstrate this same maturation of metabolic functional capacity. Or their interesting results. There were two neonates in the study that developed neck and both of them are in the antibiotic exposed group, I should say developed neck during the study period. So this study adds to the literature that even very short, early antibiotic exposure changes the gut microbiome and metabolic function.

Ben 24:48

Yeah, I'm mesmerized by this figure six. Like yeah, I mean, it looks like a colorblind test, but you can see so well hide the diversity is just changing, impacted. Yeah so much. Yeah. This is Monday's tweet already committing that to Monday's tweet.

Daphna 25:06

An eye catcher. Yeah. All right. You're

Ben 25:10

Okay, my turn. I'm taking you to Jama Jama jump IDs, maybe Jama peds so this paper is called associations between prenatal urinary biomarkers of Dalit exposure and preterm birth a pooled study of us 16 Us cohorts. It is published in JAMA peds first author is Barrett Welsh. So, what's the what's the background there? The group who wrote the paper says that while the underlying risk factors for most preterm birth are unknown, exposure to environmental chemicals like phthalates may play a role. Italys are synthetic chemicals used in everyday consumer products such as personal care items, and food processing or packaging. So it's really pretty ubiquitous, actually. And exposure can occur through many sources, including household dust diet, personal care products like cosmetic, and consequently, salad exposure, like we said, is something that pregnant individuals could really be exposed to a significant level during the pregnancy. So the question they pose is, can we look at pulling some individual level data from 16 prospective studies conducted in the US to examine whether there is an association between prenatal urinary biomarkers of tallied exposure and preterm birth, preterm birth, so they systematically reviewed the literature to identify epidemiologic studies conducted in the US with data on urinary if Dalit metabolites quantify during pregnancy and gestational age and delivery, they focused and I quote, they focused on us studies to facilitate generalizability of results to the US general population. So this was intended for the US audience, which experiences relatively high levels of dilate exposure and high rates of preterm birth. So, preterm birth Sure, I was not really aware that we were more highly exposed to that dilate in this country. So all studies prospectively enrolled participants during pre pregnancy or pregnancy and all participants had live births between 1983 and 2018. They, they they had a close relationship with all the different authors of the cohort and the number of cohorts and the specific cohorts they worked with were actually filtered based on how were they able to actually get data sharing agreements, and so on and so forth. You can read more about that in the methods. preterm birth for the purpose of this study was defined as a delivery before 37 weeks of gestation. And, sadly enough, and that's an important point, and probably an important limitation, they did not have access to the information that would explain why a mother if had to deliver early, why they delivered early. So in the end, the analytics sample included a total of about 6045 participants. So how did they make sure that the fatality exposure assessment was consistent? So all participant provided urine samples during pregnancy for quantification of metallic mono Ester metabolites, urinary fidelity metabolites are the preferred biomarkers have tallied exposure and are highly stable in the urine. And that's why it's it's it's this is the mode in which it is used to be to be measured. All the studies that they included used, the US Centers for Disease Control and Prevention, the CDC or some form of CDC developed method and targeted the same metabolites as the CDC bio monitoring program. So this really made sure that all the studies that they were pulling from were consistent in the way that this was measured. And I really do not have the strength to read the 11 metabolites that based on the Yeah, so it's, they're, they're, they're impossible to pronounce, but the the list them in the methods. So in terms of the results, it was quite impressive. And that's the reason why we're bringing up this study the overall study population, consistent as we said, of over 6000 pregnant individuals, and of whom 9% delivered preterm, which is kind of it's always cool, right? Because that's what right that's what that's Yeah, exactly. Participant characteristics were similar between individuals who delivered the term and individuals who delivered pre term. Concentrations of urinary fairly metabolites included for analysis were detectable in 96% or more of urine samples. Bath Blood. I know.

Daphna 30:01

Yeah. I mean, that's just the stuff we're paying out, I don't know.

Ben 30:06

So, in terms of the association with preterm birth regression analysis showed that higher concentrations of most dilate metabolites were associated with slightly higher odds of preterm birth. After covariate adjustment, there was a 12 to 16% higher odds of preterm birth associated with an IQR interquartile range increase in urinary concentration of the list four metabolites, the MBP, the mono isobutyl of dilate the MEC PP and the MC PP. So 12 to 16% when these metabolites,

Daphna 30:50

now that's a big number. Wait, that's a big number. And sorry, those four metabolites are not the ones they put on the outside of stuff. It's not, doesn't say that they're those metabolites free

Ben 31:05

and IQR increase. IQR stands for interquartile range, I'm going to keep using IQR and IQR increase in the mixture of nine phallic metabolites was associated with a 25% higher odds of preterm birth, although the confidence interval included the know. So. Yeah, quite impressive. And then they did this hypothetical evaluation to see if, let's say you were to reduce your exposure to phthalates. What would that mean in terms of preterm birth. And so they said that hypothetical interventions to reduce the phallic metabolite mixture were estimated to prevent a mean of two to 32 preterm births per 1000 live births. And they have this graph, figure two of the paper, where they basically give you the estimated preterm births prevented per 1000 live births. So, and if you do a 10% reduction, you reduce 1.8 per 1000 births. If you do a 40% reduction, it's 8.3. If you do a 70%, reduction, 18.3, a 90%. Reduction, let's say you try to go family free, it's like a 32% reduction per 1000 live births. So crazy. And so in this, yeah.

Daphna 32:22

You were gonna say something, but they didn't. But they don't tell us how to do that.

Ben 32:25

Oh, yeah, I know, I was looking for that. And so the conclusion of the analysis is that in this pulled analysis of these 16, prospective us studies, higher concentration of several urinary metabolites in pregnancy, were associated with preterm birth, these findings highlight the need for public health and policy measures. And that's done right to reduce daylight exposure among pregnant individuals. So the one question that I guess I want to continue discussing is, in the in the discussion, what you might be wondering is, how is that mediating one and the other is it's just a statistic statistical association, or is there potentially a mechanism? And I'm going to be very upfront, I am really not an expert in this field. And I'm reading this, like most of you all from as an outsider, and so I don't know, but the authors, right. Yeah. The authors do suggest that the association of talent metabolites with preterm birth may be mediated by oxidative stress and inflammation at the maternal fetal interface. And that some additional mechanisms may include this relate dysregulated trophoblast differentiation and endocrine disruption as valid biomarkers have been associated with downregulated expression of placental genes responsible for these processes. So they do venture a little mechanism. But I don't know I felt like this is a paper that you know how like, there are papers that you read them and you're like, alright, this changes practice right away. You read this paper and you're like, this should mandate some policy or some, some guidance from a cog the CDC because this is this is significant.

Daphna 34:06

Well, there are lots of things that are associated with preterm birth that we're not fixing as a society right?

Ben 34:12

I know that this feels like this feels like you could potentially I mean, right it's not like saying hey, if you don't drink water, which is like hey, how am I supposed to do that? But like you could potentially correct for that right? I'm assuming that if you did an inventory of what you have at home and then you were bit my everything you think so? Yeah. Tell us in the on Twitter people like is there a way to go valid free? In France, they started to label things that have they call them endo endocrine disruptors, right. And this This is now added to labels in in France. So maybe maybe this could be done but now like you said, Look,

Daphna 34:54

yeah, vinyl flooring, lubricating oils, personal care products like soaps, shampoos, hairspray. With polyvinyl chloride plastics are used to make products such as plastic packaging, garden hoses and medical tubing. For example,

Ben 35:08

you know, medical tubing. We know we reviewed some of that stuff already. When we looked at Yeah, yeah. So anyway, interesting paper. I mean, this is this is like,

Daphna 35:21

this is this article from it's called? phthalates. The everywhere chemical.

Ben 35:29

Oh, that's, that's terrible. deflating, okay, today.

Daphna 35:35

Okay, well, thanks. No worries. I'm gonna do this. Study this article physiologically based cord clamping for infants that are 32 and Oh weeks gestation, randomized clinical trial and reference percentiles for heart rate and oxygen saturation for infants 35 And oh, weeks gestation. The title is a mouthful. That's enough. This the lead author and is a Shiraz, but durian. And this is coming to us from Australia. So what's the question? The question was, are there changes in the physiologic parameters of the BB, and if you did, this technique of PB CC, which stands for physiologically based cord clamping. So what that means is you give stimulation to the baby, you basically do the initial steps of resuscitation, including PPV. And basically establish that the baby has regular spontaneous breathing and co2 color change on the co2 detector. And this is a non intubated baby, this is a baby who they put the co2 detector between the the mask and the the T piece. So basically, you complete resuscitation while the baby is still attached to the placenta, and then you clamp the cord. And they wanted to compare this to delayed cord clamping, which was until greater than two minutes after birth. And compare it to early cord clamping, which means that basically, and I'll talk to you about the randomization, but basically this baby was randomized immediately after birth. And as soon as that electronic randomization occurred, that they cut the cord. So

Ben 37:42

hold on, hold on, hold on, hold on. So you said the physiologic is the baby gets resuscitated. And you do everything very much at the delivery site and still connected to the placenta. And then And then you said delayed cord clamping is two minutes after birth.

Daphna 37:58

Yes, so delayed cord clamping was.

Ben 38:07

Yeah, cuz that's, that's, that's way longer than I mean, I do 30 years 30 to 60 seconds, two minutes is a long time.

Daphna 38:15

And in fact, in fact, they said that they're normal, quote, unquote, delayed cord clamping was 60 seconds. Okay. But they were using this deferred cord clamping for two minutes in this observational study arm because they what they basically wanted to do in this observational study arm was compared to babies that were still attached to the placenta, but like didn't require resuscitation versus the babies and kind of give them the same timeframe. So that makes sense.

Ben 38:48

I think that makes sense. Okay, well, well, I'll give

Daphna 38:51

you some more details, and then you'll tell me more, if it makes sense. So between July 2018, and may 2021. infants born at 32 weeks gestation, and had a pediatrician called to attend the delivery. So these were high risk deliveries greater than 32 weeks gestation. So any reason the pediatrician would be called as they are preterm, they're less than 37 weeks they had fetal growth restriction with conium breech in instrumental birth or an unplanned C section. That's why they would call the pediatrician. So basically, as soon as the babies were delivered, they used a electronic randomization sequence and they randomized the babies one to one within 60 seconds of birth using this smartphone, link to either this physiologically, physio hold physiologically based cord clean I think or the early cord clamping. And I'll tell you the early cord clamping. They told us the time to early cord clamping so the mean time to cord clamping in the early cord clamping arm was 27 to 51 seconds. So you know that. So basically they waited they just randomize the baby whenever the baby was randomized early cord clamping, that's when they would clamp for that group. And then the babies with PVCC ventilation, and they looked for ventilation being established by either positive pressure ventilation or effective spontaneous breathing prior to cord clamping. So they received PPV. And they had umbilical cord clamping deferred until two minutes after birth, and until 60 seconds after they had color change on the co2 detector. So for some babies that was longer than two minutes for somebody whose it was less than two minutes. Infants in the PVCC group who breathed without PPV had their umbilical cords clamped at two minutes after birth. And then non randomized infants, those infants that were vigorous after initial stimulation so that they weren't going to need additional resuscitation. And were not then randomized to PVCC or ECC, and they have this deferred cord clamping for 120 seconds in this observational study arm and I'll tell you more about that later. The primary outcome was mean heart rate between 60 to 120 seconds after birth, which I thought was an interesting time period, and measured using this three lead ECG and then extracted from video recordings. baseline characteristics they had 500 named babies enrolled 123 babies were randomized 63 to PB CC and 60 to early cord clamping the mean gestational age was 39.9 and PVCC and 39.6 in ecc. There were more babies interestingly in the PVCC arm who were affected by quote unquote complications of pregnancy. And that was like a catch all hypertensive disorders, diabetes, sepsis, oligohydramnios antepartum, hemorrhage and placental previa. There were 43% of those babies affected by complications of pregnancy in the PVCC compared to 25%. In early cord clamping and 26% in the delayed observational arm, I told you cord clamping in the early clamping was 27 to 51 seconds and the cord clamping occurred at a median of 136 seconds and the PVC arm, which I thought was pretty good to me led to the primary outcome. So the mean heart rate between 60 to 120 seconds after birth was 154 for PVCC and 158. For ECC so no significant difference in heart rate at 60 to 120 seconds after birth. There are also no evidence of difference between study arms in each of the subgroup analyses. So they looked at Babies who are 32 to 35, and six weeks gestation, they looked at Babies who needed emergency deliveries versus non emergency deliveries. And there was no statistically significant difference. They also looked at 31 secondary outcomes. And really the only difference they found were that more infants in the PVCC arm received any resuscitation compared to the ECC arm in the ECC arm. Infants establish regular cries shortly after randomization did not receive resuscitation including vigorous stimulation. So they were more likely to actually not need additional resuscitation. A higher proportion of the infants in the PBC arm received PPV. And the one potentially positive thing was that respiratory support was initiated sooner in those babies than in the ECC. The median time from birth was 63 seconds versus 93 seconds. No really major other difference. There are no major differences in adverse events like admission to the NICU or first measured temperature. So they were really hopeful that they would see an improvement in kind of these physiologic parameters, but they just showed no difference. Other interesting results so then they took these non randomized infants who just got a delayed cord clamping without recessive additional resuscitation for two minutes and they created this observational I need to look at the heart rate and oxygen saturation norms. And we have those right, they dictate our first 10 minutes in the delivery room, even in our NRP. But they wanted to look at this group of babies because they were considered, quote unquote, high risk infants as compared to the norms. And that we currently have, which are really for low risk term infants. So I will leave that for people to go take a look at the heart rate and saturation plots, what I would have liked to have seen as this third group be plotted against the first two groups in the earlier graphs, right, they're all there for people to look at.

Ben 45:45

Yeah, I mean, this is this is a bit controversial, right? I mean, there's, there's, there's this belief that if we could perform all the steps of resuscitation at the on the sterile field are almost right. Things will be better. And now this is showing that maybe we don't need to. So interesting. All right, I have to I have to we have to get moving because we have a few more papers. And I would like to get to them and you have one more after that correct. Okay, so let me go to the next one, then. This one is called bronchodilator. responsiveness and di synapses. In bronchopulmonary dysplasia. first author is our good friend Leif Nealon. And co authors are friends from Nationwide Children's Hospital. This is obviously from Columbus, Ohio, and this is in the ER J open. So lots of stuff to define even in the title. The first thing we need to talk about is this group out of nationwide has published in the past the possibility of performing infant pulmonary function testing during the NICU hospitalization. And when they did this, this study looking at pulmonary function testing in the NICU. In patients with BPD, they were able to actually define several phenotypes of babies with BPD. And these are obstructive genotype restrictive phenotype or mixed phenotype. So, I mean, if you remember, pulmonary physiology not really earth shattering, but interesting that they were able to define that in a in a paper that was published in pediatrics that was called infant pulmonary function testing and phenotype and severe bronchopulmonary dysplasia. And that was published in what year 2018. So the term I was not so familiar with, was this die, synaptic long growth. And and what does that mean? And so basically, this refers to the non proportional growth of airways and long, resulting in a relatively small airways for long size. Does that make sense meaning your, your conducting airways don't grow as much as your parenchyma. And so basically, there's this differential growth of airways and lung parenchyma. I was not familiar with that until this paper came around. And I had to look this up a little bit more. And why they're using that is because it has been suggested they die synapses ratio can be used as a non invasive method of describing the relationship between the airway caliber and lung size, where the smaller the die synapses ratio, the greater the die, synaptic long growth. So what are they trying to do here? So they tested the hypothesis that in infants with BPD, and who were being assessed for their response to bronchodilators, which is another study that they did, that those babies with bronchodilator response would have a smaller die synaptic ratio than non responders, meaning that their that their disproportional lung growth would be more pronounced. In other words, infants with Bronco dilator response would have relatively smaller airways relative to their lung size than non responsive infants. And I think you may say OB, and you're just like, nerding out on some BPD stuff. Why is that relevant to us?

Daphna 49:10

And the truth irrelevant.

Ben 49:12

So right, so I guess the overarching theme of what I believe these guys that these guys and gals that at at nationwide are trying to do is trying to be able to define the patient characteristics of these babies with PPD. Right? We tend to put them all in one big bucket or you have severe BP, but they all they are differences between each one. And right now, we have a systematic approach where we give them a few sets of medications, and that's really it, but they have individual profiles that could help us maybe to tailor their their treatment. And that's interesting, and that's probably going to help us be more comfortable in the management of these babies because, I mean, even if I enjoy managing babies with BPD It is terrifying. You don't know how they're going to respond to anything. And it's complicated and don't get better quickly. So it is very tough. The patient's in so the study was designed as follows the subject from this cohort, were actually a subset of a cohort that was described in the pulmonary function test publication in pediatrics that I just mentioned, who had bronchodilator response testing done. And so briefly, what did they do? Infants who were hospitalized in their NICU with a primary diagnosis of BPD, were referred to their first infant pulmonary function testing between 22,003 and 2015. These babies basically what? Let me actually, yeah, so I'll talk. So in order to do infant pulmonary function testing, obviously, right, if you remember, the adult pulmonary function testing, you breathe into a mouthpiece and they stop the airflow and they try to measure your lung volume. But because babies cannot follow command, they actually have to sedate them with chlorohydrate. And they undergo rapid volume, then then they undergo raised volume, rapid thoracic compressions pyrometry, and body plethysmography measurements, as they've described in prior papers, that it's it is scary. And so then you may want to why would you even do that. So they are pretty clear that in their BPD unit, they do refer these babies to infant pulmonary testing, when they're kind of getting stuck, meaning they're trying everything, and the babies fail to make significant progress. And so when they are stuck, they then resort to this pulmonary function testing to try to get a better understanding of where they could effectuate some some some positive momentum right. And this is not done lightly. The decision to go for IPF T is made by consensus of the multidisciplinary, BPD team. So they have a lot of eyes looking at this. And they think carefully about who goes and who doesn't. And they estimate that the cohort that that this cohort represents about 15%, one five of all BPD patients admitted to their BPD unit during the timeframe. So it's not the majority either bronchodilator response testing. So basically, what they would do is that infants were randomly assigned to receive I'm sorry, to receive albuterol. And, and the way they do this, give me one second. And so albuterol is held for eight hours prior to testing. And after pre bronchodilator. pulmonary function testing is completed, they give two puffs of albuterol every two minutes, until there's a 10% increase in heart rate, or a maximum of eight puffs are given. And then pulmonary function testing is repeated. They define a bronchodilator response as a 10% increase or more in FEV 0.5 million forced expiratory volume in less than have been half a second, which represents two or more standard deviation above the normative mean for change in FTD 0.5 in infants. In terms of the die synapses ratio, the dice and EPS this ratio is calculated from the forced expiratory flow at 50%. Or forced vital capacity using an equation that's in the chart that's in the dark in the manuscript. You can look it up, I'm not going to use I'm going to lose you guys if I if I go over that. It's not complicated. The bottom line is the die synaptic ratio is inversely related to die, synaptic long growth, ie, the smaller the ratio, the more dicen abscess you have, the more you have this, this I'm losing my words, I'm tired, I apologize. This differential growth of airway and lung size. Okay. So let's go into the results. They had 93 patients that underwent bronchodilator Response Testing 63% met criteria for a response to a bronchodilator. And they were called for unquote responders. 37% didn't respond to bronchodilators. And they were termed non responders. So that's not insignificant right there. At the time of pulmonary function testing, they were no difference between groups in terms of postmenstrual, age, length, weight type of respiratory support, the breakdown of BPD, most of them had severe BPD 60 to 62%, had grade three BPD 24 had grade two 2% had grade one, they were using the Jensen criteria. The phenotypes 51% were obstructive 41% had a mixed BPD and 9%. Were restrictive. There were more infants with moderate to severe obstruction in the responder group than in the non responder group. And what you will see is that the responders have a more have a more serious I guess, profile. So responder had lowers responders had lower FEV 0.5 and FEV 0.5 over FVC than non responders. The responders had greater indices of hyperinflation on the pulmonar array function testing and the median die synapses ratio in responder was significantly smaller than the median ratio in the non responders meaning their die synapses was actually worse than the kids who did not respond, suggesting greater die synaptic lung growth in responders and non responders. There was also there was no correlation between the DI synaptic ratio and postmenstrual age. And when they were looking at other relationship, looking at the dice analysis ratio, and FEV 0.5, which is basically FEV, one that we are familiar with in adults and older children, but it's an infancy it's FEV 0.5. using linear regression, they found a significant correlation between the die synaptic ratio and FEV 0.5. They also found a significant relationship between the die synaptic ratio and total lung capacity. And using and that's, that's I'm going to stop here. I'm going to stop here. So the conclusion were that these findings demonstrate that they are pulmonary function test parameters associated with Bronco dilator response. And responders have experience of greater die synaptic lung growth and non responders. And I think, again, all the patients that we have who have severe BPD in our unit, for example, are being tried on inhaled medications. And we don't know we just we just do it, we hope that it helps. And it's interesting to see that there are ways to learn more about your patients, even when they're on these extremes of of this of BPD and this disease in order to actually try to optimize even there, I think this is this is this is a degree, I guess this is my takeaway. This is a degree of excellence and care that inspires me to deliver better care, right? I mean, you could just say, Well, I have some severe BPD. I'm just giving him some broker dilators. And I'm already doing pretty well. But to know that there are people who are thinking even harder on all this is quite fascinating. And so yeah, this is this is very neat. This is very inspiring stuff.

Daphna 57:00

Yeah, I mean, it's just over and over and over again, how important individualized medicine is right? And even for any any of the diseases we treat any of the pathologies we treat. They there are these phenotypes, right, that are just we haven't totally elucidated and I think one day will totally direct our management. So yeah, it's a step in that direction. Okay, I have a paper I know we're getting short on time, but I have this paper that is also generated quite a bit of buzz. So it's an important paper for us to review. It's entitled associations and maternal milk feeding with neurodevelopmental outcomes at seven years of age, and former preterm infants, the lead authors and Dr. Mandy Belfour from the Brigham and Brigham and Women's Hospital in Boston. This is published in JAMA Network open so they wanted to look at the associations between maternal milk feeding and cognitive, academic and behavioral outcomes of preterm infants born at less than 33 weeks gestation. You know, we feel pretty good that maternal or breast milk exposure changes these outcomes. But most of the studies have been done in the full term infant. And so that's why they wanted to study these babies, and they manage to follow this cohort to seven years. So this cohort study is actually part of a larger study the dyno randomized clinical trial, which was looking at DHEA D H A for improvement of neurodevelopmental outcomes. So then this was a subset of the groups they looked at, again, maternal or milk, moms own milk exposure. So they wanted to look at milk dose in like 25 mL per kilo increments and overall milk duration over NICU admission. Okay. The primary outcomes was looking at overall intellectual ability, they use the Wechsler abbreviated Scale of Intelligence, probably the most common used in developmental studies, especially looking at the NICU population. They wanted to look at the full scale IQ and verbal and performance IQ subscales but they also wanted to look at academic achievement and behavior, because this is a place where it preterm children also perform more importantly than full term children. So they looked at the wide range achievement test. They looked at symptoms of Attention Deficit Hyperactivity Disorder using the Connors third edition. They looked at the strengths and difficulties questionnaire and executive function was evaluated using the behavioral Reading Inventory of executive function. So they also looked at a bunch of covariates. It looked at income, educational level, occupation, race, smoking satis alcohol use number of people living in the home. They had people pour through the medical records looking at parity, antenatal steroid exposure, a lot of neonatal characteristics, sex, birth weight, gestational age, multiple birth, and then a bunch of neonatal diagnoses neck BPD, sepsis, severe ivh, and PVL. All potential confounders when we're looking at neart neurodevelopmental outcome. So from dinos trials original cohort of 657 infants, they excluded 20 participants who died before seven years of age and 51 participants who are not able to be evaluated at seven years of age. So in total, they had 586 participants remaining infants were born at a mean birth weight of 1323 grams, and a gestational age of 29.6 weeks. So we'll just get into the meat of things. So they wanted to look at I told you, I Q. And so they found that a higher intake of milk in the NICU and a longer duration of milk feeding was associated with higher full scale, verbal and performance IQ scores. when adjusted for clinical and social variables. This did attenuate most of the associations, though they still remained positively association with performance IQ. And you like these. So you're gonna appreciate this, but they said that there was an increase in performance IQ by point six, seven points for every 25 ML is per kilo per day increment that a baby received in the NICU. Similarly, a higher intake of maternal milk in the NICU and a longer duration of maternal milk feeding were associated with higher reading standard spelling and math computation scores when unadjusted. And again, when adjusted for all the potential confounders the estimates of academic achievement were attenuated, but still positively associated with higher reading standard and math computation scores, and a longer duration and milk feeding was also associated with higher spelling scores. Again, for example, each additional intake of 25 miles per kilo per day of maternal milk in the NICU, the reading standard score was 1.14 points higher at the math computation score was point seven six points higher. With adjustment longer duration of maternal milk feeding was still associated with higher reading standard point three three points per month of milk received math computation was point three points per month of milk received and spelling point three one points per month received. And they do talk about that for people who are less familiar with the studies. They they you may say, are they statistically significant? Or are they clinically significant, but for example, one point on the reading score per each additional 25 ML is per kilo per day of milk translates to approximately six to seven points, potentially when multiplied over the typical daily intake, which is a clinically significant change in outcomes. They also I told you wanted to evaluate ADHD symptoms and higher milk intake in the Niki was associated with a lower Connors ADHD score. So a lower score on the Connors is a good thing. Theoretically, it means you have less of these ADHD type symptoms was not, there was no significant association with the brief or the SD Q scores. The other interesting findings, these were great tables, I wish that they were graphs I'd love to see them in graph form because I think they would be really impressive. But the effects were even greater for babies born less than 30 weeks of gestation, and you can see, the more preterm you are the greater effect. So I thought that was really interesting. The only time they didn't see that the Connors for the ADHD scores were actually strongest among infants born at greater than 29 weeks of age. They also looked at a variety of factors like babies who were SGA and maternal milk intake was associated with better performance IQ for non SGA infants only. I thought that was interesting. They wanted to look at effect by sex or the dyno treatment group. So with the risk See of DHA, and they didn't see any difference with those modifications. So the takeaway is that like in term infants in this cohort cohort of preterm infants, and milk feeding during the neonatal hospitalization and after discharge were associated with better performance, IQ, academic achievement or reduction in ADHD symptoms, especially for those babies less than 30 weeks gestation.

Ben 1:05:32

Yeah, I mean, I think this is a great paper, I just wonder how many more paper I mean, these the I have a feeling that the, the benefits of breast milk are well established at this point. And I think the authors in the background, they're saying that some domains are not reliably assessable, and just school aged. So this is where they're really trying to create a space for them to publish this paper. But I mean, yeah, I mean, I have not surprised by the findings. And you always, you always wonder, though, the confounding effects of parental dedication, saying the mother who made the effort to really provide breast milk to come to feed the baby, and so on and so forth, maybe a parent who will be really behind their kids in during school years, and maybe they will perform it better. There's no way to correct for all these things. And it doesn't negate the benefits of breast milk, in my opinion, based on all the evidence that is out there already. So yeah,

Daphna 1:06:38

yeah. And I mean, when we talk about confounders, right, so there are so many things that make it possible for certain families to provide breast milk versus families who can't provide breast milk, right, above effort that we just can't totally account for in the literature. But I think I think we know that more breast milk is better, but the dose response is cool, right? Because our, our, our AR benchmarks are really about like any breast milk, and then like, did you get like a sip of breast milk a discharge when it's really the total daily amount, and the length of time makes a difference?

Ben 1:07:21

Yeah. And so I guess on this note, we should mention that the AAP published a policy statement called breast policy statement, breastfeeding and the use of human milk. first author is Joan younger, meek. last author is one of my residency mentors, Lawrence noble, who's a phenomenal physician. And it's a very nice report. And I don't think there's anything controversial, anything that you guys are probably not aware of breast milk, and breastfeeding is good. And you should support it.

Daphna 1:07:57

I think but the the exact terms just so people know what the hoopla is about. But they, the AAP recommends exclusive breastfeeding for about six months, with complimentary food introduction at about six months. And this is the major change is mutually desired by family supports continued breastfeeding until two years or beyond or beyond. That's right. So that's the major change. And you know, it's a good review on some of the challenges with getting breast milk. So they talk about what we can do the hospital like what pediatricians can do, what are some of the equity concerns, and they talk about the language we use around breastfeeding or chest feeding? And so it's, it's useful to evaluate some of the some of the buzz about the paper is obviously that it doesn't exactly explain how we're going to support pumping and chests feeding people to get this done. Right. So

Ben 1:09:07

yeah, and I think it's, it's maybe a good thing that you just you just have to support because I think if they if they had outlined anything, then you may have find yourself boxed in I think this leaves all the possibilities on the table. So yeah, absolutely. And I think yeah, I mean, it's, it's, it's especially true considering that they are making the recommendation to promote exclusive breastfeeding for such a long period of time. Definitely need to find ways to support mothers. I mean, I remember when my wife was trying to breastfeed as a med student like it's it's hard like just it's so taxing on the schedule never

Daphna 1:09:47

done. Yeah,

Ben 1:09:49

I mean, so yeah, definitely. Try to yet and I think I don't know how you take this but when they say that they recommend can do It says the AP supports continued breastfeeding, along with appropriate complimentary food introduce at about six months. I'm assuming obviously this means that if you could exclusively breastfed for six months, it would be best. But I also don't think it means that your baby is going to be awfully affected if you partially breastfeed for the first six months. So I think I think the maternal wellbeing has also to be taken into account. I think, ideally, I'm taking it from the standpoint of ideally, exclusive breastfeeding for six months is what you should aim for. But looking and speaking to parents who who are breastfeeding, it is so hard that I also am very conscientious of making sure that these mothers who have needs of their own are not completely ignored as well. And there was a very interesting editorial in JAMA, I don't have it at the top of my head, which talks about this where the pressure of breastfeeding had some significant negative impact on the mother herself. And so it's a balance at the end of the day, it is a balance and any breast milk that can be provided, as you've shown in the last paper you reviewed, it is already beneficial. So so that's, yeah, that's that's the way I understood it. And I'm sure people will interpret the data as as they wish. But

Daphna 1:11:24

yeah, I think I think that is an optimal. It's an optimal recommendation. If and when we can. We can we can do it. Right? Yeah.

Ben 1:11:35

Yeah, absolutely. Absolutely. All right, we went over time. Remember to grab your CME credits at the end of this episode, you can find that on the on the episode web page. And yeah, there's, there's no, that's really it for today. I'm not gonna I'm not going to extend the show any longer. Thank you, Daphna, for making the time and see you guys later this week.

Daphna 1:11:58

All right. Bye, everybody.