Hello Friends,

We have a packed episode for you today. This week we review a series of papers published in Pediatrics, The Lancet, and in Circulation all related to umbilical cord management after delivery. Daphna reviewed some interesting papers as well. One meta-analysis looking at repeat surfactant dosing, and another study on the risk of malignancy after CT scan exposure in the pediatric population. In addition to more interesting papers, we also have the pleasure of hosting on the show Dr. Karen Puopolo and Dr. Dustin Flanery from CHOP for the EBNEO Commentary. This month Dustin and Karen shared their thoughts on the recently published NEJM paper on maternal vaccination for GBS. We hope you enjoy this Journal Club and as always ... Happy Sunday!

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

Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.

Katheria A, Szychowski J, Carlo WA, Subramaniam A, Reister F, Essers J, Vora F, Martin C, Schmölzer GM, Law B, Dempsey E, O'Donoghue K, Kaempf J, Tomlinson M, Fulford K, Folsom B, Karam S, Morris R, Yanowitz T, Beck S, Clark E, DuPont T, Biniwale M, Ramanathan R, Bhat S, Hoffman M, Chouthai N, Bany-Mohammed F, Mydam J, Narendran V, Wertheimer F, Gollin Y, Vaucher Y, Arnell K, Varner M, Cutter G, Wilson N, Rich W; RRT; Finer N.Pediatrics. 2023 Dec 1;152(6):e2023063113. doi: 10.1542/peds.2023-063113.PMID: 37941523 Clinical Trial.

Short, medium, and long deferral of umbilical cord clamping compared with umbilical cord milking and immediate clamping at preterm birth: a systematic review and network meta-analysis with individual participant data.

Seidler AL, Libesman S, Hunter KE, Barba A, Aberoumand M, Williams JG, Shrestha N, Aagerup J, Sotiropoulos JX, Montgomery AA, Gyte GML, Duley L, Askie LM; iCOMP Collaborators.Lancet. 2023 Nov 14:S0140-6736(23)02469-8. doi: 10.1016/S0140-6736(23)02469-8. Online ahead of print.PMID: 37977170

Deferred cord clamping, cord milking, and immediate cord clamping at preterm birth: a systematic review and individual participant data meta-analysis.

Seidler AL, Aberoumand M, Hunter KE, Barba A, Libesman S, Williams JG, Shrestha N, Aagerup J, Sotiropoulos JX, Montgomery AA, Gyte GML, Duley L, Askie LM; iCOMP Collaborators.Lancet. 2023 Nov 14:S0140-6736(23)02468-6. doi: 10.1016/S0140-6736(23)02468-6. Online ahead of print.PMID: 37977169

Late surfactant administration after 48 hours of age in preterm neonates with respiratory insufficiency: a systematic review and meta-analysis

Solís-García G, Elias S, Dunn M, et al. Archives of Disease in Childhood - Fetal and Neonatal Edition Published Online First: 23 November 2023. doi: 10.1136/archdischild-2023-326333

The Role of Medical Education Podcasts in Pediatrics.

Parga-Belinkie JJ, Cosmini M, Hill D, Berk J, Lockwood K, Patrick M, Novak C, Tarchichi TR.Pediatrics. 2023 Nov 1;152(5):e2023062911. doi: 10.1542/peds.2023-062911.PMID: 37881834 No abstract available.

2023 American Heart Association and American Academy of Pediatrics Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Yamada NK, Szyld E, Strand ML, Finan E, Illuzzi JL, Kamath-Rayne BD, Kapadia VS, Niermeyer S, Schmölzer GM, Williams A, Weiner GM, Wyckoff MH, Lee HC; American Heart Association and American Academy of Pediatrics.Circulation. 2023 Nov 16. doi: 10.1161/CIR.0000000000001181. Online ahead of print.PMID: 37970724 Free article. Review.

Risk of hematological malignancies from CT radiation exposure in children, adolescents and young adults.

Bosch de Basea Gomez M, Thierry-Chef I, Harbron R, Hauptmann M, Byrnes G, Bernier MO, Le Cornet L, Dabin J, Ferro G, Istad TS, Jahnen A, Lee C, Maccia C, Malchair F, Olerud H, Simon SL, Figuerola J, Peiro A, Engels H, Johansen C, Blettner M, Kaijser M, Kjaerheim K, Berrington de Gonzalez A, Journy N, Meulepas JM, Moissonnier M, Nordenskjold A, Pokora R, Ronckers C, Schüz J, Kesminiene A, Cardis E.Nat Med. 2023 Nov 9. doi: 10.1038/s41591-023-02620-0. Online ahead of print.PMID: 37946058

EBNEO Commentary:

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

Madhi SA, Anderson AS, Absalon J, Radley D, Simon R, Jongihlati B, Strehlau R, van Niekerk AM, Izu A, Naidoo N, Kwatra G, Ramsamy Y, Said M, Jones S, Jose L, Fairlie L, Barnabas SL, Newton R, Munson S, Jefferies Z, Pavliakova D, Silmon de Monerri NC, Gomme E, Perez JL, Scott DA, Gruber WC, Jansen KU.N Engl J Med. 2023 Jul 20;389(3):215-227. doi: 10.1056/NEJMoa2116045.PMID: 37467497 Clinical Trial.

EBNEO Commentary: Safety and immunogenicity of GBS vaccine in pregnancy and determination of a serocorrelate for infant protection.

Flannery DD, Puopolo KM.Acta Paediatr. 2023 Nov 10. doi: 10.1111/apa.17038. Online ahead of print.PMID: 37950357 No abstract available.

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

Ben: 1:06

Hello everybody, welcome back to the incubator podcast. It is Sunday. We're doing Journal Club Daphna. How are you?

Daphna: 1:12

I'm chuckling.

Ben: 1:13

Yeah, definitely chuckling. You wanted to like swap the intro. You got all flustered in the beginning of this episode.

Daphna: 1:20

You know we're getting to the end of the year.

Ben: 1:22

We're checked out In the chaotic year. It's been a great year, by the way.

Daphna: 1:29

For the podcast.

Ben: 1:30

For the podcast. For, yeah, it's been the great year for the podcast. That's what I meant, and we will, you know what? Since we're doing this, then let's do a little bit of housekeeping. So we have this episode of Journal Club this Sunday which, by the way, is also coinciding with the release of another Journal Club episode in the French podcast. So if you are French speaking, go check out Thank you, but they are not with Gabriel Altit and myself. And next week we'll have another mini series to close out the year. This one will be on respiratory distress Kind of an interesting one with some very interesting guests, most notably Dr Richard Poland. So that that was that was fun to put together. And then we will have our end of year episode on the 24th where we will announce the winners of the Ebino impact article of the year campaign and we will do a lot of announcements for what's coming next in 2024 for the incubator podcast. So stay tuned and, yeah, this will be fun. In the meantime, I don't think I have anything else to announce. The board review stuff will continue. We might be taking a break between in the holidays, like in the 24th and the new year, but we will definitely resume everything in January, so definitely did I forget anything? Did I commit us to something I should not have committed us to?

Daphna: 3:02

No, I think that's all correct.

Ben: 3:04

Yeah, and thank you for everybody who listened to the episode last week. This was great to have on the transition to home team. This was. I was really listening to that podcast and, man, these guys have really done such a good job at building a robust and successful follow up program. If you are doing anything related to follow up, you know that this is very, very hard and it's just very hard, so the fact that they were able to do this is quite staggering. Okay, today we have a bunch of stuff lined up, so we have a few articles. This week I'm doing a bunch of articles on umbilical cord management. I mean, so many things have been published. The time has come for us to review these papers. We will have an EBNO segment and you will tell us about some more papers. So where should we begin? Do you want to start or do you want me to start?

Daphna: 3:52

I want to hear about all these, uh, this collection of articles that you have.

Ben: 3:58

So the first paper I will be talking to you about is a paper that was published in the journal uh pediatrics, not the journal of pediatrics, pediatrics from the AAP. It's called a milical cord milking versus delayed cord clamping in infants 28 to 32 weeks a randomized trial. First author is our good friend, a new kathiria, which was on the show not too long ago, so if you are interested in a new work, he's a rock star, he he. He was on the show and talked to us about his work on the milical cord management, so definitely go check out this podcast. The background is very interesting, right? So they they talk about a bill, cold, cold milking, delayed cord clamping. I've highlighted a few things in the background that are interesting. Basically, this survey that they mentioned, where they basically talk about the recent survey of obstetrician and perinatologist in the U S that reported that 39% provide umbilical cord milking in healthy term and preterm infants and in 25% of infants who need resuscitation, which to me was surprising because I thought umbilical cord milking is something that had fallen out of favor, and so it's interesting it's. If you're also interested in that, go watch the Delphi conference that we posted on YouTube from Fumi Hiko Namba from Japan where they talked to us about, where he talked to us about how they manage babies, ELB, double use in their NICU and that they use umbilical cord milking. So it's very, very insightful. Now what? Let's talk about some definitions. Umbilical cord milking is basically an unclamped umbilical cord that is grasped and the blood is basically pushed towards the infant three to four times before clamping. This is going to be discussed in the case of this paper, in comparison with delayed cord clamping, which, for the purpose of this study, meant like 30 to 180 seconds of delay in clamping the cord. Now, this trial is the pre-mod two trial, but the pilot study, the pre-mod one, which was also ran by a noop and his colleagues, from 2015, showed how umbilical cord milking led to higher systemic blood flow with preterm infants. These infants had a mean gestational age of 28 weeks compared with delayed cord clamping, and so the pre-mod two trial was designed as a non-inferiority trial, hypothesizing that umbilical cord milking is non-inferior to delayed cord clamping with respect to the primary composite outcome of severe IVH or death. Now there's a lot of context that need to be mentioned about this study, because this study did not go as planned, so the study was paused during enrollment of 474 infants because they had some safety signals that showed that the neonates that were born before 28 weeks of gestation, specifically showing a possible increase in severe IVH associated with umbilical cord milking in infants born between 23 and 27 weeks. So that very immature population was showing poor signs that they were not tolerating umbilical cord milking. The data and safety monitoring board also reviewed the rest of the cohort and showed that there were no safety signals in more mature babies with gestational age of 28 to 32 weeks, and so what they did is that they paused the study for some time and then they resumed the study, changing the inclusion criteria now and saying, well, we're going to just keep looking at this, but only for the babies that are 28 to 32 weeks. So they stopped including those smaller babies because of the safety concerns. So the inclusion ended up being 28 weeks to 32 and six weeks of gestation. The intervention was either delayed cord clamping for 60 seconds versus umbilical cord milking four times, so four sort of pushes. The primary outcome had to be shifted. So they shifted the outcome from severe IVH or death to a two year neurodermatal follow-up outcome, which is currently ongoing. So it's very confusing because technically then, the primary outcome of the study is two year neurodermatal outcome and they're not reporting on that in this paper. However, the NICHD, which is the group taking on this study, requested that the original composite outcome of severe IVH and or death following delivery be reported in a timely fashion as an important safety endpoint in the 28 to 32 weeks gestational age infants. So that's I mean. To me that's super interesting because the paper really goes into those details and you can see a little bit about what does it mean to have safety monitoring and see how a study can take different path depending on what some of these outcomes are. So the sample size was calculated for 600 infants in each group to detect a non-inferiority margin of 1% for the outcome of severe IVH or death, with a 90% power, and then for the results of the neurodermatal follow-up test using a barely two or three. At two years, they found they powered this. This would power the study to detect a 2.5 point non-inferiority margin with a power of 85%. Okay, so then let's get into some of the results. A thousand and 19 infants born between 28 and 32 weeks were enrolled from June 2017 to September 2022, with 511 randomized to milking, 508 randomized to this delayed cord clamping. The average age at enrollment was 31 weeks. The meantime to umbilical cord clamping was higher in the delayed cord clamping group compared to umbilical cord milking group 58.4 seconds versus 24.5 seconds. Not really surprising, since one of them is called delayed cord clamping. So fine, but it is important to know because we're going to talk about some of these outcomes that could be related to that. A greater number of newborns were breathing before the cord was clamped in those randomized to delayed cord clamping. I think that's a huge result. So more were breathing before the cord was clamped when they performed DCC delayed cord clamping 86% versus 75%. Looking at the primary outcome, they didn't really find any difference when it comes to severe IVH or death. 1.4% of infants randomized to milking had severe IVH or death compared to 1.4% in infants randomized to delayed cord clamping. Not statistically significant, pretty much identical. The sensitivity analysis for the 28 to 32 week cohort after the restart of the study showed a severe IVH rate that was similar between the two groups as well 1% and 1%. So there wasn't anything really different when it came to before and after. There were no significant differences in severe IVH death, any grade IVH hemoglobin at four hours of life and all exploratory outcomes. So when you're looking at severe IVH specifically, we're looking at overall rates it's basically less than 1% compared to 1%. That was not statistically significant. Death was basically 1% versus 1%. Any grade IVH was 12% versus 12% and what else? What that's really it. The conclusion of the study are that this is the largest randomized trial to date comparing a biblical cord milking to delayed cord clamping among preterm infants born between 28 and 32 weeks. There were no differences in the composite rate outcome of severe IVH or death. Hemoglobin and hematocrit values were equivalent and no other secondary outcomes were noted. So the takeaway is that maybe a biblical cord milking may be a safe alternative to delayed cord clamping for preterm infants who require more immediate resuscitation. There's a few thoughts on this topic. Obviously. Number one is that, I guess, to the credit of the teams participating in this trial, the event rates for the primary outcome are very low, and the same for the two groups, and so the 95% confidence interval, which includes the 1% non-inferiority margin, cannot really formally demonstrate non-inferiority of the umbilical cord milking. But would that differ if the non-inferiority margin was a bit larger, like 2%, and because the protocol shifted and the recruitment shifted as well to exclude babies who were less than 28 weeks. The target sample size was not really increased to account for the resulting lower event rate. So everything was calculated to include babies that were born 23 weeks and on. But because now you're losing that population that is at a much higher risk, should they have recalculated and try to readjust the power analysis maybe, and they didn't have the opportunity to do that. And they're saying in the discussion that a sufficiently powered study would require approximately 3,000 infants born between 28 and 32 weeks to test the non-inferiority, with a 1% margin for the outcome, of severe IVH and or death. So kind of like a huge undertaking, three times the size of what they currently had. So I think we take that with a grain of salt. But the thing that's interesting is that we will talk about some more papers that have come out in the Lancet to talk about the same topic and we'll see if the outcomes are similar and maybe helping us interpret those results.

Daphna: 13:47

I think the body of literature is growing. I think it's super exciting time for us to really delineate this question about what is the? I think that was the point Initially. We said what is the right type of management for all babies? I think we're finding that it's not the right answer for all babies.

Ben: 14:08

That premies is no longer a category that works, Correct. What kind of premies? That's right, Very immature 20, 22 to 25 weeks. Are we talking 28 weeks to 32? Are we talking 32 to 37? That makes a huge difference. Do you want me to go into these Lancet articles? Since we're on the topic, let's hear it all. There's two articles that came out in the prestigious Lancet on this topic specifically. The first one I'm going to talk about is called Deferred Court Clamping, Court Milking and Immediate Court Clamping at Preterm Birth a Systematic Review and Individual Participant Data Amid Analysis. This is from the ICOMP collaborators. The background is interesting because obviously the Lancet is a European publication, so we get more of a European take on this topic. Talking about that, how more than 100 randomized trials have compared different court clamping strategies at Preterm Birth and systematic reviews have reached different conclusions about the effectiveness of these strategies, as we were talking about, I think a lot of parameters come into play when it comes to the gestational age and the status of the baby vigorous, non-vigorous at birth. Ilcor, the organization that regulates the neonatal resuscitation, recommends 60 seconds of delayed court clamping, which has been shown to improve hemoglobin and hematocrit and reduce iron deficiency. Whether this practice is beneficial in preterm infants generally, especially very preterm infants and extremely preterm infants, is less clear. This uncertainty about the optimal court clamping strategy, particularly for infants at high risk of death and morbidity, which means the babies that are very preterm needing resuscitation has led to discrepant recommendations in court management at Preterm Birth in national and international guidelines, which is exactly the confusion and the fog that's surrounding us right now. The aim of the study is to conduct a systematic review and individual participant data and meta-analysis to evaluate the effects of deferred court clamping, court milking and immediate court clamping on mortality morbidity for preterm infants. Now, this is a systematic review and meta-analysis. The participants basically included any infants that was born before 37 weeks of gestation. For studies that included both term and preterm infants, only preterm births were included. They were looking at randomized control, trial, evaluating court management, intervention to enhance ability for court flow or facilitate respiratory transition, and immediate court clamping were included. So the interventions were grouped into three pre-specified comparison groups. First, we had any deferral of court clamping versus immediate court clamping as soon as possible or within 15 seconds. That's what we define as immediate court clamping. Second, they looked at any court milking either with an intact cord or with a cut cord versus immediate clamping. And third, they looked at court milking versus deferred court clamping, which is sort of what we just reviewed with the catheteria paper. The primary outcome for the meta-analysis was death before hospital discharge for all infants born before 37 weeks of gestation. They had a lot of pre-specified secondary outcomes need for blood transfusion, hypothermia. On admission IVH, BPD, late onset sepsis, neck, PDA, NICU admission for infants born after 32 weeks. So they were able to identify 48 randomized control trial, 6,367 infants included. It's a very long paper so I'm going to try to. I am not going to do this paper justice.

Daphna: 17:43

So thank you for digesting it for us.

Ben: 17:45

Yeah, and that's why I'm going to go straight to the comparison groups, because I think that's what people want to hear about, and then I will let you dive into the different things. I'll tell you at the end why I'm sort of going straight to the meat of the paper. So the first comparison they looked at was what about delayed court clamping versus immediate court clamping? They found 21 studies that were eligible to be included and the babies in that cohort had a median gestational age at birth of about 29 weeks. Differred court clamping ranged from 30 seconds to at least 180 seconds, with some trials encouraging deferrals for up to five minutes where feasible. This would not fly at our Our bees, would chop our heads off.

Daphna: 18:23

Yeah, we're going to take a stepwise approach to getting there. Multiple PDSA cycles.

Ben: 18:32

Interestingly enough, deferred court clamping reduced death before discharge compared with immediate court clamping, with a nods ratio of 0.68. The number of units to treat with delayed court clamping instead of immediate court clamping was 40. So the key secondary outcomes compared with immediate court clamping, the deferred court clamping reduced the need for blood transfusion. It had no clear evidence. There were no clear evidence of an effect on other key secondary outcomes, but it did show a slight increase in the risk of hypothermia for infants born before 32 weeks. So I think it was very low. So the difference was like 0.13 degrees centigrade, so it's minimal.

Daphna: 19:13

That's something we can work on, right.

Ben: 19:15

That's exactly right. I think that as we implement and they talked about this in the conclusion as we implement these new strategies, we have to keep in mind hypothermia. We have a great series on hypothermia, by the way if people are interested in listening to that, but definitely something we can work on, and there has been reports I think I read one paper in the archives where people have mentioned how they implemented delayed court clamping and yet were able to maintain no more thermia for their babies. So it is something that's achievable, okay, the second comparison they looked at any form of milking versus immediate court clamping. They found 18 studies, 1,565 infants included. Median gestational age at birth again 29 weeks. What they found is that there's no clear evidence of a difference for umbilical cord milking compared with immediate court clamping when it comes to the primary outcome of death before discharge. Their certainty of the evidence, however, was ranked as low or very low due to insufficient sample size. So how much can we extrapolate that? I don't know. Umbilical cord milking, however, probably made no difference for any IVH for infants who were born at less than 32 weeks of gestation and probably reduced the need for blood transfusion for these infants and those born at 32 weeks of gestation or later. No differences in all grade or severe IVH were found when comparing milking with immediate court clamping, even when they restricted the population to the infants who were born before 28 weeks of gestation. In a post hoc sensitivity analysis, no difference in key secondary outcomes. But they may have seen improvement in hemoglobin measures for the umbilical cord milking group compared with the immediate court clamping group in the different gestational ages group. The last comparison is the one that we talked about in the previous review of the papers that we did, which is any form of umbilical cord milking versus deferred cord clamping. So obviously these papers all came out at the same time so the study that we just reviewed is not included in this mid analysis. They found 15 eligible studies. 1,655 infants were included. The median gestational age at birth was 30 weeks, so a similar patient population. For the primary outcome of death before discharge, no evidence was found of a difference between umbilical cord milking and deferred cord clamping, although the certainty of the evidence was low. Now, if you remember correctly, we talked about death but we talked also about IVH. So umbilical cord milking, compared with deferred cord clamping, increased the odds ratio for severe IVH to 2.2, although no difference was found for all grade IVH. So interesting that now umbilical cord milking seems to be increasing the rates of IVH in these babies. But this finding was mostly driven by events in infants born at less than 28 weeks of gestation. So almost exactly the same findings as the catheteria paper, where they found that for babies that are less than 28 weeks, when you're comparing umbilical cord milking versus deferred cord clamping, you may have more severe IVH in the smaller gestation. So the conclusion is that they combined 48 trials of cord clamping strategy with individual participant data from more than 6,000 preterm infants across three comparisons and they found high certainty evidence that deferred cord clamping reduces death before discharge in preterm infants and this effect is consistent across different population groups. The effects of the umbilical cord milking on mortality were inconclusive, but severe IVH is a potential safety risk. Together with the other paper that we're going to talk about, they're thinking that we can use that data to help update guidelines. So very interesting. I'm going to let you weigh in, if you want, before I go on to the next one.

Daphna: 23:02

No, I think you're painting us a picture about the different sub-cohorts here.

Ben: 23:11

And so the last paper, also published in the Lancet, by the ICOM collaborators now looks at short, medium and long deferral of umbilical cord clamping compared with umbilical cord milking and the immediate cord clamping at preterm birth a systematic review and network mid-analysis. So now it seems that from the study that we looked at, delayed cord clamping seems to be the best thing, right. We're looking at something where we're saying if you can do delayed cord clamping, this seems to be the best way to go. If you cannot do delayed cord clamping in babies that are 28 to 32 weeks, you might get away with just doing umbilical cord milking. But let's look at delayed cord clamping a bit further, and so this mid-analysis was really trying to look at what about different types of cord clamping. We know that Anup has mentioned that 30 seconds of delayed cord clamping is not really delayed cord clamping. Many people think that we need to extend that delay to several minutes maybe. So this is a mid-analysis that included all randomized trial comparing umbilical cord clamping strategies at preterm birth, the same eligible participants, preterm infants as in 37 weeks, and the interventions were grouped into five nodes because they had to do like these multiple comparisons, very sophisticated statistical things that compared either immediate clamping, which means either as soon as possible or within 15 seconds. Then we had quote short deferral, which was 15 seconds to 45, to less than 45 seconds, to like 44 seconds. Then we have medium deferral, which looks at 45 seconds all the way to 120 seconds, so 45 seconds to two minutes. And then we have long deferral, which looks at over two minutes. And then the fifth node is any form of umbilical cord milking. So the trials were included, regardless of whether initial neonatal care was provided with the cord intact cluster. Randomized and quasi randomized trials were excluded and the primary outcome was death before hospital discharge for all infants born before 37 weeks of gestation. They included 47 trials, 6,094 infants. The median trial sample size was 60. And in total they have about 34% of participants that were randomly assigned to immediate cord clamping and about 21% were assigned to some form of delayed cord clamping with different timings, and about 20% to intact cord milking. The median gestational age at birth for all the included trials was 29.6 weeks and 61% of these infants were born via cesarean section. Again, it's a long paper, so I'm going to go straight into the comparisons. So for the first one, which is death before for death before discharge 30 trials. So we're going to look at three, three outcomes. We're going to look at death before discharge, ivh and the need for blood transfusion. So for death before discharge 30 trials, 4700 infants report and with 4700 infants reported at least one event and were available in the network. They created this sort of network for eligible comparisons for each of the outcomes. So, like all the different possible comparisons and there's like a nice figure in the paper that looks at that and the direct comparisons were available for all but one intervention, which was they couldn't do a comparison for the long versus medium deferral. The long versus medium was 45 to two minutes or two minutes plus, so they didn't have an opportunity to do this specific comparison. Compared with immediate clamping, the long deferral reduced death before discharge with an odds ratio of 0.31. Moderate certainty and the number needed to treat of 18. The confidence intervals for medium and short deferral crossed the threshold of one with and so there's no effect. Intact cord milking also crossed the threshold. So they calculated the ranking probabilities of the different interventions and that's shown in figure four and that's, I think, quite interesting. But long deferral, which was defined as having a delayed cord clamping of more than two minutes had a 91% probability of being the best treatment to prevent death before discharge. Short deferral was second. Medium deferral was third. Intact cord milking was fourth best. You may wonder, like well, how come it's not then in order? Why isn't it like long, medium, short and milking? Well, I would suggest that you go read the post by Keith Barrington on these papers, because this is when you can start really digging into the data pretty deeply and see at how many trials influenced the analysis, because there's one trial from the UK that has quite some strength and is probably weighing those outcomes a little bit more significantly than others. So yeah, so I'll just leave it at that. Now, immediate clamping had less than 1% probability of being the best treatment for preventing death and a 53% probability of being the worst treatment. 33% of the trials that we looked at the 30 trials in this particular Evaluation were rated as having a low risk of bias. 14 had some concern, which was about like 47% had some concerns, and 20% of them having a high risk of bias. Now to go back to what I was saying, so long deferral more than two minutes seems to be the best, and there's figure I think it's figure three A shows that and then they rank the different probabilities. But when it comes to short deferral, medium deferral and cord milking it really always crossed. So there's no statistically significant result there. But they did still do the ranking. But the significance was really only reached with the long deferral. When they were looking at IVH, they found 27 trials, 4,283 infants. Trials were available for all head-to-head intervention comparison except long deferral, for which only one trial with immediate clamping as a comparator had data available. There's no clear difference that was seen for the incidence of IVH across any of the comparison and major uncertainties exist around ranking of the intervention for this outcome 26% of the trial had the low risk of bias, 22, some concerns. 52% had a high risk of bias. So as we're trying to compare the different lengths of time during which the cord is not being clamped, there's no good data to actually make a definitive statement, as if one is better over the other. The last thing we will look at are the need for blood transfusion. They had 29 trials, 4,746 infants. Direct comparisons were available between all intervention group except the long deferral, for which only one trial comparing this to immediate cord clamping. Again, it's that same trial Compared with immediate clamping, short and medium deferral and intact cord milking all reduced the odds ratio for the need of any blood transfusion. For the long deferral evidence was inconclusive, with a wide confidence interval. I mean, if you look at that forest plot it is wide and that confidence interval is what really gets to lose the significance because and they had insufficient events for this particular comparison. When it comes to the trial themselves, 14% had a low risk of bias, 28% had some concern, 59% had a high risk of bias. So I think what we're seeing is that this mid analysis it's still very hard to say whether or not, when you compare this to the first paper that we reviewed, where it's a real randomized control trial, you can really control for so many variables. How much residual confounding we're gonna have in these mid analysis. It's hard to say and it gets tricky to try to tease apart all these different aspects of the care when we're comparing studies where the patients may have been different. The conclusion of the paper is that they found that long deferral of court clamping by at least 120 seconds is likely to lead to a large relative reduction in death before discharge for preterm infants. I think this has huge implications on both the developed world and low and middle income countries. Results are not generalizable to infants assessed as requiring immediate resuscitation unless resources and equipments are available to provide initial respiratory support with the court intact, which is not always feasible. They're again talking about whether this will lead to change in clinical practice. And again, multidisciplinary work, multidisciplinary teams to work closely together to successfully defer court clamping, is what really will be the source of high quality care. And these are the three umbilical court papers.

Daphna: 32:04

Well, I appreciate you doing that. I think this is a really important step in the field. I mean, I think this is gonna be well. One, definitely a clinical shift in practice, but two, I mean, really has the potential to change outcomes. It's interesting, it's like the steroid saga. Right, there are lots of options. There are different outcomes depending on age group, but hopefully we'll have more luck with a bill of court management.

Ben: 32:36

I don't know if you are going to talk about this paper, but in pediatrics, right, they do. They did publish some AHA updates on the, so you are gonna mention that On NRP. Yeah, yes, yeah, cause I think I mean, at the end of the day, do delayed court clamping. Basically Delayed court clamping works for everybody and it seems to be the way to go. Now, if you have an OB that is really in a tough position and says I got to climb this court soon, then in babies that are a bit more mature, could you start milking the court. I think to me the mid analysis and the kathiria paper show that, yeah, in 28 to 32 weeks maybe. Maybe milk that court a little bit. There shouldn't be. Yeah.

Daphna: 33:20

Like how you said that milk that court a little bit, but I think that's the point too. There are different ways to milk the court, right, and I just think we haven't standardized it, so yeah. So, I wanted to I mean, since we're talking about it and everybody's trying to like put in their minds what that looks like, dr Sakthian, and I'm gonna get it. Dr Lakshmin Ruseema has a great pictorial, I guess, of the short term neuro outcomes in court milking by gestational age, based on a noobs string of papers that he posted on November 13th. So I thought that was a really neat pictorial as we're learning the data.

Ben: 34:08

Why are you taking?

Daphna: 34:09

us next. Well, you've kept us quite busy.

Ben: 34:12

I'm gonna shut up for the rest of the episode now.

Daphna: 34:14

No, I'm gonna just touch on a few papers. I'll try to kind of blow through them quickly. The first one was this another meta-analysis looking at late surfactant administration after 48 hours of age in preterm units with respiratory insufficiency. The lead author, gonzales Solis Garcia. This is in the Archives of Disease, fetal Neonatal Edition, and the team is out of Sick Children's in Toronto. They wanted to look at this cohort of papers that looked at kind of late surfactant quote unquote late surfactant after 48 hours and does it improve long-term outcomes. Like I said, it's a meta-analysis. They only included randomized controlled trials which identified preterm infants born before 37 weeks who were mechanically ventilated and who received surfactant beyond 48 hours. The primary outcome was a composite outcome of death or BPD at 36 weeks, and the secondary outcomes included BPD at 36 weeks, pre-discharge mortality, postnatal steroids, post-discharge hospitalization, post-discharge steroids and post-discharge respiratory support. So they screened nearly 4,000 articles. They found four RCTs and one follow-up of one of the original studies. It included an N of 850. The mean gestational age was between 25 and 26 weeks for all five studies.

Ben: 35:41

Yeah, there's not. When I was reading the paper and I saw that they had 5,000, like there's not 5,000 papers on this and I think the major one that was ever published like was looking on the kids with nitric oxide. So I was that's exactly right.

Daphna: 35:54

Yes, and then those are some of the important details, for sure, for sure. But what I will say is this is a kind of a relatively small early group of babies, so I think it has that going for it. Like I said, a mean gestational age of 25 to 26 weeks for all five studies and, like you said, one of the inclusion criteria for two of the studies included that babies were on nitric oxide. So I think that's interesting to note. It does also indicate that some of them are reasonably moderately sick group of babies. The other thing I will say, just to take with a grain of salt, is that of the five studies, numerous types of surfactant were used. I think we should take that into consideration. However, across all domains the risk of bias was felt to be low for all studies. So the pooled analysis of the four randomized control trials showed no statistically significant differences between late surfactant and control group for the incidence of death or BPD at 36 weeks, with a risk ratio of 0.99. And then of the secondary analysis, the pooled analysis of two randomized control trials N of 522, showed that, compared with the control group, the preterm infants who received late surfactant had significantly reduced post discharge respiratory support over the first year and otherwise there were no statistically significant differences between the two groups for the other pre-specified secondary outcomes. So again it's a meta analysis, not only included in five papers. I think it was a representative group of babies but still overall very small. But the takeaway is that late surfactant so they're calling it less after 48 hours did not show any difference in the combined outcome but that the babies who did get it had reduced post discharge respiratory support in the first year.

Ben: 38:00

Thoughts. We use repeat surfactant doses frequently in our unit and I think to me it's interesting how our babies are at risk of surfactant deficiency. We talk about all these other things that could potentially deactivate surfactant, like infections and things like that. These things happen during the course of their hospitalization, so it's not theoretically completely unreasonable to say why not give them, why not replenish their stock of surfactant? So I think I do agree that the effectiveness of the repeat doses are definitely not as pronounced as the initial one, but there seems like there is a benefit, so I was happy to see that yeah.

Daphna: 38:35

And again with all data, it seems like for we know that late surfactant is not that effective, but there's still some groups of babies that it seems to really make a difference for. I wanted also to review this paper that you had tagged is definitively interesting A risk of hematological malignancies from CT radiation exposure in young adolescents and young adults. So not entirely our group, but we can imagine that our babies would be at least the same effected, potentially, if not more. This is coming from the Journal of Nature Medicine and this study group is the EpiCT. Epi-ct. It's a multinational cohort of nearly one million individuals who underwent CT examinations before the age of 22 years in nine European countries. They estimated radiation doses to the active bone marrow based on the body part scan, the patient characteristics, the time period and the inferred CT technical parameters they looked at not only did you get a CT scan, but what was your dose of CT radiation? The analysis included 876,771 individuals who altogether underwent 1.3, just over 1.3 million CT exams. So this is a mean of 1.52 CT examinations per patient, and they were followed up for at least two years following their first CT to look if they got more radiation. And then they saw what developed. So they identified 790 hematological malignancies, including 578 cases of lymphoid malignancies and 203 cases of myeloid malignancies and acute leukemia. The mean follow up was 7.8 years, but 6.5 years, four cases, those who developed malignancies. 51% of the cases were younger than 20 years of diagnosis and 88, almost 90% were younger than 30 years of diagnosis. They have a lot of data, they have a lot of supplementary materials, but since we're short on time, I will get to the gist of the results. And they did find a significant association between cumulative dose and risk of all hematologic malignancies, with an excess relative risk of 1.96 per 100mg. So for those who didn't know and I didn't, I had to look at it this is really a low dose radiation CT. So we're not even talking moderate dose, we're talking severe dose. These are really low, low dose. Similar estimates were obtained for both lymphoid and myeloid malignancies and results suggest that for every 10,000 children examined today with a mean dose again low dose, mean dose of 8mg, 1 to 2 persons are expected to develop a hematologic malignancy attributable to radiation exposure in the subsequent 12 years. So I think it's just a reminder that all of sometimes our diagnostic odyssey is not benign and if we can study something a different way, then maybe we should.

Ben: 42:13

Yeah, yeah, I mean, think about this. I think about this all the time. Do we need a CT scan or not? What are the long-term implications of ordering that imaging? What are the implications of all the x-rays that we're getting in the NICU, all the x-rays that we're getting to a baby that's in an open bay adjacent to another? baby that doesn't need to be exposed to radiation. I think all these are collateral casualties that we need to work on and reduce. Yeah, so thank you for highlighting that paper, and I think it's giving us a foot for thought and it's published in a pretty reputable journal, so, yeah, we'll post that as well. Should we cue the jingle for the Ebenio segment? Let's do it. Cue the jingle.

Karen Puopolo: 43:07

The article of the month commentary brought to you by the evidence-based neonatology team. Make sure to follow Ebenio on Twitter at Ebenio, or on the web at ebenioorg.

Daphna: 43:24

Dr Karen Papalo, dr Dustin Flannery. Thank you both so much for joining us today. Thanks for having us.

Dustin Flanery: 43:30

Yes, thanks so much for having us.

Daphna: 43:32

Well, we've reviewed this article before, but we are so happy to have you both on to do the full review and give us your expertise. You're going to talk to us about vaccines for Group B strep today.

Dustin Flanery: 43:47

Yes, we're really excited to speak about this article. Just like with the RSV study, I do have to give a caveat that I'm a neonatologist and a clinical researcher but I am not an infectious disease expert or vaccinologist or obstetrician. Dr Papalo actually does have significant lab experience with GBS, but I do not. So I'll do my best to walk you through the study and then Dr Papalo can give us some interesting context, hopefully. So this was a study published in the New England Journal in July 2023 by Dr Maudian colleagues and it's titled potential for maternally administered vaccine for infant Group B streptococcus. And I'll start with the PICO question, which was in healthy pregnant women, does administration of a single dose of GBS6 vaccine at three different doses and with and without aluminum phosphate, compared with the placebo, result in fetal transfer of antibodies associated with reduced risk of invasive GBS disease without adverse events? And that's through 12 months after delivery. And this was really a two part study. So the first was a phase two randomized placebo controlled trial, which we can refer to as the vaccine trial, and the second part was a parallel case control longitudinal observational cohort study, which we can refer to as the sero epidemiologic study. So for the vaccine trial, healthy women from three research centers in South Africa who were 18 to 40 years old and pregnant with an uncomplicated singleton pregnancy between 25 and 36 weeks gestation, were randomly assigned in a one to one to one ratio to receive the vaccine in the three different doses, with and without aluminum phosphate or a placebo. They use Sentinel cohorts to assess safety to allow progression to the next higher dose. During the study and trial, staff who dispensed and administered the vaccine or the placebo were not blinded, but all other trial personnel and participants were blinded. For maternal participants, they looked for solicited local and systemic events for the seven days after injection and then any unsolicited adverse events for one month after injection and also obstetrical complications through 12 months after delivery. For the newborns, unsolicited adverse events were monitored for six weeks after delivery and serious adverse events were monitored through 12 months after delivery. There was really no formal statistical hypothesis and the sample size was determined by the likelihood of adverse events being observed and analyses for safety and immunogenicity were largely descriptive. For the sero epidemiologic study, pregnant women who presented for antenatal care at one of the participating clinics in South Africa or the delivery hospitals were prospectively enrolled and monitored for infant invasive GBS disease in the 89 days after birth. Cord blood serum antibody concentrations were measured from cases, and the cases were infants who had invasive GBS disease, as well as controls who were infants without invasive GBS, born to mothers who were colonized with GBS, and infant serum antibodies were measured at the time of infection for presentation with invasive disease. It's important to recognize that in the study setting South Africa, neither antenatal culture based GBS screening or intrapartum antibiotic prophylaxis for GBS prevention was standard of care, and so that's important for the study implications and the outcome of the sero epidemiology study was risk of invasive GBS disease as a function of the distribution of the antibody concentrations, and for both the vaccine trial and the parallel sero epidemiology study they used a quantitative direct immuno assay to determine IgG concentrations to anti-capsopolar saccharide, and this was for serotypes 1A, b2, 3, 4, and 5, so the six most common serotypes causing infant disease, and they used a Bayesian model for antibody concentrations among cases and controls. Moving on to the results for the sero epidemiology study, we'll review that first, there were 24,000 pregnant women who were prospectively screened and 125 infants with invasive GBS disease who were retrospectively screened for enrollment within 72 hours after confirmed illness, and so there were 77 cases and 250 controls. In the final analysis, 26% of the women who underwent GBS screening were found to be colonized with GBS and the overall incidence of early onset and late onset GBS disease was 0.72 and 0.83 per 1000 live births respectively, and this was higher among preterm births compared to term. The sero correlate for infant protection, which we'll talk a little bit more about. Because of the sample size, the investigators only determined risk concentration relationships for serotypes 1A and 3. The assay was cross-standardized to allow for comparison between serotypes and risk concentration curves were compared between cases and controls for those two most common serotypes and then the other four serotypes combined, and they found that an anti-CPS IgG concentration of 0.184 to 0.827 micrograms per milliliter was determined to be the threshold associated with a 75% to 95% risk reduction for invasive GBS disease. And then, lastly, for the vaccine trial, there were 494 pregnant women screened and 73% of those were enrolled. 40 pregnant women received vaccine in each of the six vaccine formulation subgroups because, remember, there were three different doses 5 micrograms, 10 micrograms and 20 micrograms, and then each of those was with and without the aluminum phosphate. So 120 women were assigned to placebo. There was one pregnancy in the vaccine group that resulted in a still birth and two women in the placebo group withdrew from the study, and so the safety analyses included data from 360 maternal participants and 357 infants and the two outcomes the first is safety, the second is immunogenicity. The safety was overall very reassuring. Maternal adverse events were similar at all time points between the groups, except for pain at the injection site, which was not too surprising. Among the women who received the vaccine with the aluminum phosphate component, again was one still birth in the vaccine group that was determined by the investigators to be unrelated to vaccine. Infant adverse events were also comparable between the two groups. There were three infant deaths, one in the vaccine group and two in the placebo group, and all were determined by investigators to be unrelated to the treatment. For immunogenicity, all vaccine formulations led to higher maternal antibody production compared to placebo, but there was variation in antibody response by serotype, and higher vaccine doses led to higher antibody concentrations. They found placental transfer ratios of 0.4 to 1.3, and these were observed for the different serotypes across the vaccine formulations. And so, for the higher vaccine dose, 57 to 97 percent of infants had antibody concentrations above the 75 percent risk reduction serocorrelate of protection, which again was that 0.184 micrograms per milliliter. So that was a mouthful. But just to kind of review and conclude, or to discuss what the authors concluded. They stated that maternal antibody responses to all six GBS serotypes were induced and transferred to newborns at protective threshold levels. They did not find any safety concerns, both maternal or infant, with the vaccine, and the formulations with aluminum phosphate were more immunogenic but also associated with more local reactions. And so they basically concluded that a single protective threshold again not serotype-specific of 0.184 micrograms per milliliter of anti-capsopalosecariot IgG may be associated with a 75 percent risk reduction for invasive infant GBS disease.

Daphna: 52:37

Well, thank you, Dustin, for the kind of comprehensive overview. I know it was a mouthful, like you said. I mean I think this is hopeful regarding the safety and the immunogenicity of the vaccine. Before we dive kind of more into the details of the paper and what effect this might have, Karen, I'm hoping you can give us a little bit more kind of historical context. Obviously, our strategies to prevent invasive GBS have changed over time and we actually did review it on the Neonatology Board Review Podcast in episodes 96, 97, 98. And we had you on for great discussion as our guest expert on episode 99. But maybe for people who don't realize how far we've come in tackling the GBS dilemma, yeah, where do we begin?

Karen Puopolo: 53:35

GBS was not always the most common bacterial cause of early onset subsist. Over the years that award has gone to E coli, to Staphylococcal species, but in the since the 1970s it's been GBS and it was recognized in a seminal work published by Carol Baker and Dennis Casper in the New England Journal in the 1970s that the primary thing that seemed to differentiate in a mother and infant whose baby got GBS disease from that couple that didn't was whether or not the mother had serotype-specific antibody impacted to the capsular antigen of the GBS that she carried. And that kind of makes sense, right? So she carried a bacteria. She wasn't getting sick from it, she had antibody to it. She passed it across the placenta to her newborn. Her newborn may or may not have been exposed to that bacteria, but they were armed with effective antibody and they were able to show that in infants who got sick, who got infected. This was not true, so in some ways it seemed like great right, it's like you know polio, right, you make a scene, you give it to people. They don't get polio. It's all a win. And this story that started in the 1970s is still going on in 2023 because it actually turned out to be really complicated. One of the complications has been the fact that you need antibody to a polysaccharide antigen, and I'm sure we've discussed before that those are problematic antigens for newborns, so newborns don't immunologically see those well, which is part of the reason that they are prone to infections with polysaccharide encapsulated antigens like E coli and H flu and GBS. And humans don't see GBS very well either from their immune standpoint. And so the antibodies that women have and men have because, by the way, men can be colonized through GBS too are pretty variable and it's a complicated issue. Number one. So number two we have to make a vaccine, and that vaccine probably needs to be given to pregnant women, and for a long time that was a huge hurdle. Making the antigen was complicated, understanding the microbiology of GBS was complicated, and then, even if a bunch of scientists funded by the NIH, as they were with the Streptococcal Initiative, u01 mechanism that funded basic science around this topic for like 15 years to catalyze vaccine development. So after all of that gets done, then you have to get a pharmaceutical partner who wants to make the vaccine and test it in pregnant women and, as we learned from COVID right, and we learned with H1N1 as well. Nobody wants to touch a pregnant woman. Oh yeah, we got to protect them from all of this. Except then when those pregnant women start being terrible victims of the thing you are not touching them H1N1, covid it becomes clear that we need to think about pregnant persons and we need to think about how to protect them from disease and how to protect their newborns. So the basic science needed to produce a GBS vaccine has been available for decades, and this project has been passed from pharmaceutical company to pharmaceutical company like a hot potato. And it really was after the 2009 H1N1 pandemic where it became clear that there was an imperative to immunize pregnant persons for their own sake, and that, it turns out, nothing bad happened to them, except that they didn't get a potentially deadly viral disease. There was a regrouping in the GBS world, and that regrouping involved scientists who have been involved for decades, family advocacy groups that have been involved for decades, the Bill and Melinda Gates Foundation, which is a explicit sponsor of the research published in this article, as well as some pharmaceutical partners, and there was a concerted effort over the past decade to actually solve this problem get a multivalent vaccine made, get it tested, get it approved, get it into clinical use.

Daphna: 58:25

Yeah, it sounds like there's. It's been no small feat, and actually Dr Carol Baker has an editorial on the same issue of the New England Journal. A group B streptococcal vaccine, sisyphus reconciled is what she said.

Karen Puopolo: 58:39

Dr Baker has literally dedicated her life from the time she was a postdoc in Boston with Dr Dennis Casper and published that seminal paper on the role of antibody to this day in solving this terrible disease that kills babies.

Daphna: 58:57

Absolutely, and we know it's still an ongoing problem, though I imagine some of the younger attendings and faculty don't remember when you know GBS was a quote unquote much bigger problem because we have made strides in screening in antenatal treatment. But I'm hoping you can speak a little bit still about the amount of the GBS burden and especially GBS that goes undetected despite our screening methods. We know there are false negatives. We know we have so many infants in our units who deliver preterm and the birthing parent was never screened. How big is the ongoing GBS?

Karen Puopolo: 59:39

You know, when I was a fellow in Boston, my attendings would talk about the days when at any time in our 50 bed NICU at the Brigham Women's Hospital there are at least a couple term babies being treated for GBS disease like every day all the time. That was the frequency of disease that is occurring at a rate of like two to three cases per thousand line births. It was a big birth center. Gbs prophylaxis, which was first recommended in a consensus statement in 1996 between CDC, acog and AAP, has effectively lowered the rate of early onset disease in this country from about one to two cases per thousand line births down to about 0.2 cases per thousand line births. So that's been huge. That has come at a cost of treating at this point at least half of women, one for one reason or another, with interpartum antibiotics, and so babies are born exposed to antibiotics in their blood all over their body in about 50% of the cases for all the reasons, about a third of that due to GBS and there's a lot of implications to that and there's a lot of research around that and my group has been involved in that. But the trade-off here is oh okay, so you're a little chubbier or you have sort of a peanut allergy or you have whatever people want to attribute to early antibiotic exposures asthma but you're not dead from GBS. So it's a choice we make, and we make it in a country that can afford the screening and the technicalities of that during prenatal care and can afford to put an IV and interpartum antibiotics into a bunch of women. And around the world this is not true. So the burden of early onset disease continues throughout the world. Late onset disease, which again occurs in about 0.3 cases per thousand line births, has not changed at all. That's true in the US, it's true around the world. There are good estimates for the number of stillbirths and preterm births that are probably caused by GBS, and so the inner presentation that Dustin is gonna be giving this month later at the international GBS meetings, he points out that GBS is probably responsible worldwide for so first of all, hundreds of thousands of deaths and inforns and fetuses and far more than is even attributed to RSV disease, for example. And one of the reasons that this study was done in South Africa is that is a sort of low-middle income country that does not use prophylaxis, does not have a infrastructure to use prophylaxis and actually has a very high rate of GBS colonization in the population. And, if you do, the statistics are given in the text about the ongoing rates of early and late onset disease in South Africa and they are more on the order of 0.7 to one case per thousand for both early and late onset disease. So it's a much higher burden there.

Daphna: 1:02:48

Dustin, I thank you for leading me right into my next question. Do you think the data is applicable to our population here, say in the US, given that this the phase one and the phase two trials were done in this exclusively South African cohort?

Dustin Flanery: 1:03:04

Yeah, I think it's definitely something we need to keep in mind when thinking about the implications of the results and the generalizability. As Karen mentioned, the routine practices in South Africa are much different than here in the US. But I also want to make it clear that and I'm surprised that some people have asked me about this and this is not common knowledge that it's not just low and middle income countries. Some high income countries, including the United Kingdom. They have decided not to use a screening and interpartum antibiotic prophylaxis approach. So for different philosophical reasons, I'll say, but I think it's important to know that the participants of this study were generally young, so less than 30 years old. The majority were multi-Paris or multi-Paris and black African race ethnicity. At about a third we're living with HIV infection, which is very different than the population we see here in the US. So I absolutely think that the generalizability is going to be slightly different.

Karen Puopolo: 1:04:08

I'll point out, though, that it is likely in terms of the vaccine response and transplacental antibody transfer. It's likely if you move to a different population that's not that doesn't have such a high percentage of pregnant persons living with HIV as well as living with chronic malaria and acute malaria at times. Both of those infections can impact your response negatively and definitely negatively impact transplacental antibody transfer. So, if anything, in a different population that didn't have those ongoing challenges, you may see better transplacental antibody transfer, for example, and I do think we should talk about why this was done there. So it is an unproflaxed population, so there is a real opportunity for a secondary positive impact from a study that is not so. Phase two is not an efficacy trial. It's not a disease efficacy trial. It is a scientific trial looking at antibody response and looking at safety. There is a lot of debate about how a GBS vaccine, even if shown to be safe and effective in terms of antibody response and transfer to the fetus, is going to get licensed in the United States. Because usually again, you give a vaccine, you show that the people who get the vaccine have less disease, ie you look at vaccine efficacy or vaccine effectiveness and you say great, that's a win. So how are you going to do that here? And so one of the proposals is to license and this actually is the intent is to license this such a vaccine on a serocorrelate. So you go and you say I have shown that antibody at this level will prevent this disease and I have shown that this vaccine can generate antibody at that level. So that is a correlate of disease protection and I'm going to license the vaccine on that and then do post-implementation studies to look in the end at effectiveness. And that's different for a primary licensing. Some vaccines are licensed that way every year, for example influenza vaccines, because there's already been a disease effectiveness study done and all you're doing is kind of tweaking it. You're looking at the serocorrelate in the tweaked vaccine and it gets licensed that way. But to do a primary licensing around a serocorrelate instead of actual disease prevention, effectiveness would be different and ultimately disease rates remain high enough in South Africa where you could, from an ethical standpoint, eventually probably do something of a disease effectiveness study. But even there the size of that study, the end that's needed to generate that study, is going to be in the tens to 100,000 participants and that's going to be challenging if that ever actually is, even ever done. So this approach is different and important to think through how that is working, the next thing that'll come up, as you might imagine. So let's zoom ahead and decide that maybe it's not a decade from now but, realistically speaking, maybe it'll be a few years from now. So there is a license, safe and effective GBS vaccine and you go to your obstetrician and they say, hey, we have this. And then, like you know, if we have this, you don't need to screen you for GBS, we don't need to worry about those interpartum antibiotics. What would it take to get the doctor to say that? Well, it'd take for the patient to believe that. How will we swap out this vaccine and prophylaxis? Should we swap it out? Should it actually be an adjuvant that would eventually totally eliminate disease if we did both prophylaxis in a vaccine? I don't have the answers to these questions. They are being very actively thought about and debated in the world of GBS vaccine development and it'll be a really interesting time when it comes to it.

Dustin Flanery: 1:08:59

And to add to that Defna, just like we talked about for the RSV vaccine. I think the timing of vaccine during pregnancy has yet to be determined, and also how many doses, which I think is important, given that now we're recommending flu vaccine, covid vaccine, rsv vaccine, now we're going to throw a GBS vaccine into the mix. When can these be given? Can they be given together? How early can they be given? We know that a substantial portion of early onset GBS disease occurs among preterm infants, so how can we maximize protection for them? So there's definitely a lot of questions that remain.

Daphna: 1:09:37

Yeah, absolutely it's quite a tall task and that was one of my questions. I think, given this growing vaccine hesitancy across the board, but especially, I think, in pregnant people, as this is coming down the line, what sorts of things do you think we can do? I think people still don't know enough about GBS disease and the burden of GBS disease and I think there's this misperception that you know course of antibiotics potentially less scary than a vaccine, given all of the misinformation that is happening, rapidly growing in the last few years. So what are kind of our obligations as clinicians and scientists to prepare people for something like this?

Karen Puopolo: 1:10:34

I think it's important for people who are clinicians like us, as well as scientists, to demystify vaccination. So one thing to say is that the antibodies that are being induced by this vaccine are antibodies that women make naturally, so there's nothing really weird or novel in this vaccine. We just recently completed a study of sort of naturally acquired seroepidemiology that Dustin will be presenting again at the big GBS meeting later this month. So, first of all, this vaccine is boosting, hopefully, what you already have. Second, we need to. You know vaccine. People talk to themselves a lot. For example, you might say what is cross-reactive material 197, which is in this vaccine? That sounds scary, that sounds like something they make on Mars and that's actually a naturally occurring version of diphtheriotoxin. It is in a lot of other vaccines. So maybe if you tell people that they'll be worried about it, it's in Prevnar, it's in Hib and you know we should be able to say to people some vaccines are hard, it's hard to get your body to make an adequate response and when we take this sugar and we bond it to a protein, your body makes better antibodies. Better for you, better for your baby, that's all. That is Just a little piece of protein. Your body's already seen it in many other vaccines you've gotten and it's been proven to be safe. The aluminum issue comes up. The preservative issues come up. Interestingly, it didn't, although when you measured it it looked like the vaccine preparations that had alum in them were more immunogenic, but actually not by that much. We've seen responses to alum, so whether that'll ultimately be used or not I don't know, but the amount of aluminum that's in that is less than there is in like baby formula. So I think that getting beyond this idea that some alien from out of space is injecting your body with a microchip is something that we have to be real about. Take on, demystify again, make it plain and simple and explain what we're doing. I think that the issue of how to use the vaccine and how to use prophylaxis is something that is going to be an evolution. I don't have an answer to it. Cdc doesn't have an answer to it. It's going to be something that we are going to have to get smarter about, work through and it'll probably be a dynamic issue. But a lot of people don't like the idea that they're getting antibiotics as a precaution rather than antibiotics for infection. There are many implications of antibiotic exposure at birth and I think we need to be more real about that with families, not to scare them but to say here's the pluses and minuses. One of my colleagues who works with Justin and I often says that just because you describe an unintended consequence of a medical intervention doesn't mean you don't want to do the medical intervention. It just means that you need to know what you're choosing and you need to know the pluses and the minuses. And there are pluses and minuses to intrapartum antibiotic prophylaxis and when, hopefully, you can maybe make a choice between vaccination or intrapartum antibiotics, you should have a realistic understanding of the pluses and minuses of both of those strategies.

Daphna: 1:14:38

And let's say that we reach a panacea. We can give a one-time vaccine that's safe and effective. Dustin, what do you think this will mean for our neonatology practice in terms of sepsis screening and this early antibiotic use?

Dustin Flanery: 1:14:55

Yeah, that's a really great point. You know, intrapartum anabolic prophylaxis has made such a dent in early onset GBS disease, at least among term infants. But I think there are other bacteria that are on the list that we're going to have to go after next. So you know, GBS luckily we have intrapartum anabolic prophylaxis as an approach. Potentially we'll have a vaccine in the near future, but there are many others on the list. You know E coli comes to mind as the second most common cause of early onset sepsis, Number one for preterm infants. E coli, unlike GBS, is universal colonizer, so it's going to be more challenging to develop a vaccine for that organism, and so we may need to be thinking about other approaches. But I will say that we'll have to think about how to take this into account when we use things like the sepsis calculator and to determine an individual infant's risk for infection soon after birth.

Daphna: 1:15:55

Dr Poplow, Dr Flannery, we're already over time, which I'm not surprised about. I still have more questions. But any closing thoughts as we wrap up the episode today.

Dustin Flanery: 1:16:04

I think my biggest closing thought would be that it's just a really exciting time to be in this field of perinatal infectious disease, to see things like, you know nocivamab coming out, a maternal RSV vaccine, potentially a maternal GBS vaccine these are all diseases that we've all taken care of and had, you know, patients who suffered incredible morbidity and mortality, and so it's a really exciting time to be part of this field and to see these changes happening.

Karen Puopolo: 1:16:37

I'm really excited to see so much attention given to the physiology, the clinical care of pregnant women, pregnant persons. I'm sorry, I need to. I really need to clean up my language there. I was a pregnant person four times and pregnant people count. We are not simply to be patted on the head and told to eat well and, you know, be careful. That's all about the baby. We need to understand that pregnancy is a life-threatening medical condition as well as a wonderful and welcomed joy in person's lives. And dealing with that realistically and dispassionately for the many wonderful things about pregnancy and the newborn period, as well as the very clear medical implications of exposure to infectious diseases, is really important. I think it's great that we are talking about research to protect pregnant women and newborns not protecting them from research, but protecting them with research. As Dr Bianchi has said repeatedly during the COVID pandemic, pregnant people count, newborns count, and we should be doing our best for them with the scientific tools that we have at hand.

Daphna: 1:18:07

Wonderful. Thank you both so much for your time and thank you for the ongoing dedication and the work that you all are doing, both in study and in education. Thank you so much.

Dustin Flanery: 1:18:17

Thank you for having us.

Karen Puopolo: 1:18:19

Thank you, lovely to chat.

Ben: 1:18:23

Okay, that was great. Thank you, davna, for talking to our friends from the Ebineo team, and so exciting to see so many different vaccines being developed for some of the festering infections that we've been dealing with in pediatrics and perinatology, so that's very exciting. Do you have any other articles to review for us today, davna?

Daphna: 1:18:46

I did. I have two more.

Ben: 1:18:48

Go ahead.

Daphna: 1:18:49

Yeah, yeah, perfect, yes, all right, I'll finish this out, but I think this is important. You alluded to it, that there is an update 2023 American Heart Association and American Academy of Pediatrics focused update on neonatal resuscitation, and I'm going to give you straight from the page the top text take home messages for neonatal resuscitation. I wish all updates looked exactly the same. It's very helpful. And then, of course, they have the data there for you to look at by the working group. So number one for term and late preterm newborn infants greater than or equal to 34 weeks gestation who do not require resuscitation, delayed cord clamping greater than or equal to 30 seconds can be beneficial compared with early cord clamping less than 30 seconds. Take home point two for term and late preterm newborn infants greater than or equal to 34 weeks gestation who do not require resuscitation, intact cord milking is not known to be beneficial compared with delayed cord clamping greater than or equal to 30 seconds. Number three for non-vigorous term and late preterm newborn infants, that's, 35 to 42 weeks gestation, intact cord milking may be reasonable compared with early cord clamping less than 30 seconds. Number four for preterm newborn infants less than 34 weeks gestation who do not require resuscitation, delayed cord clamping greater than or equal to 30 seconds can be beneficial compared with early cord clamping less than 30 seconds. Number five for preterm newborn infants those between 28 and 34 weeks gestation who do not require resuscitation, in whom delayed cord clamping cannot be performed, intact cord milking may be reasonable. Number six for preterm newborn infants less than 28 weeks gestation, intact cord milking is not recommended. So that's really the synopsis of what you gave us early in the episode.

Ben: 1:20:53

By the way, I just want to make a clarification there because I guess I did not really talk too much about this, but there's this whole distinction between intact cord milking versus clamped cord milking, which is that intact cord milking meaning the OB holds the baby for you, you use milk, the cord while the baby is still connected technically to the placenta, and then there's clamp. So you clamp first and then you milk whatever bit of cord you have. The catheteria paper did intact cord milking.

Daphna: 1:21:20

I will finish out with these last few updates. Number seven effective positive pressure ventilation is the priority in newborn infants who need support after birth. Number eight using a T piece resuscitator to deliver positive pressure ventilation is preferred to the use of a self-inflating bag. Number nine because both T piece resuscitators and flow inflating bags require a compressed gas source to function, a self-inflating bag should be available as a backup in the event of compressed gas failure when using either of these devices. And number 10, the use of a supraglottic airway may be considered as the primary interface to administer positive pressure ventilation instead of a face mask for newborn infants delivered at greater than or equal to 34 and oh weeks gestation. So an interesting set of updates.

Ben: 1:22:09

Yeah, I think. Number one it's so nice to have papers come out with everybody on the same page when it comes to new recommendations, new papers. I think this is very helpful. I think if you are a training program, this is a great opportunity to have like a group discussion with fellows reviewing these papers, looking at how it's so great to see how you like evidence translates into recommendation.

Daphna: 1:22:33

Yeah, and I think it just so happens that we have the recommendations. It's a great, you know, jumping off point for these papers, absolutely.

Ben: 1:22:42

And so you could have somebody review the actual RCTs. You could have someone review actually the recommendations from the AHA, looking at how that evidence was ranked compared to other papers. There's a lot of very interesting educational stuff to be done parsing out these articles.

Daphna: 1:22:57

Yeah, I think obviously the work on the Millical Cord Management is growing. I think it was really cool that they I mean, we know about PPV, right, we use PPV all the time, but how many times do you enter the room and somebody's called you, they're working on the baby, but they're not giving PPV right? It's just a reminder that we have to breathe for these babies, and I think the conversation about starting to include superglottic airways is another really interesting one. I only had one more thing of note. I wanted just to highlight this paper from Pediatrics Perspectives the role of medical education podcasts in Pediatrics. Lead author Joanna Pargabilinky.

Ben: 1:23:40

Who's the co-host of the Pediatrics on Call podcast. So if you still have an active flame for your former love of general pediatrics, they are a great podcast to listen to, and they are, I think, they are the official AP podcast, so I think it's always very polished content that they provide, so please go give them a listen.

Daphna: 1:24:03

Absolutely, and they list a number of pediatric podcasts there that may be of interest, but I think it's interesting. I wanted to give a shout out to our community that already listens to the podcast, because I think we have numbers pretty close to some of these major pediatric podcasts, so I'm pretty proud of our community for that. I'm not going to read the whole thing, obviously, but it's an interesting approach to how our podcasts moving the needle on medical education I really like. They highlighted this article from Academic Medicine that reported podcasts demonstrated non-inferiority compared with traditional teaching methods and were associated with self-reported practice change and quote. Moreover, podcasts offer an effective form of asynchronous passive learning, and one study even revealed that podcasts consumed while driving were just as effective for short and long-term retention as those heard while seated, without distraction. And based on our community, that's what we hear people are doing. They listen while they're driving, they listen while they're doing the laundry, walking the dog, so it's nice to know that the studies are showing that there's still valuable retention from doing that. And then I will just leave with their kind of closing argument that I think we agree on as podcast hosts that now that podcasts are turning 18, employing them as a legitimate educational resource is a must. Not only should academic institutions financially support them, but they should also promote podcasts to educate pediatric trainees. There are many ways to incorporate podcasts into learning. Podcasts can be integrated into formal medical curricula as self-directed learning resources or as part of a flipped classroom model. This practice can lead to increased engagement in the subject matter and the potential increased retention of information. The infrastructure exists and has for quite some time, to make this format into a more formally accepted educational resource.

Ben: 1:26:10

It feels both good and silly at the same time because as neonatologists, we're always lagging a bit behind. But that's something that other specialties have known also for some time. My wife was an adult physician. To them it's been its podcast predate, the incubator and a lot of the Piazzo. We're lagging a bit behind and definitely the wave of the future. It's very exciting to see how the community, more of the stakeholders not the listeners, but the universities, the institutions how will they leverage that platform, those platforms, to continue advancing education forward? Because, yeah, I mean, is this the same as the revolution of the publication industry that happened in the early 20th century? We'll see. It's interesting. It's fun to be a part of that. If you want to find out more about what's going to happen on the incubator podcast, then you're done with your papers. I was finding the nice segue to wrap up the episode. In two weeks, on December 24th, we'll announce the giveaway winners and we will talk about all the new content that will be coming to you in 2024. Some of the stuff is I'm containing myself, not to reveal right now what it is. We're really excited, by the way, and it's not content, by the way, for some may be disappointed, but I think for most it will be refreshing. It's not coming from us, it's not going to be Daphna yes, it's not the Daphna Ben show.

Daphna: 1:27:39

New voices.

Ben: 1:27:40

New voices, quality voices. So yeah, stay tuned.

Daphna: 1:27:46

Sounds good, buddy.

Ben: 1:27:48

Have a good one.