Hello Friends 👋
In this latest episode of The Incubator Podcast Journal Club, Ben and Daphna explore studies that may shift clinical practices in neonatal care. They begin with a study from India examining oral calcium phosphate as an adjunct to phototherapy in treating neonatal jaundice. This double-blind, randomized, placebo-controlled trial investigates how calcium phosphate may help reduce bilirubin levels by binding to unconjugated bilirubin in the gut, potentially minimizing the need for prolonged phototherapy. The findings suggest that calcium phosphate could lower phototherapy duration and decrease cases of rebound hyperbilirubinemia, offering a possible new approach for jaundiced newborns.
The episode also covers an intriguing study on alternative treatments for persistent pulmonary hypertension of the newborn (PPHN). By comparing oral sildenafil to bosentan, this research sheds light on the potential of sildenafil to reduce PASP more efficiently, especially in resource-limited settings. The team discusses these insights and examines how they may influence care for PPHN cases worldwide.
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The articles covered on today’s episode of the podcast can be found here 👇
Ghorui A, Chowdhry BK, Manjhi PK, Kumar P, Kumar CM.BMJ Paediatr Open. 2024 Oct 11;8(1):e002902. doi: 10.1136/bmjpo-2024-002902.PMID: 39395818 Free PMC article. Clinical Trial.
Kallimath A, Deshpande S, Singh P, Garegrat R, Lakshminrusimha S, Maheshwari R, Suryawanshi P.BMC Pediatr. 2024 Nov 1;24(1):698. doi: 10.1186/s12887-024-05107-0.PMID: 39487423 Free PMC article. Clinical Trial.
Bomback M, Everett S, Lyford A, Sahni R, Kim F, Baptiste C, Motelow JE, Tolia V, Clark R, Dugoff L, Hays T.Am J Obstet Gynecol. 2024 Sep 23:S0002-9378(24)01013-5. doi: 10.1016/j.ajog.2024.09.101. Online ahead of print.PMID: 39322018
Ziegler A, Koval-Burt C, Kay DM, Suchy SF, Begtrup A, Langley KG, Hernan R, Amendola LM, Boyd BM, Bradley J, Brandt T, Cohen LL, Coffey AJ, Devaney JM, Dygulska B, Friedman B, Fuleihan RL, Gyimah A, Hahn S, Hofherr S, Hruska KS, Hu Z, Jeanne M, Jin G, Johnson DA, Kavus H, Leibel RL, Lobritto SJ, McGee S, Milner JD, McWalter K, Monaghan KG, Orange JS, Pimentel Soler N, Quevedo Y, Ratner S, Retterer K, Shah A, Shapiro N, Sicko RJ, Silver ES, Strom S, Torene RI, Williams O, Ustach VD, Wynn J, Taft RJ, Kruszka P, Caggana M, Chung WK.JAMA. 2024 Oct 24:e2419662. doi: 10.1001/jama.2024.19662. Online ahead of print.PMID: 39446378
Lazarus MF, Marchman VA, Brignoni-Pérez E, Dubner S, Feldman HM, Scala M, Travis KE.J Pediatr. 2024 Nov;274:114190. doi: 10.1016/j.jpeds.2024.114190. Epub 2024 Jul 14.PMID: 39004169
Chakkarapani E, Ingram J, Stocks S, Beasant L, Odd D; CoolCuddle‐2 study research team.Acta Paediatr. 2024 Oct 25. doi: 10.1111/apa.17466. Online ahead of print.PMID: 39451123
Singh P, Gallo MF.JAMA Pediatr. 2024 Oct 21. doi: 10.1001/jamapediatrics.2024.4276. Online ahead of print.PMID: 39432283
Mitev K, Frewin KL, Augustinova M, Niedenthal PM, Rychlowska M, Vanderwert RE.Pediatr Res. 2024 Oct 15. doi: 10.1038/s41390-024-03540-6. Online ahead of print.PMID: 39406952
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The transcript of today's episode can be found below 👇
Ben Courchia MD (00:00.834)
Hello everybody, welcome back to the Incubator Podcast. We are back this Sunday for a new episode of Journal Club. Daphne, how are you?
The Incubator (00:08.156)
I'm doing well buddy, well. I'm excited to do some articles today.
Ben Courchia MD (00:14.262)
Yeah, same here. Before we begin, we have, I guess, a few announcements that we have to get out of the way. Number one, for the people who are wondering about Delphi, we have the Delphi talks that are pretty much all edited and all ready to go. And so these are going to be uploaded to our YouTube channel very soon. Look out for that. You may have missed.
But we have a special episode that was released earlier this week on Wednesday talking to the organizers of Hot Topics, which is obviously a big neonatology conference. We're quite excited that we will be in attendance at Hot Topics this year, providing some live coverage, talking to speakers and attendees and so on. And so go check it out, because I think to me, it's the first step of if you are interested in attending a conference, whether in person or virtually, check out the content, see who will be there.
I think it's one of these where the people who are there are quite exceptional, and you might meet some pretty interesting individuals. And we have a special discount for you if you are interested in registering, whether online or virtual. And it is Incubator Pod. If you go on our website, it's spelled out, and it's there. So Incubator Pod, I think the I and the pod are capitalized. But you can see it there, and you can put it in during your registration. So check that out.
The Incubator (01:14.898)
Mm-hmm.
Ben Courchia MD (01:39.747)
And I think that's pretty much it for today. I am not going to spend much more time on that. We can dive right into a lot to cover. I'm not even going to ask. I know you say that I should begin Journal Club. The first paper I'm talking about today is a paper that's coming out from India, a paper that Gabriel Altit sent to me, very interesting one. First author is Arnab Ghorui.
The Incubator (01:45.052)
We have a lot to cover. Yeah.
Ben Courchia MD (02:07.13)
And it is called evaluation of efficacy of oral calcium phosphate as an adjunct to standard of care regular phototherapy in the case of neonatal jaundice, a hospital-based double-blind randomized placebo control trial. interesting paper looking at calcium and hyperbilirubinemia. Now, I think, again, a very interesting background that goes over a lot of basic pathophysiology of hyperbilirubinemia. I'm going to go over a few things that are pertinent to this paper.
They're mentioning things that we are aware of that because of its non-polar, non-water soluble and fat soluble nature, unconjugated bilirubin crosses the gut wall and enters the enterohepatic circulation. Stasis or delay in the passage of meconium may also increase the enterohepatic circulation. So that's really the principle that they're going to try to target with this intervention. Amorphous calcium phosphate selectively
binds to unconjugated bilirubin in a dose-dependent manner and converts it into an ionic compound that cannot cross the intestinal wall. And thus, basically what they're saying is that this compound of calcium and unconjugated bilirubin can basically act. The calcium basically traps the unconjugated bilirubin inside the intestine.
preventing enterohepatic circulation, effectively dismissing the bilirubin, hopefully allowing you to not see a rise in bilirubin levels. They're saying that normally approximately 10 to 20 percent of bilirubin enters the enterohepatic circulation, so not negligible. And with the use of oral calcium phosphate, you can then maybe potentially expect a similar decrease in bilirubin load, which the hepatic conjugation system or phototherapy has to otherwise deal with. So a very interesting premise.
The question they're trying to answer is obviously to see if there is any efficacy of using oral calcium phosphate as an adjunct, obviously, to phototherapy. This is not a replacement of phototherapy. And they have some secondary objectives that we'll talk about. So it's a double-blind randomized placebo control trial with an allocation ratio of one to one. It was conducted in the NICU of a tertiary care medical college hospital in eastern India over an eight-month period.
Ben Courchia MD (04:34.998)
The inclusion criteria are basically all neonates admitted to the NICU with neonatal jaundice requiring phototherapy. Which guidelines did they use for phototherapy? Well, if you were 35 weeks or above, they use the AAP guidelines. So that's super relevant for us in the US because that's what we're using as well. If babies were below 35 weeks, then they use the National Institute for Health and Care Excellence, the NICE guideline, and for the therapy cutoffs. So what was the intervention?
The intervention group received basically your standard of care phototherapy, which included double surface phototherapy using the Phoenix Brilliance Pro Light Emitting Diodes, if you guys are geeking out over phototherapy devices, now you know. But the intervention group also received an active drop containing 125 milligram of elemental calcium and 400 international units of vitamin D3 per ml administered every six hours.
Feeding was continued with Katori spoon feedings of express milk with minimal interruptions to the phototherapy. Now the dose of elemental calcium used for the study was 75 to 80 milligram per kilo per day, along with vitamin D3 at a range of about 200 to 1,000 international units per day. They're talking about why they're using this higher physiological dose. And they're saying that it's based on the understanding that phototherapy is associated with an increased risk of hypocalcemia. And so that's why they had to.
increase that. Now, the control group receives standard of care phototherapy in a similar manner. In addition, they're also receiving just the vitamin D supplementation that would be standard of care for these infants. In terms of the outcomes they're looking at, but no calcium, right, obviously. The outcomes they're looking at is that they're looking at the serum, the total serum bilirubin level estimated from venous blood samples every six hours in both the intervention of the control group, which is continued until the serum level is below
is 2 milligram per deciliter below the phototherapy cutoff as per the AAP nomogram or the NICE guidelines for phototherapy, whichever was applicable. After phototherapy is stopped, then they measure it again 12 hours later to monitor for a new rebound. And in addition to bilirubin measurement, they also measure total serum calcium levels once a day. So far, good. So a very interesting study. I was very eager to read the results because obviously,
Ben Courchia MD (06:55.682)
To me, it's very relevant as for babies that have issues with hyperbilirubinemia, any intervention will throw at them to avoid kernicterus and exchange transfusions and so on. So they analyzed their data and they had 40 cases, 50 % term, 50 % were preterm. And in the control group, 57 % were term and 42 % were preterm. So they had...
They had 80 and 80 infants in each group.
The demographic profile was nearly identical. And it's very important for me to mention that there were no significant differences in the mean hours of life at the start of phototherapy or the mean total serum bilirubin level at the initiation of phototherapy across group rates, because I think that it would kind of be an issue. Now, interestingly enough, they showed that from six hours on, there was a statistically significant difference in the mean total serum bilirubin level across both groups, except at 30 hours of phototherapy.
where they saw lefts of a difference, but that also has to do with the fact that it can be attributed to the wide disparity in the number of cases, as most of the cases in the intervention group completed treatment early. So they lost a lot of their intervention group by 30 hours. But it's a very interesting graph where you can see the mean serum bilirubin and you can see that basically the children who received the calcium, the intervention, the calcium supplementation,
actually had consistently lower bilirubin levels throughout. And they had statistical significance, I would say, at 6, 12, 18, and 24 hours. Now, the result that we're really interested in is that the mean total hours of phototherapy was significantly lower in the intervention group as compared with the control group, 18.8 hours versus 24.3 hours.
Ben Courchia MD (08:52.874)
Looking at some of the secondary outcomes, the rate of fall of the bilirubin was significantly higher in the intervention group as well compared to the control.
And then finally, the incidence of rebound hyperbilirubinemia in the intervention group was 7.5 % compared to 25 % in the control group. So even then, sort of kept its effect. I forget the name of the figures. They have these two graphs that are kind of like purplish in their hue or something. But you can see the hours of phototherapy and the rate of bilirubin fall. It's quite impressive to see that difference between intervention and control.
The conclusion are that the use of oral calcium phosphate resulted in a statistically significant reduction in phototherapy hours, an improvement in the rate of bilirubin decline, and a decrease in rebound hyper bilirubinemia incidence. This allows for shorter hospital stays, reduces the need for real hospitalization resulting in less mother to baby diet separation, lower hospital resources consumption, and reduced financial burden on parents. I thought this was a super interesting study. I've seen all sorts of weird...
The Incubator (09:57.116)
Very interesting.
Ben Courchia MD (10:00.576)
weird crap being done to hyperbilirubinemia babies because we just wanted to bring it down. So it's nice to have something that's rooted in evidence, rooted in pathophysiology. so, yeah, pull out your calcium phosphate.
The Incubator (10:11.206)
Yeah. And I wonder, you know, for those kids that are getting up there, right? Will this, will this help us? I mean, I mean, I don't think it means you're never going to need IVIG. But I'm just saying, I think, and it's falling out of favor anyways, but it's interesting. It's very interesting. Loved it. I like, I like the Billy Reuben. My division chief.
Ben Courchia MD (10:30.626)
I know you would like that. I can see you ordering that next time.
The Incubator (10:40.518)
used to say, don't tell me about the belly room. Just don't let the baby get kernicterus. So I've always remembered that. Just don't let the baby get kernicterus.
Ben Courchia MD (10:46.11)
Ha.
Ben Courchia MD (10:50.464)
Yeah, and you have a particular propensity to attract these exchange transfusions. So you have a vested interest. No, but you have a vested interest in keeping them at bay, I guess.
The Incubator (10:54.804)
I know, I don't know why. I don't go looking for them. tell you. Epic. That's exactly right. Totally. Okay. My turn. Okay. I have a kind of a quick paper here. This is actually another paper out of India, but with collaborators in California, the UK and Australia.
Ben Courchia MD (11:08.458)
Yeah, yeah, it's your turn.
The Incubator (11:18.716)
This is oral sildenafil versus Bosentan for treatment of persistent pulmonary hypertension of the newborn or randomized controlled trial. author, Aditya Kalimath, senior author Pradeep Suryawanshi. I got it. But the author list includes Dr. Satyan Lakshminarusimha, so a good friend of the podcast. This is in BMC pediatrics.
The design is a single center open label randomized controlled trial. It included term and late preterm neonates. I didn't sleep very well last night. Okay, neonates with PPHN. And they defined PPHN as pulmonary arterial systolic pressure greater than 35 milligrams of mercury using the TR jet velocity and requiring a fraction of inspired oxygen greater than 21%.
So you needed to be on oxygen and you needed to have a PASP greater than 35. Okay. Then the babies were randomized to receive either oral sildenafil or oral bosentan. And the goal of this is really like, what are the other options for babies with PBHN, especially in resource poor situations that where nitric is not available.
And the primary outcome was reduction of the PASP by 25 % within 48 hours after the start of the medication. 63 neonates were diagnosed to have PPHN using the functional echo criteria. 36 were randomized eventually, 18 to sildenafil and 18 to bosentan.
The baseline maternal and neonatal characteristics were pretty similar and the median time taken for the PSAP to reduce by 25 % was significantly shorter with sildenafil compared to bosentan. This is a p-value of 0.008. So again, reduction by 25 % occurred with a median time of 36 hours in sildenafil compared to 96 hours with bosentan.
The Incubator (13:31.644)
Bummer. In the sildenafil group, three or 16 % of cases required addition of another pulmonary vasodilator due to lack of response, cardiac dysfunction, or hypotension. All three of these subjects received milrinone of the three neonates. One was diagnosed with the MISN, the multi-system inflammatory syndrome of the neonate. And this baby unfortunately developed kind of severe catecholamine resistant shock requiring a number of pressors.
Ben Courchia MD (13:32.715)
Yeah.
The Incubator (14:01.96)
In the Bosentan group, 11 or 61 % of cases required additional pulmonary vasodilator therapy, again, compared to 16 % in the sildenafil group. The additional pulmonary vasodilators in this group, milrinone or sildenafil, depending on the presence or absence of cardiac dysfunction was required due to lack of response, cardiac dysfunction or hypotension.
Also, there was observed a statistically significant decrease in the PSAP at numerous time points in the sildenafil group compared to the bosentan group. So at 24 hours, again at 48 hours, and at 72 hours, so at each of the time points. And clinically, the mean-inspired oxygen requirement at start of intervention was similar in both groups.
But by 24 hours, the decrease in inspired oxygen in the sildenafil group was more significant than for the Bosentan group with a p-value of 0.021. And by 48 hours and 72 hours, there was further reduction in inspired oxygen requirement in both groups, but this decrease was not statistically significant. So as I mentioned, treatment failure was significantly higher in the Bosentan group as compared to sildenafil. The need for additional pulmonary vasodilators was higher in the Bosentan group as compared to the sildenafil group.
There was no statistical difference in median duration of invasive ventilation, noninvasive ventilation, number of days to reach full feats time to reach room air, interestingly, duration of hospital stay. There was only one death in the study. It was this one baby in the Sildenafil group with MISN with this catecholamine resistant shock. So I was hoping we would have something new in our little pharmacy bag, but no, alas.
Ben Courchia MD (15:44.032)
Ha
The Incubator (15:51.073)
It does work, but not as well as the benefit.
Ben Courchia MD (15:54.326)
Yeah, think that's reassuring, I guess. We can use Sildenafil more. Especially with PPHN, sometimes you feel like, am I using something that might work better in another place or something like that. But no, it doesn't look like it. So that's exciting. I'm happy about that.
The Incubator (16:01.5)
Yeah.
The Incubator (16:08.383)
Mm. Mm-hmm.
The Incubator (16:15.862)
Very good.
Ben Courchia MD (16:19.055)
OK, well, we're going fast then. I'm next, I guess. So we have two articles, and then we have, so let me explain to what's going to happen next. So we have an article that, I know, it's complicated. So we have one article, we have two articles about genetics. And so we're going to have, yeah, we're going to have one article that I'll review here. And then we'll have a second article where actually we had the pleasure of speaking to the senior author. I'll.
The Incubator (16:22.536)
Mm-hmm.
The Incubator (16:30.588)
The buildup here is...
The Incubator (16:36.744)
Oooooh
Ben Courchia MD (16:45.01)
through these two articles and then we'll segue into our little conversation with our guest. So the first paper I'm looking at is a paper published in the American Journal of Obstetrics and Gynecology. It's called Genetic Disorders and their Association with Morbidity and Mortality in Early Preterm Small for Gestational Age Infants. First author is Miles Bomback and it's coming out of the US. Senior author is our good friend Dr. Tom Hayes.
But this is data that we've been wanting to look at for some time. I think there's a big discussion about how quick should we be in evaluating our patients for genetic conditions. And so I think this is a first step in that direction. So the background mentions that genetic disorders are more prevalent in small for gestational age infant and that multiple genetic disorders are associated also with fetal growth restriction, which often precedes SGA.
And they're saying that it's particularly twin babies that are born prematurely before 32 weeks. Now the question this group is trying to ascertain is, what is the proportion of genetic disorders in this specific population of SGA babies compared to appropriate for gestational age infants? And what is the association of genetic disorders with morbidity and mortality in SGA early preterm infants? So the study is a retrospective cohort study.
of infants care in about 400 US community and academic hospital NICUs. And this is data that's coming from the pediatrics clinical data warehouse, which is a very famous data set that you've probably seen used in other studies. Congenital anomalies were defined as major birth defect that cause mortality or that require consideration of intervention to correct anatomic or physiologic dysfunction.
Now, these congenital anomalies, as they define them, were grouped into several categories. They had cardiac, they had gastrointestinal, which included your omphalocele, gastroschisis. You had neurological, you had pulmonary, and you had renal genitourinary. They also included high drops, that it's high association with perineural disease and genetic disorder. So who did they include in this study? Any preterm infants born at
Ben Courchia MD (19:12.162)
between 23 weeks, 23 and zero days, all the way up to 33 and six weeks, and who were discharged between the year 2000 and 2020. They excluded cases of death in the delivery room before NICU admission, they excluded cases of multiple gestation and cases transferred after birth or before death or discharged to limit the certain bias. Now they were classified as SGA based on their growth, and if they were below the 10th percentile,
They were considered LGA if they were above the 90th percentile, and otherwise they were considered AGA. They compared SGA classification to Fenton SGA criteria and an NICHD consensus fetal growth restriction criteria. So I want to get into the results because I think it's quite interesting. So the results. Following exclusion, their cohort consisted of 223,431 infants.
pretty large cohort, almost a quarter of a million babies. 21,180 were SGA. The rest were AGA, and about 20,000 were also LGA. So you have a nice split where you almost have the same number of SGA and LGA babies, and then you have these AGA kids that are pretty much in the middle. So then they divide the SGA kids, and they want to find out, which ones are considered to be quote unquote isolated SGA, meaning just more for gestational age, but no other...
fear congenital anomalies. That's about 8%. But they said that the rest were considered SGA accompanied by congenital anomalies. what was interesting is that when they did... So we'll get into actually the different results. don't want to start spoiling the results. talking about association of genetic disorders with early preterm SGA, genetic disorders were found in...
2.3 % of isolated SGA and 10.8 % of SGA with congenital anomalies. So I think that's quite interesting that if a baby has SGA and has any of these anomalies, you can consider the likelihood of having a genetic disorder in about 10%, even more close to 11 % of these cases. They're saying comparatively, the genetic disorders were found in only 1 % of AGA infants without congenital anomalies.
Ben Courchia MD (21:38.71)
They did some studies, they did some analysis looking at the birth weight of these infants. And they said that the proportion of infants with genetic disorders increased with lower birth weight, especially if the infant had congenital anomalies. And the proportion of genetic disorders in infants with congenital anomalies also increased as their birth weight increased. And so they define this U-shaped distribution that is quite interesting to see.
for the proportion of genetic disorders between these babies with congenital anomalies at both low birth weight and high birth weight. And they're saying that this U-shaped distribution was not observed in infants without congenital anomalies. So I guess it's quite interesting and important to make sure we have a complete overview of these patients. Early preterm infants with genetic disorders had an adjusted odds ratio of 2.1 for isolated SGA.
compared to appropriate for gestational age without congenital anomalies. So pretty high odds ratio of having a genetic diagnosis. Now they're saying that the presence of a genetic disorder was the factor that contributed most strongly to the odds of isolated SGA status. I think that's very interesting.
The infants with genetic disorders had an adjusted odds ratio of 12.8 for SGA accompanied by congenital anomalies compared to babies who were AGA without congenital anomalies. Now the presence of a genetic disorder was the factor that also most strongly contributed to SGA accompanied by congenital anomalies. So let's dive a little bit deeper into these genetic diagnosis. So they were saying that there were greater odds
of isolated SGA status were found for early preterm infants with the following genetic disorders. Turner syndrome, Klinefelter syndrome, trisomy 13, trisomy 18, trisomy 21, unspecified aneuploidy, unspecified pathogenic CNV copies of normal variant, sickle cell disease, cystic fibrosis, hypophosphatasia, and for infants with multiple genetic disorders. Greater odds of
Ben Courchia MD (23:59.282)
SGA accompanied by congenital anomalies, so these babies who were SGA and had something else were found for early preterm infants with the following disorders. These include a lot of the same things that we just discussed, Klinefelter, Trisomy 13, Trisomy 18, Trisomy 21, unspecified aneuploidy, Cree-Du-chât syndrome, diGeorge, unspecified CNVs, hypophosphatasia, as well as infants with multiple genetic disorders.
They were saying that trisomy 13, 18, and 21 demonstrated the strongest association with isolated SGA and SGA accompanied by congenital anomalies. And I think that's something we tend to ignore because whether it is a complete diagnosis or mosaicism or something like that, but some of these babies sometimes can get missed. I know it sounds stupid to say, but you could miss this infant, especially when they're born preterm and
The Incubator (24:45.138)
Mm-hmm.
Totally.
The Incubator (24:52.134)
Right? Mm-hmm.
Ben Courchia MD (24:54.454)
their faces, their appearance can be deceptive in my opinion.
The Incubator (24:59.11)
Yeah, you know, there are some babies that have been in the unit and it's not until a few weeks where you're like, hmm, that's interesting. You know, this baby, didn't quite notice this before, you know? This is really interesting.
Ben Courchia MD (25:05.376)
Yeah, exactly. That's exactly right.
Ben Courchia MD (25:10.562)
Mm-hmm.
Yeah. So looking at morbidity and mortality, they're saying that of the 21,000 early preterm SGA infants, 32 % experienced predischarge morbidity and mortality. I mean, this is just a staggering number. Of the early preterm SGA with congenital anomalies and genetic disorders, they're saying that 68 % experienced predischarge morbidity or mortality.
Genetic disorders were present in 4.5 % of early preterm SGA with morbidity or mortality. And these consisted of 233 cases of aneuploidy, six cases of pathogenic copy of normal variants, 62 cases of single gene disorder, and three cases of multiple genetic disorders. Comparatively, they're saying that genetic disorders were present in 2.3 % of early preterm SGA that did not experience morbidity or mortality. And these sort of are much less.
clear 163 cases of aneuploidy, some CNVs, and other single gene disorders. I'm almost done. The proportion of infants that they said with genetic disorders increased with lower normalized birth weight for infants with and without morbidity or mortality. So if you're looking at it from these kids who have experienced some form of NICU complications or who have experienced unfortunately mortality, and they're saying that the proportion of genetic disorders in infants with morbidity or mortality also tended
higher as birth weight increased. Again, another U-shaped distribution that was not observed in infants that did not experience morbidity or mortality. So we'll post these graphs because they're quite eloquent, showing you how it lowers in the middle but really goes high on the extremes. I think that I thought this was very interesting. Early preterm SGA infants with genetic disorders
Ben Courchia MD (27:08.3)
had an adjusted odds ratio of 2.2 of morbidity or mortality. And the question they're trying to answer here is, what are the covariates that actually played a role? And what they're saying is that the covariates that were associated with a decreased adjusted odds of morbidity or mortality was antenatal steroids. The discharge year was mentioned in there. Maternal identification as Asian or Black compared to White. Greater gestational age. Greater birth weight for gestational age and sex.
Now the variants that were associated with an increased odds ratio of morbidity or mortality was male sex, maternal identification as Hispanic as compared to white, intubation within 72 hours and the presence of congenital anomalies. So I thought this was a very interesting paper because I think these SGA kids are always giving us a lot of trouble and we always say, these SGA kids are trouble, but we never really understand them fully. And I think that having a genetic background
elucidated for these infants could help us tremendously. The conclusion are that in a representative retrospective cohort of early preterm infants, the author says that we found that SGA, particularly SGA accompanied by multiple specified congenital anomalies or by morbidity or mortality was associated with genetic ideologies. so, yeah, trisomy 13, 1821, which have well characterized association with SGA demonstrated the strongest association.
with early preterm SGA. They also found robust association of Turner, Klinefelter, DiGeorge cystic fibrosis, and hypophosphatasia with early preterm SGA. The absence of genetic testing results from most of the cohort limits these findings. The authors are saying that the findings support the contribution of genetic disorders to SGA.
and that association is present in early preterm infants and that genetic disorders may explain a substantial portion of the morbidity and mortality in early preterm SGA infants. They're also mentioning that this supports the current guidelines regarding the use of genetic testing for SGA, particularly in the setting of early preterm birth. And they're saying that this obviously emphasizes the need for prospective investigation with detailed prenatal and postnatal phenotype and appropriate genetic testing. I think it's very interesting to me.
Ben Courchia MD (29:26.792)
because understanding SGA babies is something we don't do very well. I think we send, think the same way you would say, SGA, let me send Torch, right? We do these things with Torch, but we don't automatically say.
The Incubator (29:31.11)
Right.
The Incubator (29:36.314)
I was just going to say that. In fact, I think we get a lot, we don't get very many hits, right? We send a lot of torch titers. We rarely get a hit. Yeah. And probably we should be sending genetic testing even above torch titers.
Ben Courchia MD (29:45.802)
and negative. Yeah.
Ben Courchia MD (29:51.04)
Yeah, you ask the mother, are you like, you a kindergarten teacher by chance? No. But I'm going to send CMV anyway. But we don't the same reflex in saying, hey, SGA isolated. I'm not sure. Let's send some genetic testing. Very interesting. Congratulations to this team.
The Incubator (29:56.156)
That's right. Do you raise a lot of cats? Yeah.
Right.
No.
The Incubator (30:13.2)
And probably then it also means, I mean, duh, okay, but you have an SGA baby. You really got to take a look at that baby, right? Turn that baby all around and make sure you're not missing some minor anomaly that you didn't pick up previously. Very cool baby.
Ben Courchia MD (30:29.91)
Yeah. Yeah. All right. I'm going to just go quickly over the next paper and then we'll get our guest to come on. So this paper is actually published in JAMA and it's called Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions. First author is Alban Ziegler and this is coming out of the US. I just want to mention that I think it's important for people actually as a general rule of thumb to pay attention to who's funding
your research just because it's important. The same way that if this was presented at a conference, they would have a slide having conflict of interest disclosures. It's important to know. So this is a study that's funded by industry, including Sanofi and GeneDx, which our guest actually collaborates with. But the data is interesting nonetheless. So I think it anytime.
a paper that is relevant to the neonatal population is published in JAMA. think it's something we should be aware of. where is this setting? What is the setting of this paper? The paper mentions that there's growing support from rare genetic disease advocate, parents and public health professional to expand the newborn screen to enable timely access to new and often precision rare disease therapies. We've had an episode on this topic with Dr. Kruszka in the past.
So if you're interested in learning more about the newborn screen, Daphna is going to tell us when that episode was. But what they're saying is that, for example, a pilot newborn screen study in New York State for spinal muscular atrophy type five demonstrated high opt-in rates, 93%, and supported the addition of spinal muscular atrophy to the recommended uniform screening panel following US Food and Drug Administration for the approval of a new therapy.
The question they're asking, what about genome sequencing? Could we include genome sequencing as part of your newborn screen? They're saying that the use of genome sequencing for newborn screen has raised concerns because people are saying, well, what about its acceptability, its equity, its scalability? Are we going to be able to do this for everybody with expected challenges such as potentially adverse cycles, social impact, assay costs, workforce limitation, patient privacy concerns? There's a lot of different things that are associated with the
Ben Courchia MD (32:49.939)
the processing of genome sequencing. And so what they would like to know is that, it even feasible? And so the question they're asking is exactly that. Assessing the feasibility of scaling genomic newborn screening, the genomic uniform screening against rare disease in all newborns, it's called the Guardian study, is initiated with the aim of screening a diverse population by parent reported race and ethnicity of newborn in the New York City area within the context of the New York State Department of Health newborn screening.
So this is a multi-site, I'm going to go quickly over the study, we'll talk about this with Dr. Kruszka in a second. This is a multi-site single group prospective observational investigation of supplemental newborn genome screening with a planned enrollment of about 100,000 participants. Parent reported race and ethnicity are recorded at the time of recruitment. The results of the first 4,000 babies from six New York City hospitals is what is being reported here as part of a pre-specified interim analysis.
Now the sequencing of 156 early onset genetic conditions with established interventions were selected by the investigators. And it also included 99 neurodevelopmental disorder associated with seizures in that screen. The primary outcome was to see how many would screen positive. And additional outcomes included enrollment rate, successful completion, and so on. So over the 11 month,
5,555 families were approached and 4,000 consented to participate. So a consent rate of about 72%. We'll talk about this again, but obviously this is a very important metric as to are people willing to even do this? Enroll participants reflected a diverse group of parent reported race and ethnicity. New York City is very well known for it being a very multifaceted, multicultural city. So that's not surprising. And the majority of families consented to screening of both group of conditions.
We talked about these early onset that have treatment versus the 99 ones that had neurodevelopmental concerns. Testing successfully was completed in 99.6 % of cases. I think that for CBCs, our rates are lower in our hospital based on the numbers of QNS that are lost. And I'm sure you all can relate to these pesky, there's not enough, it clotted.
The Incubator (35:00.976)
my god, it's a sura subject.
Ben Courchia MD (35:09.452)
Having a successful completion rate of 99.6 % on such a large patient population is quite staggering. The screen positive rate was 3.7%, including treatable conditions that are not currently in the newborn screening program. I'm going to stop here, and I'm going to let us transition to our discussion with Dr. Kruszka just now so that he could tell us a little bit more about what he thinks the impact of this paper is and what are potentially the next steps. So please welcome to the show Dr. Paul Kruszka.
Ben Courchia MD (00:00.672)
Okay. And we have the pleasure of having on for this episode of Journal Club, Dr. Paul Krzysztof. Am I pronouncing that correctly? Yes, yes. Absolutely. remember. Yeah, you got it. European colleagues. Yeah, you got it. Actually, for those of you who remember, Paul has been on the podcast before for an episode of Tech Tuesday. it here. Episode 153. 153, where we talked about the work that you're doing with GeneDx. But obviously, you're here today to talk about this new publication in
JAMA, called Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions. Paul, guess my first question to you is, what is your summary? What are the takeaways that you are taking from this particular publication and this study? First of all, Benjamin and Daphna, thank you for having me. This is real pleasure here.
I like talking about decreasing the diagnostic odyssey and this paper really highlights how we can do this. As we all know, historically we have done most of newborn screening with TANAM mass spectrometry, diagnosing inborn errors and metabolism. This has been incredibly successful, but we're limited on the technology. This paper looks at the first 4,000
infants that were screened with whole genome sequencing, targeted whole genome sequencing in New York City. This was a collaboration between GNDX, New York Presbyterian Hospitals, Illumina, and the New York State Health Department. And we looked at 450 conditions. I'm sorry, version two is up to 450 conditions. We looked at a little bit over 200 conditions for this study.
And we used whole genome sequencing, which is different than tandem mass spectrometry. And there were two different groups. There was group one, which is treatable conditions. There was group two, which is related to epilepsy. And so families had the consent for this project, because this was a research project. 72%, over 70 % of parents,
Ben Courchia MD (02:25.004)
consented for this. I'm not surprised. I'm quite surprised actually. are? Yeah, think there's a lot of talk in the media in popular culture that I think would make people very reluctant to say yes to genetic testing in the current day and age. So I'm very impressed that 70 % actually volunteered for that. And I think it's different when we're talking about ourselves versus our children. I think that obviously is a big factor, but it's quite impressive. Yeah, I was surprised as well. I was very surprised.
that we would have that high level of consent, but that shows you parents are interested. I'll also mention this study took place in New York City, a very diverse population. Only about 40 % self-identified as white European. So the PI is Wendy Chung. She was consenting in Spanish, Mandarin, and English. And it really is incredible, the consent rate. So group one, treatable.
72%, then 90 % of that group went for group two. So that shows you that parents also want to know about genetic conditions that their child might have, even if there isn't a known treatment. We had roughly 4%, a little bit under 4 % positive rate. A lot of this was due to G6PD. If you take out G6PD, you're more around.
One percent, three states do screen for G6PD. I also practice on Fridays at Children's National Medical Center. We're one of the states that, or we're not a state. think DC wants to be a state. Big controversial topic right now. Yes, yes, yes. Let's shelf that one. But yes, we do screen for that. So it's really fascinating. And I think this ties into the conference here.
when we're talking about the NICU and neonatology, because a lot of these kids did go on to coming into the NICU afterwards. You can imagine there was a CDKL5 case, know, these epileptic encephalopathy cases, sometimes they don't present in the first few weeks of life. One important piece of information is we did not consent families in the NICU.
Ben Courchia MD (04:45.112)
So that would be going from birth straight from the delivery room into the NICU. So they weren't part of it. Obviously, the pre-test probability would be really high. I think that's a future consideration for these types of studies. So yeah, it's really exciting. we published the first 4,000. We've actually done 15,000 cases. It takes so long to get a paper through the review process. We're up to 15,000 cases that we've done so far.
And that's a combination of the Guardian and early check study where we did the pilot. And I think this is, know, that the diagnostic odyssey is alive and well. It can be up to six years. And this is really a big step forward to getting that diagnosis early. So really excited to see where this goes. Yeah, I'm very intrigued by the data and the results. I'm also very interested
in the process and the collaboration. So what you had here is a collaboration with basically local health officials, hospitals, and industry. And I think that's one, remarkable, and two, I hope will serve as a model in the future for how we move medicine faster. So tell us a little bit about that process. And if somebody's interested in a process like that, what does it look like? Yeah, I'm glad you brought that up. It is a collaboration from different
from academia, public health, industry. And I will say, first of all, everyone had the same goal. And that's eliminating the diagnostic odyssey. I think all parties were very interested in that. So let's start with the state. The state actually used the same dried blood spots of traditional newborn screening. they punched out a couple holes, small holes in the dried blood spots.
extracted DNA, sent it to us, we did the sequencing. So really the state was crucial to doing this and think about the convenience, we didn't have to draw an extra sample. That's huge. And also just having them on board because ideally this would be a public health initiative at some point. And then industry really, this project needed the support.
Ben Courchia MD (07:11.32)
I feel not, you know, I'm going to brag for a second. You know, GNDX, you know, we're good at this. We can scale. We provide a lot of genomic testing. So we know how to scale and do tens of thousands of tests. That's what we do. So we were crucial to that piece. And then the academic, this is a research study and the design of it and having a partner like Dr. Chung was crucial.
to get it published, to do this as research. And it was interesting. A lot of my colleagues were quite critical when I talked about Guardian three years ago. And they said, what about this? What about that? What about privacy? Parents are going to go for this. What about false positives, false negatives, overwhelming the health system? All these questions about doing a study like this were often brought up to me.
And my response was, these will forever remain questions unless we do it. And now is the time is right to do this. Over half of new drug applications to the FDA are for rare disease. Now is the time to do it. Things are changing. The price of sequencing is coming down. There's new treatments. I think now is the time to do this.
So let me ask you some questions because I think these are the things that are probably people are wondering as they're listening to the commentary. What is the turnaround time that we were looking at in terms of these specific tests? Yes, so at first our turnaround time was about six weeks and that was the first few samples because we were just getting our process down and how to do this. Now it's well under four weeks.
theoretically it could be a few days. you know, that's when you think about genetic testing, how much time does it spend on a machine is really the time of testing. So theoretically we could get it down to a few days and that's all process. that's really the, that's what we do well at GNDX. We do the commercial piece well, that's our job is to get the turnaround times lower and get the process down. So in the ideal world, sooner is
Ben Courchia MD (09:30.176)
Always better. Both of you are neonatologists. You know that. The quicker, the better. And I think one of the potential pitfalls of the publication is that we might see the screen positive rate that is reported at 3.7%. But I think that if we don't take that into account with the point you made earlier about scalability, and if this were to be widely used, then the number of people that could be positively impacted
by an accurate diagnosis could reach hundreds if not thousands of babies. I don't think that in this particular space we can shrug off those kinds of numbers when we're talking about hundreds of children who may be diagnosed early and for which especially as it is reported in the paper conditions for which they are treatable options. Yes, that's a great question.
you think about those numbers, let's just remove G6PD from the conversation and get the number a little bit lower, more manageable number. Let's say it's twice as much as current. And we know if you talk to a geneticist at a major university or children's hospital, like where I work on Fridays, it takes about maybe average of an hour and a half. I'm kind of spit balling this, but an hour and a half of someone's time to address each positive newborn screen, whether that's
Sometimes it's a few minutes, sometimes it's a few hours. So what you're saying is, let's say we double this, that's going to be doubled amount of time. But my, my thought too is though these babies are going to present into the health system eventually anyways. Why not get it early when you can treat it? One of the criteria for the study was the conditions had to have a penetrance of 90%. That means you get a positive result. You have a 90 % chance of getting sick.
And so that was really important for the criteria. Also, for the Guardian study, you had to present, the conditions had to present typically before age five. So our positive predictive rate is actually relatively high. The PPV is relatively high for the study. Dr. Chung just did a presentation at
Ben Courchia MD (11:53.176)
at ICONS, the International Conference on Newborn Screening that was in New York City a few weeks. And one of her slides had, for group one, a high positive predictive value, somewhere around 80%. And you think about it, for rare disease, that's really incredible. you know, that's just, at GeneDx, we have a large database. We have over 700,000 exomes and genomes.
A, we're able to scale, automate, but also our precision is excellent. And it really goes against what we're taught because positive predictive value is directly proportional to incidence of disease. that, think, bringing this back, Ben, do I call you Benjamin or Ben, by the way? Ben is fine. Ben is fine, I'm sorry. Ben, Ben's point is that false.
You don't want to have a lot of false positives. You want to have a positive predictive value, because I think what you're getting at is it's really going to overwhelm the health system if we do have that. Yeah, yeah, yeah. But I was also trying to get to the point of if we have the ability to identify, just like the newborn screen does, where the screening is justified if it's going to save lives. And I think that, as you were mentioning, these are conditions that were not picked up by the newborn screen. so the ability to make a difference for these patients and these families is critical.
Well, I mean, this was not a part of the study, but in terms of cost and time saving, I think we under recognize how much burden there is on the healthcare system for even a handful of patients undergoing a diagnostic. Absolutely. Years and years. And with the timeframe in which you guys have been able to expedite the testing, I mean, before we'd say it's six to eight to 10 weeks to turn around the genetic testing. And during that time we're doing
a lot of stuff in the NICU. And we don't stop testing the baby just because the whole exome or the genetic testing is out. We send whatever markers or things that labs that we think maybe we can figure it out before the genetics come back. And so I think it's under recognized how much we spend on testing, especially if you guys can get that time frame down to a week. mean, to me, it's just
Ben Courchia MD (14:13.912)
crazy that we're already at this point. Because I remember when we were just, when genome sequencing was in its infancy and we were like, how much it costs and where we are now, it's kind of, you know, when people used to say, hey, you'll see this in your lifetime that it will be rapid turnaround and cheap. And you're like, we'll see about that. But yeah, here we are. I know. Here we are. I thought same thing 10 years ago. I would have been a little skeptical. Yeah, that's exactly right. But here we are in, you know,
You know, talking about the families and the diagnostic odyssey, you getting back to your point. When you talk to families, just the indirect cost of this odyssey where they're moving around and getting second opinions, it's really, you know, an incredible burden on them. And when they do get that diagnosis, it really changes their lives. find their group. They feel like they're seen. They get a lot of great advice from these patient advocacy groups.
can't emphasize enough the power of patient advocacy that won't go into the paper or formulas or where payers won't consider that as actionable, but it is actionable in the eyes of the family. And I just really love talking to patient advocacy groups and families and getting their bet because really in the end, this information is for them. They're really at the top of the pyramid. And I think you bring up something that we really can't measure. And when we talk about health care inequities, some families
will never be able to afford the diagnostic odyssey, right? They'll never get the answers if we don't have a program like this because they can't go to get a second opinion. They'll never be able to do that. So I think it's really interesting. I wonder, does the future look like? Well, the future is unknown. How are we going to do this? We have a system, we have the recommended uniform.
screening program that's run by HRSA. How are we going to get these, you know, show, make enough evidence to show that this is worth putting on newborn screening? I, what I, my prediction is that there's a lot of different studies out there around the world. England is doing genomics, England is doing the same thing as Guardian, they're doing a hundred thousand and combining our data, showing that it's actionable, showing that early intervention makes a difference. But,
Ben Courchia MD (16:38.648)
The Rust, they usually approve two conditions a year and right now we're up to 450 conditions, we're version two. So we're trying to figure all this out. And if people want to find out more about the Rust, it's something that we've covered on our advocacy series. It's episode 121 to 124 of the podcast so people can learn more about that process, about the newborn screen.
And that was an episode that we did with Dr. Beth Terini, which you're probably familiar with. Yeah. Yeah. Paul, thank you. Thank you so much for sharing your thoughts and coming on the podcast. And congratulations again on this on this important publication. Well, thanks for having me. It's always a pleasure to talk to both of you. Yeah, same. Thank you.
Okay, and thank you to our guest. are back. Daphne, I think it is now your turn. So please take it away.
The Incubator (35:53.8)
It is my turn. did want to mention you had said we'd reviewed a little bit about the newborn screening before we did a advocacy in the NICU series and the newborn screening saves lives act with Dr. Beth Tarini was episode 121. So good. We learned a lot.
Ben Courchia MD (36:07.554)
Terini. That was so interesting about how do we decide what is included? How do specific states decide? I think that's very interesting because obviously there's the desire to test as many people as possible, but there's cost and there's processing. So super interesting inside look at this process. We have a lot of good content on the incubator. You will. Yeah.
The Incubator (36:29.264)
Yeah. Use the search bar and you're going to make you, you've got some changes coming to the website that are very exciting.
Ben Courchia MD (36:37.794)
Yeah, we're going to have very new, by the end of the year, we're actively working on this. Yep, that search bar is going to become an interesting feature, so yeah.
The Incubator (36:42.172)
But for now, use the search bar. Okay, I had some papers. I have two papers actually related to holding in different patient populations. this one's inpatient skin to skin care predicts 12 month neurodevelopmental outcomes in very preterm infants. This is in Journal of Pediatrics lead author, Molly Lazarus and senior author, Catherine Travis.
Ben Courchia MD (36:52.076)
Mm-hmm.
The Incubator (37:11.502)
So this is a retrospective chart review of 181 very preterm infants. So these included babies less than 32 weeks gestation at birth. the hospital underwent, Lucille Packard Children's Hospital underwent this quality improvement around developmental care. So nurses were charged with documenting like especially family interactions, okay?
So the sample was May 2018 to June 2022. The other inclusion criteria were that the patient received the majority of their neonatal inpatient care at their center. So inborn or transferred before seven days of life, discharged home from our center, and had no diagnosis of genetic or congenital anomaly to affect neurodevelopment. So basically,
Any very preterm infant who had this skin to skin care data observed during their NICU stay were eligible for the study. And then again, they were looking at the long-term follow-ups, I'll talk about in a second. Contraindications to skin to skin per protocol in their unit. I think this is always interesting to talk about. Included being on a high-frequency ventilator, poorly controlled hypotension.
a Vecuronium infusion or diagnosis of a critical airway as per the consulting ENT physician. Yeah. Right. So I think that's lots of people are eligible is what that means.
Ben Courchia MD (38:39.756)
That's not bad. That's not bad at all.
Ben Courchia MD (38:45.92)
Yeah, sometimes you feel like just a PIV is a criteria too.
The Incubator (38:49.064)
Depends on the day. Depends on the day. And we recognize that skin to skin is a long, is a complicated process, right? But anyways, we digress. So they looked at a number of metrics. So they wanted to look at the skin to skin care rate. So basically minutes of skin to skin care divided by the number of days of hospital stay.
They wanted to look at skin-to-skin care frequency. So how often do families do skin-to-skin? So this was basically skin-to-skin care sessions divided by the number of days, and then the skin-to-skin duration. They also looked at family visitation as a kind of co-founder for skin-to-skin. So for the neurodevelopmental outcomes, they have this California high-risk infant follow-up program, and they use the Kaput scale.
of composite scores at 6 and 12 months. So they had 181 infants, nearly equal male and female, 45 % had public insurance, the mean gestation was just 28 weeks, and the mean birth weight was about 1,100 grams. So basically, they had a visitation frequency of like 0.99, and a frequency of one would indicate that visitation occurred daily. So they had a lot of family visitation. So families visited almost every day on average.
Some families visited more than twice a day. And over their entire stay on average, infants in this unit received 18 minutes per day of skin-to-skin care. A total of 8 % received more than 50 minutes per day and 7 % did not engage in any skin-to-skin care. Families engaged in skin-to-skin care less than two instances per week, but obviously there was a wide range.
And instances of skin-to-skin care lasted a mean of 70 minutes with a range, again, a wide range, 30 to 123 minutes per session. We know this from the literature that infants from higher SES families experienced more minutes of skin-to-skin care per day. That's usually because those families are able to be at bedside more. And visitation frequency was obviously positively associated with skin-to-skin care rate. Families who visited more frequently tended to perform skin-to-skin care.
The Incubator (41:08.058)
more often and for more minutes per day. Regarding the follow-up, they had a total of 92 % at six months and 82 % at 12 months had the developmental scores. The average adjusted age at the initial follow-up visit was five and a half months and 13.3 months at the second visit. So developmental quotients varied substantially across infants. That's not surprising. At six months,
3 % of infants had scores suggesting developmental delay, and at 12 months, 6 % of infants fell into this range. Now, what did skin-to-skin care do for these babies? Skin-to-skin care was associated with six-month scores, such that infants who experienced more minutes of skin-to-skin care during their hospital stay tended to have a higher score at six months of age. Skin-to-skin care was related to 12-month scores, such that infants who experienced more minutes of skin-to-skin care
also had higher neurodevelopmental scores at 12 months of age. So they did a number of models, but this model two demonstrates that skin to skin rate uniquely predicted 12 month neurodevelopmental scores even after quote unquote, accounting for gestational age, the SES, so public or private insurance, health acuity, and family visitation.
such that skin-to-skin rate accounted for approximately 6 % of unique variants. And thusly, a 1 % increase in skin-to-skin care was associated with a 0.09 increase in the 12-month scores. So basically they're saying a 20-minute increase in the amount of average daily skin-to-skin care was associated with a 10-point increase in scores on 12-month neurodevelopmental assessments.
That's more than a two thirds of a standard deviation increase. And they graphed for us, they did a beautiful scatter plot of this. It's impressive. A beautiful scatter plot of skin to skin and the neurodevelopmental scores. It's like a perfect positive correlation.
Ben Courchia MD (43:11.133)
All right, it's a pretty impressive one,
Ben Courchia MD (43:25.654)
It reminds me of like, you know, when you're in college and you have to do the trend line for your chemistry lab. And yeah, and it's like, and you're supposed to get this line, but you don't really get it. It's like a perfect positive slope trend line. It's like, man, if everybody, yeah.
The Incubator (43:31.694)
Yeah, you had to answer the test, know, which one.
The Incubator (43:45.064)
That's right. So I thought this was impressive. I mean, you know that I love this paper. I firmly believe there's a dose response to kangaroo care. tell parents we treat kangaroo care as a medication. We try to give it to the baby every day. Now, obviously there are some things about the paper we should just talk about. I mean, in general, even in a unit who's going great with developmental stuff.
When nurses get busy, mean, are they going to chart the vital signs? Are they going to chart developmental care? So we know that we're not perfect at charting developmental care like skin to skin. Maybe this team was perfect. That's possible. Obviously we cannot, even though it was quote unquote accounted for it, they really only had one marker of SES status, you know, not other markers of parental education, job types, things like that, that we can't discount, right?
Ben Courchia MD (44:41.954)
Yeah, they were using a lot of proxies. They were using proxies. Yeah, it's an interesting trade-off, always.
The Incubator (44:44.072)
those, that's right.
The Incubator (44:51.75)
That's right. So I think the lessons are we got to get parents to the bedside how we can when we can and we have to make them comfortable with skin to skin and we have to get our staffs more comfortable with skin to skin. But that's not new. Do you want me to do my next holding paper or do you want to do your paper? Okay. So this is about holding during therapeutic hypothermia.
Ben Courchia MD (45:05.878)
Yeah.
Ben Courchia MD (45:11.744)
No, please. Please, yeah.
The Incubator (45:18.96)
So cooling and physiology during parent cuddling infants with neonatal encephalopathy and usual care. This is Cool Cuddle 2 study on behalf of the Cool Cuddle 2 research team coming from the UK. Lead author Ella Chakkarapani and senior author David Odd. You know, I congratulate myself, but I'm not sure that I do it right.
Ben Courchia MD (45:35.714)
Good job.
Ben Courchia MD (45:40.576)
Yeah, we may be completely wrong, but still, A for effort.
The Incubator (45:43.842)
But we're trying. This is an act of pediatrica. So Cool Cuddle 1 was basically looking at safety for parents holding up to two hours during therapeutic hypothermia. They looked at adverse events. There were no adverse events. They defined dislodgement of the endotracheal tube, vascular catheters, urinary catheters, or the EEG electrodes resulting in a needle stick injury.
Additionally, in that first study, there were no clinically significant effects on the rectal temperature and cardiorespiratory parameters, though there were some mild increases in the babies who were held in the rectal temperature. They didn't feel like they were clinically significant. There were also increases in the bandwidth of the amplitude EEG, so that's very interesting. We'll talk about that in this study.
Ben Courchia MD (46:27.074)
Mm-hmm.
The Incubator (46:33.584)
and decrease in oxygen saturation during the cuddle, as well as an increase in the end-tidal CO2s and mean arterial blood pressure after the cuddle compared with the pre-cuddle epoch. So this was basically a vital sign cohort study nestled within the Cool Cuddle implementation study. But they rolled it out into six level three NICUs across England. I believe Cool Cuddle was in three NICUs. So this is between September, 2022.
and August, 2023. So parents and their infants who are born over 35 weeks gestation undergoing therapeutic hypothermia are eligible for the study. The exclusion criteria, unable to complete the consent form, some postnatal depression, lack of proficiency in English, parents under the age of 16, babies...
receiving quote unquote, considerable levels of intensive care, including high frequency oscillation or receiving mean area pressure greater than 15 or receiving oxygen greater than 70%, having a chest tube or receiving three or more inotropes or in status epilepticus were excluded. I thought that's pretty, that was a reasonable exclusion criteria just like in our last paper. And so basically,
They looked at a variety of time points, the core and the surface temperature, cardiorespiratory and neurophysiologic data before the cuddle, for every 30 minutes during the cuddle, and then again, kind of post-cuddle period. So, cardiorespiratory data looked at heart rate, mean BP, ventilatory parameters, peripheral oxygen saturation and blood gases. They looked at analgesic and inotropic support. They looked at pain scores using the NPAS. And then again,
I told you about the adverse events that they looked for. They were the same in this study as well. So they screened 70 families. They had 33 families and infants excluded. These were the excluded babies. Birth injuries to the back or shoulder, seizures, too unwell, inhaled nitric oxide, chest strain, high levels of oxygen, inotropic support, preterm infant,
The Incubator (48:45.192)
Passed the cooling time, parent did not speak English, parent unwell, declined consent, or staff unavailable. So they recruited 37 families. One infant did die after recruitment. And in total then, they enrolled 36 infants. So the mean gestation age was about 38.5 weeks of gestation. The mean cord pH was 7.01 with a base deficit of minus 11, but lactates of 11.
25 % of infants had only a mild grade of encephalopathy, 12 and a half had a severe grade of encephalopathy. Notably, again, they used amplitude EEG. Well, you know, it might be not amplitude, I think EEG findings. Regardless, 65 % were noted to have a moderately abnormal EEG before therapeutic hypothermia. So this was, think, a representative.
cohort. The rest of the EEG data, 21 % were normal, 14 % severely abnormal. So 36 infants underwent 60 cool cuddles, so holding opportunities, with a mean duration of 1.5 hours per infant and a cumulative duration of 93 hours of cuddling. Most cool cuddles occurred on the second or third calendar day of life. And of the 36 infants, 40 % received invasive ventilation.
During 37 of the Cool Cuddles, morphine was infused, dobutamine was used during two Cool Cuddles, and dopamine was used in one. So these were babies who were reasonably sick. The primary outcome of physiologic stability was not impacted during Cool Cuddle. The components of the primary outcome were not affected either. There was little evidence that any of the respiratory parameters varied over the three
Ben Courchia MD (50:30.411)
Yeah.
The Incubator (50:42.792)
time periods. So there was a small change in PO2. So it actually increased during the cuddle and went a little bit lower than baseline after the cuddle. Okay. There was little to suggest individual differences during or after. That's what I was telling you before. Okay. Then we looked at some of the other physiologic parameters.
So there were a small change in blood pressure. So from a mean BP of 53 down to 50, back to 51.6 post-cuddle. Okay. That's not so bad. And so really no major differences at the physiologic parameters, the respiratory parameters, and importantly, different from cool cuddle.
one study, there was no significant differences in the peripheral temperatures or the rectal temperatures. I think that's what people are most afraid of when we talk about holding during therapeutic hypothermia. That's right. Now, interestingly, there were differences in sleep-wake cycling. So I'll tell you, before the baseline, 51.9 % had sleep-wake cycling on the EEG. During cuddling, that increased to 61.5%. So a 10 % increase in babies who had sleep-wake cycling.
Ben Courchia MD (51:46.912)
Yeah, you're going to rewarm the kit basically.
The Incubator (52:08.124)
and then it returned to baseline after the cuddle. They also had, they're not statistically significant pain scores, but there was a trend. Pain scores decreased during the cuddle and went back to baseline post cuddle. So the other thing I wanted to mention, they did not observe any of the pre-specified adverse effects events that we talked about at the very beginning. So I think that this is reassuring data.
that we can give parents at least a little opportunity to hold their babies.
Ben Courchia MD (52:43.03)
Yeah, you're gonna have to convince the staff, think. That's gonna be the problem.
The Incubator (52:47.474)
Well, isn't that always true with everything we change, right? Baby steps, as they say.
Ben Courchia MD (52:49.376)
Hahaha
Ben Courchia MD (52:53.57)
I want to be there the day you start, Daphna, okay? When you tell... Because usually, especially, I don't know, in a lot of units, the HIE kids are usually unfortunately quite sick, so they tend to go into the senior experience nurse. So I want you to... I want to be there to see the reaction when you say, let's...
The Incubator (53:05.84)
Absolutely.
I know, and I know who you're thinking of, but I'm... There are a handful of wise, wise nurses. Anyways, I'm excited. I can't wait to show them this article.
Ben Courchia MD (53:18.337)
Yeah.
Ben Courchia MD (53:25.548)
You just have to mention, I think to me the biggest sell here is the name Cool Cuddle. So good.
The Incubator (53:32.038)
Yeah, and that's what they call each event. A cool cuddle.
Ben Courchia MD (53:36.52)
A cool cutoff. That's so good. That's so good. All right. Do you have any more papers for us today? Yeah, I have one more. Go ahead. Now you go. I'll wrap up.
The Incubator (53:42.792)
I have one more. Do you have more?
You go. You go. you want to close out the show. Okay. Mine's actually a quick one. This is actually a research letter coming from Ohio State University. These are two PhDs from the School of Public Health. This was in JAMA-PEDS. It is Health and the 2024 US election. So this did come out before the election. We were not able to review it before the election. And it was the national trends in infant mortality in the US after DOBS.
Ben Courchia MD (53:52.417)
Yeah.
The Incubator (54:16.264)
So in June of this year, a paper was published in JAMA looking at the Texas ban. And so between 2021 and 2022, infant deaths in Texas increased from 1,985 to 2,240. So 255 additional deaths. This corresponds to a 12.9 % increase in a number. So you have this information that was otherwise pretty stable for a number of years.
Whereas the rest of the US experienced a comparatively lower 1.8 increase. Texas was the first, Texas was the first state to, that's true. Okay. So, okay. So basically it,
Ben Courchia MD (54:50.572)
So can get.
Ben Courchia MD (54:54.476)
We have a lot of people listening from abroad. And so what do you mean by dubs? What is dubs?
The Incubator (55:04.434)
changed the abortion criteria. And a number of states had already been changing their abortion laws, many of which are quite restrictive, including in our own state, Texas and Florida have some of the most restrictive abortion bans down to six weeks in the country. But this, this, Dobbs was more of a federal change. So this study that I just told you about,
was talking about like the Texas ban. But so now they wanted to look at the whole country.
Ben Courchia MD (55:39.914)
So daubs basically represents this point in time where the national authorization for abortion went back to the states. And now each state was given the permission to establish new guidelines for their own state, whatever, after voting and so on. So that's what daubs represents, this transition. OK. OK. Yeah.
The Incubator (55:43.218)
That's right.
The Incubator (56:03.954)
That's right. And that happened in June of 2022. So I just want to finish what they found in the Texas data because that's basically what they study mirrored. So like I said, 12.9 increase in Texas neonatal deaths compared to a overall US increase during that time period, 1.8 % increase. So there's increases all across the country, but significantly more in Texas. And they looked at congenital anomalies increased
a 22.9 % increase, but they did not increase in the US. So, sorry, deaths attributable to congenital anomalies increase. So, this current research that the research letter is describing is looking at national monthly data on total live births and infant deaths from the US Centers for Disease Control and Prevention's wide ranging online data.
for epidemiologic research, it's called CDC Wunder Database. So it's looking at 72 months from 2018 to 2023. And basically they're looking at this two time periods where June 2022 is the exposure. So from 2018 to 2023, the national overall monthly infant mortality averaged 5.6 deaths per 1,000 live births.
and mortality with congenital anomalies, 1.3 deaths per 1,000 live births. So that includes the whole time period. But basically time series analysis shows that approximately 0.38 additional infant deaths per 1,000 live births overall and 0.13 deaths with congenital anomalies per 1,000 live births in the months after DOPS. So both increased.
after June, 2022. This corresponds with a 7 % absolute increase in infant mortality, approximately 247 excess deaths, and 10 % increase in infant mortality with congenital anomalies, 204 excess deaths in the months after DOBS. There's no post DOBS month, so no month after June, 2022, that showed lower than the expected infant mortality.
The Incubator (58:25.85)
So, I mean, the article was just highlighting what the effects are in the neonatal community after these decisions. It was on the ballot in a lot of states, some of which reversed some restrictive bans, some of which did not. But it is a reminder that voting affects what happens in the NICU and that we should be engaged in the
advocacy, you know, and policy in our local states and that there's a more than ever need for palliative care in the NICU, I think.
The Incubator (59:14.246)
You're muted. I was giving you a moment, but.
Ben Courchia MD (59:17.004)
That's good, because I was coughing.
Ben Courchia MD (59:21.691)
Yeah, no, very, very interesting and still very much a dynamic process, I guess, for us. It's quite a... Yeah. I want to conclude with a light paper that I saw in pediatric research. First author is Kolojen Mitev, and the paper is called The Who, When, and Why of Pacifier Use. I was supposed to read something on BPD and then this sort of...
The Incubator (59:29.266)
Hopefully.
Ben Courchia MD (59:49.836)
felt like.
The Incubator (59:50.62)
You wanted to give us something refreshing after the Dobbs letter. I think this is a very interesting paper actually.
Ben Courchia MD (59:53.408)
I wanted to read this before.
Ben Courchia MD (59:57.738)
Yeah, I wanted to talk about this because I think have more conversations about whether we should use a pacifier in the NICU rather than how much oxygen we're using, target stats, the parents, something that they care about deeply. So interestingly enough, I love when they give us bits of history. said that pacifiers have accompanied humidity for more than 3,000 years, evidenced by excavations in Italy, Cyprus, and Greece. I never knew that we've been using pacifiers for this long.
The authors are mentioning that widespread popularity of pacifiers is reflected in empirical evidence documenting the benefits of non-nutritive sucking, including pain management and neonates, shorter duration of hospital stays, and greater readiness for bottle feeding in preterm infants. Now, despite these benefits, pacifier use remains a controversial parental practice. So while pacifier use is recommended for the prevention of SIDS, it's also been linked with acute otitis media and other infections, dental malocclusion, and excessive weight gain.
So what these authors wanted to do was just examine the demographic profile of pacifier users versus the ones who are called non-users. And among these groups, they compared the frequency and circumstances of pacifier use and the relationship between the use of pacifiers and parenting stress, as well as infant temperament. So the way they did this is that it was a cross-sectional questionnaire that they sent to 428 mothers that all had infants between 0 and 36 months of age.
The study questionnaire assessed infant and parent characteristic, as well as different aspects of pacifier use and parenting practices. So some of the highlights of the survey. There's definitely more details in the paper, so I'm just giving you a highlight version. So they were asked if they use pacifiers. Obviously, that was the yes, no beginning. Do you know how they call pacifiers in England? I never... They said they're commonly referred to as dummy. Yeah.
The Incubator (01:01:45.032)
I know, but...
Dummies, dummies, yeah.
Ben Courchia MD (01:01:50.946)
That is so bizarre. Participants who reported not using a pacifier were asked if they introduced it, but their baby refused to use it. Participants who reported using a pacifier were then presented with additional questions. One of them examined the frequency of pacifier use. It had six components.
Then participants also answered five questions about the person who influenced their decision to use the pacifier, specifically if they were asked by a family member or who this person was, or whether it was a friend or a physician that made the recommendation. Participants were also reading the extent to which the person who influenced their decision to use the pacifier and answered basically on a scale of one to five. They also looked at the anxiety and self-efficacy of
of using a pacifier. They measured the parenting stress using the parenting stress index. Infant temperament defined by the child's reactivity and self-regulation shaped by heredity and experience was measured using the infant behavior questionnaire. An all-participant completed a six-item measure of their attitudes toward pacifier. These items concerned positive attitude, reducing baby stress, and three concerned negative attitudes.
negative feeling towards the use of pacifiers and all this on a like-good scale. So let's see the results. Very interesting things. Pacifier users tended to be less educated than non-users. So mothers who had a high school diploma or lower educational degree were more likely to use pacifiers compared to mothers with a bachelor's degree or post-graduate training. I'm not exactly sure what to make of that, but that's an interesting finding.
Now within the pacifier user group, 33 % reported using the pacifier more than three times a day, 25%, two to three times a day, and daily user accounted for about 15%. Only 22 % used it less than once a week. I don't know who uses the pacifier less than once a week. That's exactly it.
The Incubator (01:04:04.976)
Yeah, I think you're all in or not at all, right? Yeah. If your baby likes that pacifier, you're really stuck with it.
Ben Courchia MD (01:04:11.798)
Yeah. When asked about the context in which they typically use a pacifier, most mothers report using a pacifier at bedtime or to comfort their crying baby. Nothing surprising there. And then they were saying that pacifiers were used less frequently in social contexts involving friends, families, and other children. It's true that when you have kids around, you don't just let them scream and have fun. Interestingly enough, the pacifier was rarely something that was recommended by physicians. When the participants were asked whether anyone had suggested
they give their baby a pacifier, 28 % said that it was a family member. 16 % indicated it was a friend. And only 10 % said that they received advice from a physician. They say, however, that the recommendations did not strongly influence mother's decision to use a pacifier. And most mothers reported 62 % said they did not even receive a recommendation. A few more interesting data points before we get to the conclusion.
Pacifier users reported less parenting stress. the people who use pacifiers reported significantly lower parental distress compared to non-user, significantly also less dysfunction and interactions than the non-users. And the parents who were using a pacifier perceived their child as less difficult. And these differences remained significant and marginally significant after controlling for dichotomized parental education. Pacifier users
reported less negative effect in their child. So the infant behavior questionnaire negative-effectivity scale measured via maternal report showed that pacifier users reported less negative effect compared to the non-users. This difference remains significant after controlling for parental education as well. There were no differences between the users, the non-users, and positive-effectivity or regulation capacity.
One statistic that I thought was very interesting was the following one that experience with pacifiers shapes more positive attitudes towards pacifiers. So to better understand the mother's attitude toward the pacifier, they examined the perception and beliefs of pacifiers versus the ones who just tried and the ones who never use them. And so they said that when it comes to endorsement of this, the following item, when they were asking them, basically that pass, when they were making the statement that pacifiers reduce a baby's distress,
Ben Courchia MD (01:06:33.726)
significantly while the groups differed where the people who used pacifiers endorsed this idea that it reduces a baby's distress much more frequently than the people who just tried. both groups actually did more so than the ones who never had used a pacifier. When it comes to the item of pacifier decreases parental satisfaction with the time they spend with their babies, the people who were using pacifier disagreed.
more frequently than the people who either tried or never used pacifiers. When they talked about having negative feelings towards pacifier, again, the people who use pacifier disagreed. They thought that they didn't have negative feelings compared to the people who tried or the people who never use them. Another item was the pacifier prevents me from understanding my baby's emotion significantly. Pacifier users disagreed more than the people who tried and the never users as well.
And so overall, think these analysis show that mothers who use, try using the pacifier had more positive beliefs and attitudes toward the pacifier than we may have suspected. So the conclusion of the paper are that previous research tended to explore the controversial aspect of pacifier use, but there's very little acknowledgement of the potential benefits of pacifier use. And here,
They show the long history of pacifiers in humans might be related to an immediate benefit to the mother and to the infant. And they found that mothers who use pacifiers report less negative effect, less negative A-effect with an A in their infant, less stress as a parent, more positive interaction with their infant compared to those who don't use pacifiers. And these important aspects to the mother-infant relationship have long-term consequences for the healthy development of the child.
So it is important for health professionals to be aware of these potential benefits and consider them when discussing pacifier use with parents. And that's really why I think this paper is important because I never really felt armed with the tools to have a concrete conversations about pacifier with parents in the NICU. And I feel like this is a super interesting data set looking at potential benefits of continuing to use a pacifier.
The Incubator (01:08:31.73)
Yeah.
The Incubator (01:08:47.528)
Yeah, I think there's some confounding factors about education. I think there's this concern about nipple confusion. So I think potentially more people who are potentially more well-educated trying to exclusively breastfeed are avoiding pacifiers. Full disclosure, we use the pacifier by 36 hours of life. And I don't think there's nipple confusion with pacifiers.
personally, in my opinion. So that may be part of what we're seeing here, but I think it's really impressive. You are?
Ben Courchia MD (01:09:23.33)
I'm very anti-pacifier. No, I'm kidding, we have tons of them at home.
The Incubator (01:09:30.598)
like three in each hand, you know? That's right. But she was a chill baby. She was a chill baby. So, I mean, that's really interesting. I think the findings about temperament and things like that are very interesting. When parents are like at their wits end, they're totally exhausted and they feel like if their baby takes a pacifier, they do better, then that's great. Pacifiers
Ben Courchia MD (01:09:32.448)
with one in the mouth.
Ben Courchia MD (01:09:47.404)
Yeah. Yeah.
Ben Courchia MD (01:09:57.132)
for
The Incubator (01:09:58.236)
have also been associated with a decrease in SIDS. So we can't forget that also. All right. Very cool.
Ben Courchia MD (01:10:01.558)
Yeah, we mentioned that. Yep. Yep.
All right, well, was a dense journal club. Thank you for the people who stayed till the end. And we will see you this week for more incubator content and more interviews. Thank you, everybody. Have a good rest of your day.