#399 - [Journal Club] - 📌 Early Vitamin D: Can 800 IU Prevent BPD in Preterms?

Ben and Daphna review a randomized controlled trial published in The Journal of Pediatrics by Dr. Ariel Salas and colleagues at UAB. The study investigates whether early high-dose vitamin D supplementation (800 IU/day starting day 1) in extremely preterm infants reduces the incidence of Bronchopulmonary Dysplasia (BPD) compared to standard care (starting day 14). The hosts discuss the physiologic rationale linking vitamin D to lung development, the use of impulse oscillometry to measure lung mechanics, and the secondary findings regarding metabolic bone disease. They explore why the "physiologic rationale" doesn't always translate to clinical significance.

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Early Vitamin D Supplementation in Infants Born Extremely Preterm and Fed Human Milk: A Randomized Controlled Trial. Salas AA, Argent T, Jeffcoat S, Tucker M, Ashraf AP, Travers CP.J Pediatr. 2025 Dec;287:114754. doi: 10.1016/j.jpeds.2025.114754. Epub 2025 Jul 24.PMID: 40714046 Clinical Trial.

Transcript

[00:00.622] Ben Courchia MD Hello everybody, welcome back to the Incubator Podcast. We are back today for an episode of Journal Club. I almost went with "The Incubator Neonatology Review"—you see I almost slipped there. We are...

[00:13.748] Daphna Yasova Barbeau MD That being said, good luck to everybody who's plugging away studying for the boards. You should be spending less time on this podcast and more time on the other podcast.

[00:18.562] Ben Courchia MD That's right, we are with you in spirit. That's true, that's true. I have a very nice article for you, Daphna. We've been talking a lot about vitamin D supplementation in our unit.

[00:29.984] Daphna Yasova Barbeau MD Okay. Mm-hmm, I saw that one.

[00:34.298] Ben Courchia MD So this is a paper by our good friend Ariel Salas. But we're not doing this paper because he's our good friend. We're doing this paper because it's an interesting question he's trying to answer.

[00:43.186] Daphna Yasova Barbeau MD It is coming up weekly in our unit.

[00:45.902] Ben Courchia MD The paper is published in The Journal of Pediatrics and it's called "Early Vitamin D Supplementation in Infants Born Extremely Preterm and Fed Human Milk: A Randomized Controlled Trial". So the background stuff is interesting. A lot of the things that Ariel mentions are things we're familiar with. Infants born extremely preterm, who are born at less than 28 weeks, face an abrupt loss of maternal vitamin D supply, which leaves nearly all of the 26,000 babies born at this particular gestational age group each year in the US at risk of vitamin D deficiency.

[00:45.902] Ben Courchia MD The current recommendations for vitamin D supplementation in these infants do vary. Some consensus guidelines do not recommend vitamin D doses greater than 400 International Units per day before the establishment of full enteral nutrition or before documenting biochemical abnormalities. The authors note that this may result in suboptimal supplementation during the first 14 days after birth, a critical window for both bone and lung development. Although vitamin D is primarily recognized for its role in skeletal health, there is emerging evidence suggesting that it also plays a crucial dose-dependent role in lung development. This is specifically true during the saccular and alveolar stages of lung growth, where vitamin D contributes to pneumocyte differentiation, regulates surfactant production, and influences alveolar formation. All these findings...

[02:21.577] Daphna Yasova Barbeau MD We forget about that. I mean, when you really think about it, vitamin D is so important.

[02:29.806] Ben Courchia MD This is the Dr. Seuss book that we should all have in the unit: All the Things You Forget. So all of these findings indicate that early vitamin D supplementation could mitigate adverse respiratory outcomes in preterm infants, including those born extremely preterm. So this trial aimed to determine whether an early enteral vitamin D supplementation dose could reduce the severity of BPD and improve lung mechanics at term equivalent age. They used something called impulse oscillometry as a bedside tool to quantify lung function. So we'll talk about that in a second.

[02:59.862] Ben Courchia MD So this was a parallel-group, masked, randomized controlled trial that included infants born extremely preterm between March 2023 and June 2024 at the University of Alabama at Birmingham Hospital. Infants with a gestational age of 28 weeks and six days or less were eligible for inclusion. Babies with major congenital anomalies, terminal illness, whatever, were excluded. Standard stuff. In terms of intervention... I mean, I feel like I read the exclusion criteria and I am getting tired, but I feel like I read the exclusion criteria and they're all the same. They're okay, they're all good, but I'm just saying, of course, the babies were very sick and all these things are excluded.

[04:07.788] Ben Courchia MD In terms of interventions, participants were randomly assigned to one of two groups in a one-to-one ratio. The intervention group received the usual human milk diet with an additional 800 units per day of vitamin D for the first 14 days after birth. And the control group went on the regular merry way of the UAB protocol, which is they usually get their human milk diet without any additional vitamin D for the first 14 days. These infants then received vitamin D only from standard sources amounting to the minimum recommended dose from fortification and so on and so forth, or from whatever was in the milk. The clinicians and the primary caregivers were masked, but the dietitians and feeding specialists were unmasked to the randomization. After postnatal day 14, vitamin D supplementation continued per routine practice at the University of Alabama with 400 International Units per day in both groups.

[04:07.788] Ben Courchia MD In terms of outcomes, the primary outcome was BPD, defined by the Jensen criteria—very happy to see the Jensen criteria being used—and death up to 36 weeks post-menstrual age to account for all study participants. The primary physiologic outcome was measured using the TremoFlo N-100 airway oscillometry device. So basically, it measures the elasticity of the lung tissue. It's a device, to be honest with you, I've never seen it before. And it looks like it measures how easy it is for you to inflate your lungs. So if inflation of the lung requires a lot of effort, it will detect that in a way. I'm speaking a little bit out of turn here because I'm not extremely familiar with this device. It measures basically resistance.

[04:07.788] Ben Courchia MD And the difference in resistance really is what they also measure. So they looked at two things. They looked at the mean area under the reactance curve, that's AX, which is a measure of the elasticity of the lung tissue where higher AX values indicate more stiffness of the lung. And then they used a difference in resistance, as I mentioned, the R7-19, which is a measure of the difference between the central and peripheral airway resistance, where a higher value indicates increased peripheral airway resistance. They had a slew of other secondary outcomes: grade of BPD, death, days of mechanical ventilation, length of stay, growth parameters, safety outcomes including NEC, SIP, late onset sepsis, metabolic bone disease, and other lab values.

[06:33.838] Ben Courchia MD Okay, so we're going to get into the results. 126 infants born extremely preterm were randomized, 63 allocated in each group. The mean birth weight was 759 grams. Baseline demographics were comparable between the two groups. The mean gestational age was 25 weeks in the intervention group, 26 weeks in the control. Infants born between 22 and 23 weeks were about 24% of the cohort in the intervention group and 14% in the control group. And then I think this is interesting as well: by postnatal day three, 47% of infants were found to have low vitamin D levels, and the mean vitamin D levels at day three was 35 ng/mL in the intervention group, 35 in the control group.

[07:12.686] Ben Courchia MD Okay. In terms of nutritional intake, the median time to full enteral feeds was 10 days in both groups. Human milk fortification was initiated postnatal day 15 in both groups. There were no differences between the groups in daily enteral fluid intake, caloric intake, protein intake, or maternal-to-donor milk ratios during the first 14 days. So you can see a lot of similarities between all the groups. In terms of the primary outcome, at 36 weeks post-menstrual age, the distribution of BPD severity did not differ between the two groups. Grade 1 BPD took place in 33% of the intervention group, 30% of the control. Grade 2, it was 18% in the intervention, 14% in the control. Grade 3, 6% in the intervention, 13% in the control group. Slight difference, but not statistically significant. And then death before 36 weeks post-menstrual age: 14% in the intervention group, 8% in the control group. Again, different, but not statistically significant.

[07:12.686] Ben Courchia MD In terms of some of these outcomes that I mentioned earlier, looking at the elasticity of the lung, they did not differ in terms of the AX measurements, the elasticity of the lung stiffness. And in terms of the resistance difference that we mentioned earlier, lower measurements were obtained in the intervention group compared to the control group, but again, that was not statistically significant.

[09:17.071] Ben Courchia MD Let's talk a little bit about secondary outcomes. Growth outcomes did not differ significantly between the two groups. In terms of other outcomes on postnatal day 28, the risk reduction of metabolic bone disease, which was defined as an alkaline phosphatase of 500 or more and a phosphorus level of less than 5.5, observed in the intervention group did not reach statistical significance. The difference was 9% versus 20%—quite a significant difference, but again, small numbers that you cannot really get to statistical significance. Regarding safety, none of the infants in the intervention group had calcium levels exceeding 12—like there was no hypercalcemia. No serious adverse events related to vitamin D supplementation. No significant difference in rates of late onset sepsis, SIP, or NEC. And then incidental fractures were observed in only 5% of the infants with no significant difference between the two groups.

[09:17.071] Ben Courchia MD And so what Ariel and his colleagues conclude is that administering 800 units of vitamin D with human milk in the first two weeks after birth does not reduce the risk of severe BPD or severe BPD/death at 36 weeks in babies who are born extremely preterm with a relatively low prevalence of vitamin D deficiency. It appears to be safe. It appears to be an effective method of achieving vitamin D sufficiency. Secondary analyses suggest that this approach may help prevent metabolic bone disease a little bit based on what we discussed. Again, with the caveat that it hasn't reached statistical significance and that further research is warranted.

[11:07.715] Ben Courchia MD So it doesn't really look like there's an urgency to rush to giving vitamin D earlier on. I think it's important for you all to know also that in their particular unit, they are reaching full enteral feeds by about day 10 of life. So they're a very quick and strong unit when it comes to reaching full feeds. So I think this is where we are. I don't know. We start vitamin D at two weeks of life. It seems like, I don't know... to me, I read this and I'm like, there's no need potentially to move that sooner. We also have a unit, thanks to our feeding guidelines, that is helping us get to full feeds quite early, which makes our rates of metabolic bone disease quite good. But yeah, curious to hear what you think about that.

[11:24.795] Daphna Yasova Barbeau MD Yeah, I mean, I think we're asking a lot of one vitamin to prevent BPD. I think it's a big ask. I think, for example, I know that BPD is a big hitter, but preventing metabolic bone disease would be enough, right? It's a very Jewish saying: Dayenu. It would have been enough just to prevent metabolic bone disease. I don't think we'd have to prevent BPD to say, "We really have to do this". It would have been super cool if we could do that.

[11:58.223] Ben Courchia MD Yeah. You know those t-shirts, those sort of self-help t-shirts that say "You are enough"? Maybe that's what we should give to the vitamin D bottle, be like, "You are enough, vitamin D. You just prevent bone disease and that's good enough."

[12:12.575] Daphna Yasova Barbeau MD Yeah, you heard it here. I was disappointed that wasn't the primary outcome, but I was disappointed that it wasn't statistically significant to lower metabolic bone disease, even though it increased the vitamin D concentration a lot—by like 30. That's a lot.

[12:31.459] Ben Courchia MD That's a lot. But think about it also. It's disappointing because you see the physiologic rationale and you're like, "Yeah, that makes sense. If I give this, then this other thing should not happen." And when it doesn't sort of follow through, you're like, "Why? Like, why not?". You read the background and you're like...

[12:53.117] Daphna Yasova Barbeau MD Yeah, why when we give it, does it not work?

[12:58.935] Ben Courchia MD No, if it makes sense, why is it not happening? So anyway.

[13:03.399] Daphna Yasova Barbeau MD I still wonder if there are, again, certain babies that definitely this will benefit. Maybe it's the growth restricted babies we talked about a few journal clubs ago. Maybe they didn't get as much, but now if we deplete it, it really helps them. I don't know. So I think that is an ask to the neonatal community to start phenotyping these babies so that way we can...

[13:29.077] Ben Courchia MD That's true. It doesn't make things worse.

[13:33.351] Daphna Yasova Barbeau MD And it's safe. I mean, I think that's the biggest question. And we know they're at risk for metabolic bone disease. Also, this is a unit who is very, like you said, aggressive with feeding, aggressive but successful. For sure.

[13:46.113] Ben Courchia MD Yeah. I want to be careful... they've reached a point where they're able to do this routinely and have tremendous outcomes.

[13:56.455] Daphna Yasova Barbeau MD Yeah. And so I wonder for some units, maybe it's not two weeks. Maybe two weeks is not your metric. Maybe your metric is, "Well, we put it on close to discharge." I don't know. So maybe... maybe we can move the needle for some babies, I guess. Good, good paper. All right, buddy.

[14:14.743] Ben Courchia MD Sure. All right buddy, thank you. I'll see you tomorrow.