#431 - [Journal Club] - 📌 Prophylactic hydrocortisone to improve BPD-free survival?

In this Daily Journal Club episode, Ben and Daphna review a massive Swedish national cohort study from JAMA Network Open examining early prophylactic hydrocortisone in extremely preterm infants. They discuss the targeted regimens used, differences in gestational age outcomes, and whether a blanket prophylactic approach is truly effective for preventing BPD. With impressive data covering 98% of all NICU admissions in Sweden, the hosts debate the nuances of targeting 24 to 25-weekers versus older preemies and the potential confounding impact of chorioamnionitis. Tune in for your daily snack of evidence-based medicine and insights into optimizing NICU steroid protocols!

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Early Prophylactic Hydrocortisone and Bronchopulmonary Dysplasia-Free Survival in Extremely Preterm Infants. Smedbäck V, Björklund LJ, Flisberg A, Wróblewska J, Baud O, Wejryd E, Ådén U.JAMA Netw Open. 2026 Feb 2;9(2):e2560146. doi:10.1001/jamanetworkopen.2025.60146.

Transcript

Ben Courchia MD (00:00.504)

Hello everybody, welcome back to the incubator podcast. We're back this Monday for another round of Journal Club. Daphna, good morning, how are you?

Daphna Yasova Barbeau MD (00:08.865)

Good morning. I love Daily Journal Club.

Ben Courchia MD (00:12.566)

Yeah. It's funny you say that because we're recording them in a bunch. I'm going to put on my Neo News hat and say that we're recording this one after another. So this is very disingenuous.

Daphna Yasova Barbeau MD (00:26.807)

I was thinking this as I was driving home and I relistened to our journal clubs. I like to remind myself what we talked about and whether I was paying close enough attention when you were reviewing your paper. I think it's the perfect thing for a daily snack of evidence-based medicine. I hope people will give us some feedback on that.

Ben Courchia MD (00:43.49)

I'm happy to hear that. We're really trying. The evolution of Journal Club has been very much driven by feedback from the community. We initially published a single long episode, then broke it up into Journal Club shorts because people wanted the shorts. Now we're spreading the shorts over the course of the week. They're easier to consume and not all bunched up. So we listen.

Daphna Yasova Barbeau MD (01:17.547)

Yes, if you have a colleague who said that business was too long, tell them we are just doing one article a day now. All right, what do you have?

Ben Courchia MD (01:22.638)

That's right. I have steroids and BPD. I know we spoke about BPD last week. This is an article that I found in JAMA, specifically JAMA Network Open, called Early Prophylactic Hydrocortisone and Bronchopulmonary Dysplasia-Free Survival in Extremely Preterm Infants. The saga continues.

Daphna Yasova Barbeau MD (01:30.463)

Okay. Yeah. Another saga of neonatal care.

Ben Courchia MD (01:50.422)

Let's talk a little bit about this paper because it's trying to do some things and answer some questions that have not been answered yet. There are numerous studies indicating that corticosteroid replacement therapy may offer significant benefits for extremely preterm infants. These benefits include hemodynamic stability, promoting lung development, and reducing inflammation. Historically, dexamethasone is what has been used specifically for babies at risk of BPD. However, early intervention with dexamethasone is known to be associated with an increased risk of short and long-term adverse effects, specifically related to brain development. Because of the risks associated with dexamethasone, researchers have been looking at alternatives, and hydrocortisone is the steroid of choice for babies in these first two weeks of life. We know that hydrocortisone has a positive effect on lung development, has a positive effect on mortality, and effects on neurodevelopment are, according to the authors, not causational. Despite these promising trial results, population-based clinical data are severely lacking to fully assess the effectiveness in the real world, and the effect of prophylactic hydrocortisone in extremely preterm infants in everyday clinical practice has previously only been reported in three smaller single-center studies. It feels like we talk about hydrocortisone a lot, but you really have to go back and see who we're talking about. Because whether we're starting hydrocortisone right after birth, waiting for the babies to be seven days old, or giving it to babies on ventilators, the inclusion criteria really matter for these types of studies. For example, in this particular paper, the study by Kristi Watterberg is not mentioned because that's hydrocortisone given to ventilated babies at seven days of life. So just be familiar with the different types of studies. We know that there have been associations reported with hydrocortisone and its use in preterm infants, including bowel perforation, late-onset sepsis, and so on. These may be related to treatment interactions or clinical practices, specifically regarding bowel perforation and the association with indomethacin.

Ben Courchia MD (04:07.43)

The rationale for this study is aiming to analyze the association between the use of early prophylactic hydrocortisone in Sweden and changes in survival without BPD in preterm infants. The authors hypothesized that the introduction of prophylactic hydrocortisone would be followed by an increase in survival free of BPD. This was a historical cohort study utilizing prospectively collected data; eligible infants were babies born before 28 weeks of gestation who were admitted to the NICU on their first day of life. They had to be admitted to a hospital where prophylactic hydrocortisone had been implemented into practice. They did not apply any specific exclusion criteria, looking at data from 2018 to 2023 and extracting data from the Swedish Neonatal Quality Register, which impressively covers 98% of all infants admitted to NICUs in Sweden. How insane is that on a country level? I know. Across all analyses, the infants were divided into an exposed and a non-exposed group based on an intention-to-treat principle. The primary exposure investigated was prophylactic hydrocortisone administered IV. The protocol included a dose of 0.5 milligrams per kilo given every 12 hours from day one to day seven of life, followed by 0.5 milligrams per kilo once daily for days eight...

Daphna Yasova Barbeau MD (05:05.064)

If only.

Ben Courchia MD (05:33.986)

...to 10, resulting in a total dose of 8.5 milligrams per kilo given over the course of 10 days. If IV access was unavailable, which usually happened when the baby was taking more enteral feeds, they switched the patient to oral administration. So IV or oral was used depending on what the patient could tolerate. This treatment was adopted across several centers in Sweden, but protocols did vary. In three out of the four implemented centers, the treatment was given to all admitted infants before 28 weeks of gestation. However, in one center, referred to as the northern center in the paper, the protocol was a bit more targeted. They gave the treatment to all infants born before 26 weeks. But for those who were between 26 and 28 weeks, it was only given if the mother was suspected to have had chorioamnionitis. In terms of the rollout, it varied slightly between the different years. Two centers in Sweden chose not to adopt the treatment protocol at all. In terms of the outcomes assessed, the primary outcome of the study was survival without BPD at 36 weeks. BPD was formally defined as the need for supplemental oxygen at 36 weeks. The team also tracked chorioamnionitis, defining it by maternal fever with clinical or microbiological signs of infection or histopathological placental inflammation. Secondary outcomes included the infant's age at their last day on mechanical ventilation and their age at their last day on any respiratory support. They also looked at the need for pharmacological or surgical treatment of the PDA, the use of systemic steroids, and safety outcomes including comprehensive lists of perforations, NEC, infections, pulmonary hemorrhage, insulin treatment, IVH, et cetera. In terms of results, 1,140 infants were born in the centers where prophylactic hydrocortisone was implemented. Of these, 1,106 infants were included in the final analysis. When looking at baseline demographics based on the intention-to-treat grouping, the gestational age was significantly lower in the group exposed to steroids. The median gestational age for the exposed infants was 25 weeks and four days, whereas the median gestational age...

Ben Courchia MD (07:47.662)

...for the control group was 26 weeks and one day. The overall cohort's median gestational age was 25 weeks and six days with a median birth weight of 780 grams. No other baseline characteristics differed significantly between the groups. Breaking down the gestational age distribution for the infants born between 22 and 23 weeks, there were 92 infants in the exposed group. That represents 19.4% of that cohort and 15% of the non-exposed cohort. For the 24 to 25-week group, this was 38% of the exposed group versus 33.7% of the non-exposed, and looking at 26 to 27 weeks, we're talking about 42% and 50%. Let's talk about the primary outcomes: 32.5% of infants in the exposed group survived without BPD. In the non-exposed group, the survival rate without BPD was 29.3%. The unadjusted odds ratio was 1.16. The adjusted odds ratio was 1.62. Covariates associated with the primary outcome included gestational age, birth weight Z-score, sex, multiple births, prenatal steroids, 10-minute Apgar, intubation at birth, the center of birth, and surfactant treatment. They ran a sensitivity analysis using a one-to-one propensity score matching, which yielded an odds ratio of 1.4 for survival without BPD favoring the exposed group. When expanding the view to the larger national cohort including all six Swedish centers, the adjusted odds ratio remained significant at 1.58. The number needed to treat to achieve one additional infant surviving without BPD was 32 based on unadjusted rates and 15 using propensity score-matched data. When breaking the composite primary outcome into its components, the adjusted odds ratio for BPD alone was 0.65. Specifically, BPD was diagnosed in 49.2% of exposed infants and 54.6% in the non-exposed infants. Mortality before 36 weeks did not differ significantly between the groups. Death occurred in 18.

Ben Courchia MD (10:09.806)

...4% of babies exposed to hydrocortisone compared to 16.1% for the babies who were not exposed. When they stratified the outcomes by gestational age, the benefit was most pronounced in infants born between 24 and 25 weeks. If you look at the data, specifically Table Two, you can see that the difference in survival without BPD was quite striking for 24 to 25 weeks. For 22 to 23 weeks, it was 5.4% versus 4.1%. We're not going to mention that because there are very few babies in that group. But for 24 to 25 weeks, the difference was 24.4% in the exposed group versus 13.6% in the control group. Again, we're talking about survival without BPD. For 26 to 27 weeks, it didn't really make that much of a difference, 52% versus 47%. In terms of secondary outcomes, there were no significant differences between the exposed and the unexposed groups regarding the incidence of a PDA, either overall or when looking specifically at the need for medical or surgical treatment. However, the exposed group did have significantly fewer days on mechanical ventilation compared to the non-exposed group, showing a relative risk difference of 0.77. In terms of safety, the treatment was generally well tolerated. The researchers found no significant differences between the groups regarding the incidence of spontaneous perforation, necrotizing enterocolitis, insulin treatment, pulmonary hemorrhage, IVH, ROP, or cystic PVL. Late-onset bacterial infection did occur more frequently in the exposed group, 23.8% versus 17.7% in the non-exposed group. However, this difference was no longer statistically significant once they adjusted for covariates, dropping the adjusted odds ratio to 1.3.

Ben Courchia MD (12:04.938)

Even in the larger national cohort analysis where late-onset infection and insulin treatment initially appeared more common in the exposed group, neither safety outcome remained significant after adjustments. The authors conclude that this national cohort study provides evidence that the introduction of early prophylactic hydrocortisone to extremely preterm infants was associated with increased survival without BPD after adjustments, without any registered short-term adverse effects; long-term follow-up and further prospective studies are warranted to assess potential risks and benefits, particularly regarding neurodevelopmental outcomes and identification of high-risk groups. Daphna, what do you think?

Daphna Yasova Barbeau MD (12:38.89)

Well, it makes sense if we're going to tackle lung inflammation, we should tackle it early, right? We know that every day of mechanical ventilation worsens pulmonary inflammation. But it's hard with those little babies where you still don't know if they are early because they're infected. I feel like we're not separating the groups out enough. Like the reason for prematurity when we do studies like this.

Ben Courchia MD (13:11.566)

For sure. I think what you're seeing—I'm going to ignore the 22 to 23-week group—but you can see that the babies most at risk of BPD, the 24 to 25-weekers, show a better response to hydrocortisone than the babies who are a bit less at risk, the 26 to 27-week group. And the adjusted odds ratio, which allows you to reach that clinical significance for the primary outcome of survival without BPD, really is based on a lot of corrections, right? You adjust for sex, multiple births, birth weight with and without Z-scores, gestational age, Apgars at 10 minutes, intubation at birth, the center of birth, prenatal steroids, and surfactants. That's a lot of covariates to account for. Without looking at each variable individually, it shows me that there's this blanket...

Daphna Yasova Barbeau MD (13:44.63)

Mm-hmm.

Ben Courchia MD (14:07.342)

...option of giving hydrocortisone to everybody because it's prophylactic is not it. This paper shows you that there are certain patients that need it more than others, even though it was given to everybody. I still think you could choose a baby based on specific characteristics and get the most bang for your buck. I would not do it wholesale for everybody. But that's me.

Daphna Yasova Barbeau MD (14:29.354)

I think we've spent a lot of time focusing on this in a number of episodes. It's like a new thread. We've been focusing on gestational age groups, right? We know the 22-weekers aren't the same as the 24-weekers, and aren't the same as 26-weekers. But the babies delivered for preeclampsia are not the same as the babies delivered in preterm labor that is precipitous due to chorioamnionitis. I think whether or not we give them steroids may make a difference. Their risks for BPD are different. I wish we had more granularity of the data, always.

Ben Courchia MD (15:10.796)

Yep. We'll put that on our list for Santa Claus. All right, buddy. I'll see you tomorrow for another episode. Take care.

Daphna Yasova Barbeau MD (15:15.36)

All right, sounds good.