#392 - [Journal Club] - 📌 Early Outcome Data After Resuscitation at 21 Weeks’ Gestation

In this Journal Club episode, Ben and Daphna review a salient study from JAMA Network Open examining outcomes of infants born at 21 weeks’ gestation at the University of Iowa. They walk through resuscitation practices, early physiologic challenges, survival trends, and short-term developmental outcomes, while placing the data in the broader context of shifting limits of viability. The discussion highlights both cautious optimism and the many unanswered questions that remain as neonatology continues to push the boundaries of what is possible.

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Outcomes of Infants Born at 21 Weeks' Gestational Age. Hyland RM, Mat HD, Boly TJ, Thomas BJ, Stanford AH, Harmon HM, Bermick JR, Davila RC, Colaizy TT, Dagle JM, Klein JM, Greiner AL, Bell EF, McNamara PJ; University of Iowa Neonatology Program.JAMA Netw Open. 2025 Dec 1;8(12):e2548211. doi:10.1001/jamanetworkopen.2025.48211.PMID: 41385227 Free PMC article.

Transcript

[00:00.856] The Incubator: Hey, everybody. Welcome back to another episode of Journal Club. We're releasing Journal Club shorts every day of the week.

[00:10.000] The Incubator: This week, this is our new 2026 sort of schedule. We hope you enjoy it. It is Tuesday this morning. And, Daphna, you're looking at which paper for us?

[00:19.867] Daphna: Yeah, I mean, you just presented yesterday this earth-shattering PDA (Patent Ductus Arteriosus) review paper. And there's another article at the end of 2025 that really got people talking. It's from JAMA Network Open (Journal of the American Medical Association Network Open), the pediatrics section. It's entitled "Outcomes of Infants Born at 21 Weeks Gestational Age." Lead author Rachel Hyland and the senior author Patrick McNamara.

[00:45.000] Daphna: Basically, the University of Iowa wanted to report on their experience with 21-weekers. And the question they were posing is: what are the outcomes of infants born alive at 21 weeks in a center that attempts resuscitation in selected cases?

[01:00.000] Daphna: So I guess for our colleagues outside of the US, even across the US, think—I mean, even since we trained—that line of where we offer resuscitation has certainly moved to kind of 22 weeks. The upper limit of where we move to full resuscitation for all babies, that's still a little vague and that is not the topic of today's conversation.

[01:34.626] The Incubator: Now I invite people to check out the discussion we've had on the podcast with Dr. Edward Bell from Iowa, because I mean, the highlight of my conversation with him was when I was asking him whether he was going to hit at one point a physiological wall for viability. His opinion was no.

[01:51.195] Daphna: Well, I think for every decade of neonatology, they thought that they had hit the physiologic wall. History is proving him right. But it seems impossible. And yet, here we are.

[02:05.881] Daphna: Well, think—yeah, on the Board Review podcast, we've reviewed the development of the fetal lung, right? And at some point you look at it and you're like, how can we sustain respiration with a lung that has literally no alveoli yet, right? No even saccules. But we're doing it. We're pushing the limit.

[02:25.000] Daphna: And so I think all of us have been faced—I mean, if you're a unit that's routinely resuscitating at 22 weeks, then you've been faced with this discussion about why not 21 and 5/7? And then when you do a 21 and 5/7, people say, why not 21 and 3/7?

[02:45.000] Daphna: And so Iowa obviously has been resuscitating small babies for some time. And they wanted to give us a report on what they were doing for the 21-weekers. Part of why they wrote this—and we've already kind of discussed it a little bit—is there's significant variability in survival at this gestational age.

[03:00.000] Daphna: Even in the kind of 22-week, 23-week group, however, reported survival as low as 0% and as high as 83% across international cohorts shows that there's variability in resuscitation and there's variability in outcomes.

[03:20.000] Daphna: And so, University of Iowa reported to the VON (Vermont Oxford Network) from 2014 to 2024 at 22 weeks gestational age. They have a 66% survival to discharge among those 22-weekers who are resuscitated. So that was kind of their benchmark moving into this discussion about 21-weekers.

[03:45.000] Daphna: And they are, of course, interested like the rest of us are: what does that mean for not just the short term—survival to discharge—but what are the long-term physical and intellectual morbidities?

[04:10.000] Daphna: They highlight in this paper that US cohorts born at 22 weeks and followed up in the 18 to 22 months period—which again is not that long—report a wide range: 39% to 55% with no or mild impairment and 18% to 33% with severe impairment. Again, those are babies at 22 weeks.

[04:23.734] Daphna: And so they wanted to look at all the infants born alive at a gestational age of 21 0/7 to 21 6/7 days between January 1st, 2010 and February 28th, 2025 at the University of Iowa. Those were the babies that were included. And just to be clear, live birth was defined as any evidence of activity or heart rate present.

[04:50.000] Daphna: Resuscitation was broadly defined as any attempt to revive or stimulate. This did not require the presence of a neonatologist or placement of an ETT (Endotracheal Tube). And NICU (Neonatal Intensive Care Unit) admission was defined as admission to the NICU for any time period.

[05:15.000] Daphna: They talk about their care briefly of the extremely preterm infants. They have some papers on that that you can also review. And basically what they're saying is that all of the care strategies that they give to the 22 and 23-weekers were extrapolated to those infants born at 21 weeks.

[05:35.000] Daphna: They talk a little bit about the antenatal counseling, which included shared decision-making between the obstetrics professionals, the neonatal staff, and the parents. They discuss the outcomes of this gestational age are basically unknown, that ability to resuscitate may be limited by the size of the patient and the equipment, and that there's basically unknown short- and long-term maternal/fetal risks.

[06:00.000] Daphna: Resuscitation was not offered at 21 weeks if there were significant congenital anomalies, and it wasn't recommended in multiplicity greater than twin gestation, though they do highlight that this has occurred historically. Now, if resuscitation was not desired by the family, if comfort care was elected by the family, this was fully supported and comfort-directed care without resuscitation was provided.

[06:20.000] Daphna: If there was no heart rate response with effective PPV (Positive Pressure Ventilation) through an endotracheal tube, further resuscitation like epinephrine and chest compressions was not recommended, but they say was individualized. And the decision to provide antenatal corticosteroids—another area of interest—was made by the obstetric team based on maternal and fetal considerations.

[06:37.714] Daphna: And so there was still decision making, one, in resuscitation and two, in the administration of antenatal corticosteroids.

[06:46.35] The Incubator: No, no, I mean, I was just trying to say like, it's really uncharted territory, basically.

[06:53.146] Daphna: For sure, yeah. And they didn't describe this, but I think they could write a whole other article on what did the counseling look like? I mean, in full disclosure, we were having these discussions in our unit with families admitted at this gestational age, but it's not been written about.

[07:15.000] Daphna: Saying to families like, "We really have no idea what's going to happen," I think is a different way to provide informed consent. So during their study period, they had 22 infants born alive at 21 weeks gestational age. During that time period, they had an additional 230 fetuses at 21 weeks classified as stillbirths. So they had 252 deliveries at the 21st week, but 22 infants of those were born alive.

[07:45.000] Daphna: 17 of the 22 liveborn infants, that's 77%, were offered resuscitation in this group. 47% were female and 53% were male. So we're down to 17 resuscitated infants in the 21st week. The median age—I think this is important—is 21 weeks and 5 days, though the range was from 21 0/7 to 21 6/7.

[08:15.000] Daphna: Now of these 17 infants, 6 or 35% were discharged home from the NICU. An additional one baby, so 6%, still remained hospitalized at the end of the study. And 10 or nearly 60% died. So what did that look like? The 10 deaths: 3 in the delivery room, 7 in the NICU.

[08:45.000] Daphna: Rates of resuscitation and NICU admission increased throughout the study period. That's not a surprise to anybody who's been following along. During the first 10 years, 2010 to 2019, 6 infants were liveborn; 3 or 50% underwent resuscitation, but none of the infants in that decade survived.

[09:15.000] Daphna: Now in the next five years, 2020 to 2025, 16 infants were liveborn, and 88% underwent resuscitation. They include demographics for the 17 resuscitated infants. The birth weights ranged from 250 to 450 grams. 41% of the 17 patients were SGA (Small for Gestational Age). Seven of the patients were part of a multiple gestation. Again, most of them were twins, but there was one set of DC/TA (Dichorionic Triamniotic) triplets.

[10:00.000] Daphna: Survivors were less likely to be part of a multiple gestation. Survivors were more likely to have received a complete course of antenatal steroids (3 of the survivors versus 0 non-survivors). However, similar numbers of survivors and non-survivors received no antenatal corticosteroids (2 out of survivors and 2 out of non-survivors).

[10:30.000] Daphna: One- and five-minute Apgar scores were low for all patients, with a median score of 1 at one minute and 3 at five minutes. Maternal characteristics and morbidity were similar between survivors and non-survivors, including frequent PPROM (Preterm Premature Rupture of Membranes) in 47% of the total cohort. All patients underwent inborn vaginal delivery, even though 41% were breech. 29% received limited DCC (Delayed Cord Clamping), meaning 15 to 30 seconds.

[11:15.000] Daphna: I thought this was also interesting—intubation attempts were performed by the most senior neonatology fellow or staff. Success at first attempt occurred only in 6 infants (35%). Multiple attempts were required in 65% and successful intubation took a median of two attempts, but up to four attempts, and was unsuccessful in one patient because the mouth did not accommodate the laryngoscope.

[11:45.000] Daphna: Time from birth to NICU admission was 20 minutes or less for all patients except one who did require extensive resuscitation in the delivery room. They did attempt umbilical access in all patients. UAC (Umbilical Arterial Catheter) access was achieved in 57% of patients, and UVC (Umbilical Venous Catheter) placement was achieved in 93%.

[12:15.000] Daphna: Surfactant was given to all patients after ETT position was confirmed on chest X-ray at a median of 1.4 postnatal hours. Their goal is within one hour; this only occurred in one patient. Again, I think that speaks to how complicated these babies can be.

[12:35.000] Daphna: On admission to the NICU, all the infants were connected to HFJV (High-Frequency Jet Ventilator) support. Their RSS (Respiratory Severity Score) varied widely during the first 72 hours from 1.3 to 11.4, with the scores being lower in infants who survived.

[12:55.000] Daphna: An initial high oxygen requirement was common. The mean FiO2 (Fraction of Inspired Oxygen) on admission was 92%. However, the mean FiO2 during the first 72 hours was 47%. Not surprisingly, early hemodynamic instability was common. They had frequent vasopressor use in 36%, inotrope use in 64%, and iNO (Inhaled Nitric Oxide) use in 64% during the first 72 hours.

[13:15.000] Daphna: That is interesting given the data that we have on the use of nitric oxide in ELBWs (Extremely Low Birth Weight infants). 12 of the infants in the NICU (86%) received one or more therapies as previously discussed. The highest VIS (Vasoactive-Inotropic Score) was 8 in survivors and 25 in non-survivors.

[14:00.000] Daphna: Non-survivors tended to have a lot more medication need than survivors. Interestingly, they were not using routine doses of nitric. The maximum iNO dose in survivors was 5 ppm (parts per million) compared with 20 ppm in non-survivors. And most of those non-surviving babies, it seems, died on maximal nitric support.

[14:30.000] Daphna: All surviving patients had bedside echo (echocardiogram) performed within the first 12 hours (86% in the first four hours), while only 43% of the non-survivor group had cardiac echo performed. Among these 10 patients who underwent echo, cardiovascular phenotypes included acute pulmonary hypertension in 90%, cardiac dysfunction in 40%, and a hsPDA (Hemodynamically Significant Patent Ductus Arteriosus) in 50%.

[15:15.000] Daphna: Many of the infants (90%) experienced multiple or transitioning phenotypes over this period. I think that’s why this whole discussion and why people like you are going to get additional TnECHO (Targeted Neonatal Echocardiography) training is crucial—even if you document one phenotype, the next few hours the baby might have a totally different cardiopulmonary phenotype.

[15:35.000] Daphna: They looked at early mean blood pressure measurements across the first 72 hours. There was wide individual patient ranges. Survivor SBP (Systolic Blood Pressure) variance was about 7.7 mmHg, and the diastolic BP variance was about 9.2, compared to non-survivors who had 24.5 variance in systolic and 16.6 in diastolic. Hypotension occurred at least transiently in 86% of infants.

[16:15.000] Daphna: All patients were treated with hydrocortisone for presumed adrenal insufficiency and/or relative hypotension. I'm not sure that is standard of care in all units.

[16:25.068] Daphna: The seven non-surviving patients admitted to the NICU died on postnatal days 0 to 6. In all cases, the cause of death was listed as extreme prematurity with complicating factors including respiratory failure in all infants, some pulmonary hemorrhage in two, and IVH (Intraventricular Hemorrhage) in four.

[16:45.000] Daphna: In four cases, care was redirected to comfort after finding IVH in the setting of significant clinical instability. Two additional patients were redirected after prolonged desaturations at three and four hours of age, even before head imaging. One patient died after cardiorespiratory failure with refractory hypoglycemia despite code resuscitation on postnatal day 3.

[17:00.000] Daphna: So what is the data for the survivors? All infants were extubated directly from high-frequency jet support to non-invasive NAVA (Neurally Adjusted Ventilatory Assist). Successful extubation occurred at a median age of 79.5 days (approximately 32 weeks PMA [Post-Menstrual Age]). Grade 3 BPD (Bronchopulmonary Dysplasia) occurred only in one patient; the remainder had Grade 2 BPD. No infants required tracheostomy.

[17:45.000] Daphna: There were no cases of NEC (Necrotizing Enterocolitis). All surviving patients were treated medically for hsPDA and 71% received interventional PDA closure—transcatheter closure in three patients and bedside surgical ligation in two.

[18:15.000] Daphna: 57% (four patients) were diagnosed with chronic pulmonary hypertension, two of whom were discharged home on enteral sildenafil. IVH occurred in 71% of survivors, but severe IVH (Grade 3) only occurred in two infants (30%). No neurosurgical interventions were needed. One patient had seizures managed with anti-seizure medications.

[19:00.000] Daphna: All discharged patients were followed up with serial developmental assessments, but they just weren't able to be followed that long yet. Only four were older than 6 months corrected age. One patient was older than two years and their assessment was "normal." The remaining three were delayed in their milestones but progressing; each scored borderline to high risk in the Bayley-4 (Bayley Scales of Infant and Toddler Development, Fourth Edition) screening test.

[19:45.000] Daphna: Two patients were diagnosed with spastic cerebral palsy, though neither used orthotics. Three of the six patients required rehospitalization for things like viral illness, inadequate weight gain, or placement of a G-tube (Gastrostomy tube).

[20:15.000] Daphna: The authors highlighted that resuscitation rates at Iowa for 21-weekers increased to 87% in the last five years, and in 2024, it was 100%. ACOG (American College of Obstetricians and Gynecologists) guidelines suggest consideration of steroids at 22 weeks, but nobody has made recommendations for 21 weeks because of lack of data.

[21:15.000] Daphna: They noted that even in a highly skilled unit, they struggled to intubate and place umbilical lines because the babies are so small. They used nitric oxide judiciously; in survivors, they only needed about 5 ppm and were able to wean off it in the first 24 hours, likely titrated using echoes to avoid opening the PDA further and causing pulmonary overflow.

[22:41.920] The Incubator: Yeah, I think it's very interesting. It shows that for units that have strong protocols, you can do quite well even with babies as low as 21 weeks. We have to be careful because we're talking about a very low number—17 resuscitated infants total. It’s a seed for potential future work.

[23:41.102] Daphna: It will be interesting to see how families look at this. We're here at the behest of their wishes. Since the line has been pushed to 22 weeks, we've resuscitated gestational ages we didn't in the past. It's happening; the question is, will it happen consistently?

[24:16.568] Daphna: There's an invited commentary by Dr. McElroy in JAMA Network Open entitled, "What Do We Do When Limits of Viability Shift?" He says we are between the obligation to push limits and the obligation to protect infants from harm. We should cautiously applaud Iowa, but we need considerably more data before adopting this as a new standard.

[25:16.462] The Incubator: Very interesting. All right, buddy. Thank you for that. I will see you tomorrow for another paper.