Laughon MM, Thomas SM, Watterberg KL, Kennedy KA, Keszler M, Ambalavanan N, et al. Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial. JAMA 2025. PMID 41364689

REVIEWED BY

Tim Hundscheid, MD PhD and Willem P. de Boode, MD PhD
Radboud university medical center, Amalia Children’s Hospital, Nijmegen, The Netherlands

CORRESPONING AUTHOR

Tim Hundscheid, MD PhD, Pediatrician-neonatologist
Radboud university medical center, Amalia Children’s Hospital, Department of Pediatrics, Division of Neonatology
Internal postal code 804, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
tim.hundscheid@radboudumc.nl Phone: +31 24 3614430

TYPE OF INVESTIGATION

Treatment

QUESTION

In preterm infants born at 22 to 28 weeks’ gestation with a protocol-defined symptomatic patent ductus arteriosus (sPDA) at a postnatal age of 48 hours to 21 days (P), does expectant management (I) compared with active pharmacological treatment with acetaminophen, ibuprofen, or indomethacin (C) reduces the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age (PMA) (O)?

METHODS

Design: multi-centre, randomized controlled superiority trial
Allocation: patients were randomly assigned (1:1) via Neonatal Research Network (NRN) data coordinating center at Research Triangle Institute International to expectant management or active treatment. Siblings from multiple births were randomized separately.
Blinding: unblinded studied since infants were randomized to management approach.
Follow-up period: primary outcome assessment at 36 weeks’ PMA. Secondary outcomes were recorded through 120 days’ postnatal age, unless hospital discharge or transfer occured earlier.
Setting: recruitment was from 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network within the United States of America.
Patients:
Inclusion criteria:
– Preterm infant (gestational age 22 weeks 0 days to 28 weeks 6 days’ gestation)
– At a postnatal age of 48 hours to 21 days
– With a protocol defined sPDA, based on the McNamara Scale, defined as
o Mild, moderate or severe clinical criteria with small or medium size PDA on echocardiogram
o Mild or moderate clinical criteria with large PDA on echocardiogram
Exclusion criteria:
– Cardiopulmonary compromise at time of randomization
– Known congenital heart defect, other than atrial or ventricular septal defect
– Known pulmonary malformation such as congenital lobar emphysema or congenital pulmonary adenomatous malformation
– Received prior treatment for symptomatic patent ductus arteriosus (prophylactic indomethacin was not an exclusion criterion according to the study protocol)
– Any condition which, in the opinion of the investigator, would preclude enrollment

Intervention: For infants in the expectant management group, treatments intended to close the PDA were not administered unless they developed cardiopulmonary compromise or reached 36 weeks’ PMA. For those in the active treatment group, pharmacological treatment with either acetaminophen, indomethacin or ibuprofen was to be initiated within 48 hours after sPDA diagnosis.

Outcomes:
Primary outcome: death or BPD, assessed using a physiological definition, at 36 weeks’ PMA.
Secondary outcomes: key secondary outcomes were components of the primary outcome (death or BPD) and BPD severity according to Jensen criteria.
Analysis and Sample Size: analysis was intention-to-treat with a sample size of 482 patients.
Patient follow-up: 99.8 % included in the intention-to-treat analysis, due to withdrawal of parental consent to use data for one infant in the expectant management group.

MAIN RESULTS
Between December 11, 2018 and December 20, 2024, 482 infants (242 expectant management, 240 pharmacological treatment) were enrolled. Median gestational age of 25 [IQR 24-27] weeks and birth weight of 760 [IQR 620-935] gram. At 36 weeks’ PMA, there was no difference in the composite outcome of death or BPD (195 of 241 (80.9%) versus 191 of 240 (79.6%); adjusted risk difference (aRD) 1.2% [95% CI -5.7% to 8.1%]). There was no difference in BPD (185 of 231 infants (80.1%) versus 168 of 217 (77.4%); aRD 2.2 [95% CI -5.2% to 9.6%]) or moderate-to-severe BPD (135 of 222 (60.8%) versus 129 of 211 (61.1%); aRD 0.3 [95% CI -8.3% to 8.9%]). Mortality was significantly lower in the expectant management group (10 of 241 (4.1%) versus 23 of 240 (9.6%); absolute risk difference -5.6% [95% CI -10.0% to -1.2%]. Adverse events and other secondary outcomes were similar, apart from a lower incidence of infections resulting in death in the expectant management group (2 of 241 (0.8%) versus 9 of 240 (3.8%)

CONCLUSION

In preterm infants born at a gestational age of 22+0 to 28+6 weeks with a protocol-defined sPDA at the postnatal age of 48 hours to 21 days the composite outcome of death or BPD did not differ after expectant management as compared to pharmacological treatment. Survival was significantly higher in those randomized to expectant management.

COMMENTARY

The trial by Laughon et al. echoes the findings of two recent trials,(1, 2) in which relevant neonatal morbidities were also not positively influenced after pharmacological treatment for PDA. Apart from the lack of benefit, these findings add to the growing concerns on potential harm of pharmacological treatment with prostaglandin synthesis inhibitors, especially for an increased risk of death.(3)

These previous trials focused on early, at 24 to 72 hours postnatal age, pharmacological treatment specifically with ibuprofen. The current trial has both a longer time frame of enrollment and pharmacological treatment with the choice of treatment, dose and route of administration at the discretion of the clinical team. The administration of ibuprofen (35.4%), indomethacin (28.8%), acetaminophen (25.8%) or more than one of these medications (9.2%) in the active pharmacological treatment group reflects the clinical heterogeneity in neonatal care.(4) One major strength of this pragmatic approach is that the findings of the trial are potentially more generalizable. Nevertheless, since prophylactic indomethacin was used in 9 of 33 recruiting centers during the trial period, it would be interesting to subgroup centers that did and did not use prophylactic indomethacin.

Enrolling patients in PDA trials is challenging, as supported by the flowchart in Figure 1. Nevertheless, the trial succeeded in enrolling a substantial amount of the most immature infants, i.e. those with a gestational age below 26 weeks, often underrepresented in trials. Regarding hemodynamic significance of the PDA, this trial, in comparison to PDA diameter based inclusion in the BeNeDuctus and Baby-OSCAR trial,(1, 2) used a protocol based definition of a symptomatic PDA.(5) Although helpful in better categorizing patients, the validity of this staging, in comparison to the PDA severity score, is questionable.(6) Whereas a PDA severity score based categorization might be the most sophisticated method to select the high-risk babies for PDA treatment, i.e. those most likely to benefit from effective treatment, it requires echocardiographic expertise hampering the generalizability.

Another limitation of PDA trials is the inefficacy of pharmacological closure in a rather large proportion of infants. PDA closure rates are not reported in this study. Although clinical outcomes are far more relevant than achieving PDA closure per se, this information would be interesting. Moreover, since findings from the pilot PDA-RCT, albeit limited in sample size, suggests that those with successful closure of their PDA have lower risk for death or BPD at 36 weeks’ PMA.(7)

The PDA RCT by Laughon et al. further supports the current guideline from the American Association of Pediatrics to refrain from routine treatment of a PDA within the first two weeks of life.(8) Alongside the growing evidence from numerous RCTs on PDA management there is also growing adherence to an interventional closure strategy, which is more effective than pharmacological treatment in closing the PDA and causes less morbidity than surgical ligation.(9) However, prior to the widespread use of this therapeutic intervention, a trial that proves overall benefit of this successful closure strategy as compared to a truly expectant management is of the utmost importance.

REFERENCES

1. Gupta S, Subhedar NV, Bell JL, Field D, Bowler U, Hutchison E, et al. Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. New England Journal of Medicine 2024; 390 4:314-25.
2. Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Dijkman KP, et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med 2023; 388 11:980-90.
3. Villamor E, Galán-Henríquez G, Bartoš F, Gonzalez-Luis GE. Beneficial vs harmful effects of pharmacological treatment of patent ductus arteriosus: A Bayesian meta-analysis. Pediatr Res 2025; 98 2:498-506.
4. Hundscheid T, El-Khuffash A, McNamara PJ, de Boode WP. Survey highlighting the lack of consensus on diagnosis and treatment of patent ductus arteriosus in prematurity. Eur J Pediatr 2022; 181 6:2459-68.
5. McNamara PJ, Sehgal A. Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 2007; 92 6:F424-7.
6. El-Khuffash A, Bussmann N, Breatnach CR, Smith A, Tully E, Griffin J, et al. A Pilot Randomized Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score (The PDA RCT). J Pediatr 2021; 229:127-33.
7. Bussmann N, Smith A, Breatnach CR, McCallion N, Cleary B, Franklin O, et al. Patent ductus arteriosus shunt elimination results in a reduction in adverse outcomes: a post hoc analysis of the PDA RCT cohort. Journal of Perinatology 2021; 41 5:1134-41.
8. Ambalavanan N, Aucott SW, Salavitabar A, Levy VY. Patent Ductus Arteriosus in Preterm Infants. Pediatrics 2025; 155 5.
9. Kuntz MT, Staffa SJ, Graham D, Faraoni D, Levy P, DiNardo J, et al. Trend and Outcomes for Surgical Versus Transcatheter Patent Ductus Arteriosus Closure in Neonates and Infants at US Children’s Hospitals. Journal of the American Heart Association 2022; 11 1:e022776.

The post EBNEO COMMENTARY: Expectant management versus medication for patent ductus arteriosus in preterm infants – The PDA RCT appeared first on Evidence-Based Neonatology.

MANUSCRIPT CITATION

Trinh C, Hodgson KA, Downes M, Manley BJ, Thio M, Assad M, Bibl K, Chabra S, DeMartino C, DeMeo S, Glass K, Herrick H, Quek BH, Iben S, Jung P, Kim J, Mehrem AA, Moussa A, Narvey M, O’Shea J, Pouppirt N, Puia-Dumitrescu M, Rumpel J, Shay R, Tingay D, Tyler M, Unrau J, Wagner M, Wildenhain P, Nishisaki A, Foglia EE. Impact of attending neonatologist presence on neonatal intubation success and adverse events: a cohort study. Journal of Perinatology 2025; PMID: 41282162

REVIEWED BY:

Dr Christopher Angus, Neonatal Research Fellow
Institution: Neonatal Unit, James Cook University Hospital, South Tees Hospitals NHS foundation Trust, Middlesbrough, UK
Email: Christopher.angus2@nhs.net

Prof Prakash Kannan Loganathan, Consultant Neonatologist
Email: pkannanloganathan@nhs.net
Telephone: 01642 850850 Ext 53517

CORRESPONDING AUTHOR

Name: Prof Prakash Kannan Loganathan, Consultant Neonatologist
Email: pkannanloganathan@nhs.net
Telephone: 01642 850850 Ext 53517

TYPE OF INVESTIGATION

Choose from one of the following: prevention, treatment, diagnosis, prognosis, etiology, quality improvement or continuing medical education, economics of healthcare or interventions, clinical prediction guides, differential diagnosis, or systematic review.

QUESTION

In neonates underdoing endotracheal intubation in the Neonatal Intensive Care Unit (NICU) or Delivery Room (P), does the presence of an attending Neonatologist (I) compared to absence (C), improve first attempt intubation success and reduces adverse tracheal intubation-associated events (TIAEs) (O), during the procedure (T).

METHODS

Design: Retrospective cohort study
Allocation: Not applicable
Blinding: Not applicable
Follow-up period: Not applicable
Setting: 19 neonatal intensive care units (NICUs), across the USA, Canada, Australia, Germany and Austria.
Patients: Neonates requiring endotracheal intubation. Inclusion: intubation occurred between October 1st, 2014, and December 31st, 2022 (16,010 endotracheal intubations). Exclusion: Intubations where an attending Neonatologist was the initial intubation operator. Intubations that had conflicting or missing data for the primary outcome (first attempt success), exposure of interest (attending Neonatologist presence) or covariates. After exclusion, there were total of 12,652 intubation encounters.
Intervention: Presence of attending neonatologist during intubation

Outcomes:
Primary outcome: First attempt intubation success, defined as successful intubation on the first attempt by the first operator.
Secondary outcomes: Severe and non-severe tracheal intubation adverse events (TIAEs), severe oxygen desaturation (≥20% absolute decrease in peripheral oxygen saturation), and multiple attempts (defined as ≥3 attempts)
Non-severe TIAEs: oesophageal intubation with immediate recognition, mainstem intubation, lip trauma, pain or agitation requiring additional sedation delaying intubation, epistaxis, emesis without aspiration, and dysrhythmia, including bradycardia with heart rate.
Severe TIAEs: direct airway injury, oesophageal intubation with delayed recognition, emesis with aspiration, laryngospasm, pneumothorax, gum or dental trauma, hypotension requiring intervention, need for cardiac compressions and cardiac arrest.

Analysis and Sample Size: 12,652 intubation encounters analysed. Directed Acyclic Graph (DAG) identified the following confounders: prematurity (<37 weeks), known difficult airway, operator grade (years), premedication, use of videolaryngoscope, nighttime intubation. Univariate logistic regression modelling was performed to estimate the unadjusted association between attending presence and each individual primary and secondary outcomes. Multivariable modelling using generalized estimating equations with covariate selection guided by the (DAG) and site clustering accounted for by use of an exchangeable correlation structure was then performed to estimate the adjusted causal effect of attending presence on each outcome. Patient follow-up: 100% of intubations meeting inclusion and exclusion criteria. MAIN RESULTS Of the 12,652 included intubations, 8391 (66.3%) had an attending present. Neonatologists were more likely to be present during intubation of infants who were of greater weight and age, had a known history of difficult airway, occurred during the day, and were in the delivery room. Intubations with an attending neonatologist present were also more likely to use a video laryngoscope. Univariate analysis found attending neonatologist presence was positively associated with first attempt intubation success (OR 1.11, 95% CI 1.04–1.20). However, on multivariate analysis, when controlling for confounders, attending presence was found to be negatively associated with first attempt intubation success (adjusted OR (aOR) 0.78, 95% CI 0.70–0.86). Similar negative association between attending presence and other outcomes are shown in table 1.

Table 1: Association of attending neonatologist presence with primary and secondary intubation outcomes: unadjusted and adjusted odds ratios (95% CI)

Subgroup analyses (Table 2) showed a similar direction of effect across operator experience, gestational age, known difficult airway, and intubation location, with the strongest association among the most experienced operators (aOR 0.67, 95% CI 0.50–0.91).

Table 2. Subgroup analyses of the impact of attending neonatologist presence on first attempt intubation success.

CONCLUSION

After adjustment for measured confounders, attending neonatologist presence was associated with lower odds of first-attempt intubation success and higher odds of multiple attempts, severe desaturation, and tracheal intubation-associated adverse events. These findings likely reflect residual confounding, particularly selective attending presence during higher-risk or more complex intubations, although other factors such as team dynamics may also have contributed.

COMMENTARY

Neonatal intubation remains a critical yet high-risk procedure, with low first attempt success rates, frequent desaturation and adverse tracheal intubation-associated events (TIAEs) (1, 2). Factors including operator experience, premedication, video laryngoscopy and nasal high flow therapy use during intubation have been shown to enhance success (3-5). Intuitively, the presence of an attending neonatologist (consultant) should enhance success by providing immediate expertise, leadership and oversight, potentially reducing risks for junior operators during this stressful procedure. Trinh et al conducted a large multicentre cohort study to evaluate this assumption, which had previously not been examined. Surprisingly, after adjustments for confounders, an unexpected association between attending neonatologist presence and poorer outcomes was discovered; lower first attempt success rates, and higher rates of ≥ 3 attempts, severe desaturation and TIAEs.

 

This study has important strengths, including a large international multicentre registry, use of a DAG to guide confounder selection, and generalized estimating equations to account for clustering by site. Prespecified subgroup analyses also suggested a similar direction of effect across key clinical strata, including preterm infants and those with difficult airways.

 

Despite these strengths, several limitations should be acknowledged. As the authors note, the retrospective observational design is susceptible to residual confounding from factors not captured in the registry, including illness severity, anticipated procedural difficulty, and the reason for attending presence, which may bias causal effect estimates. The registry also lacked data on the timing of attending involvement, attending coaching expertise, operator training differences, and changes in practice over the study period. Operator experience was measured in years rather than procedural volume or recency, making this a relatively imprecise proxy for intubation expertise. Important unit-level and procedural details, such as video laryngoscopy type, specific premedication regimens including atropine use, and variation in supervisory/coaching style, were also unavailable and may have contributed to residual confounding. Exclusion of 1790 intubations with missing confounder data may have introduced selection bias. In addition, limited power for individual adverse events necessitated use of composite TIAE outcomes, combining events of heterogeneous clinical importance and complicating interpretation. Finally, the marked reversal from a positive unadjusted association (OR 1.11) to a negative adjusted association (aOR 0.78) suggests substantial confounding, most likely related to selective attending presence during higher-risk intubations.

 

This study suggests that attending neonatologist supervision alone may not mitigate the risks associated with neonatal intubation. Further research should prospectively evaluate operator-specific and supervisory factors influencing intubation success, including reasons for attending presence, coaching style and consistency, illness severity, and procedural dynamics (for example, through video review). With declining intubation opportunities due to advances in neonatal care, balancing trainee proficiency with patient safety is paramount. This study prompts reflection: attending neonatologist presence alone may be insufficient. It underscores the need to optimise every first intubation attempt (6) by matching operators to procedures and utilising adjuncts such as video laryngoscopy, adequate premedication and nasal high flow therapy. Importantly, these findings should not be interpreted as diminishing the importance of senior supervision, which remains fundamental to governance and patient safety during neonatal intubation.

 

REFERENCES

1. Foglia EE, Ades A, Sawyer T, Glass KM, Singh N, Jung P, et al. Neonatal Intubation Practice and Outcomes: An International Registry Study. Pediatrics 2019; 143 1.
2. O’Donnell CP, Kamlin CO, Davis PG, Morley CJ. Endotracheal intubation attempts during neonatal resuscitation: success rates, duration, and adverse effects. Pediatrics 2006; 117 1:e16-21.
3. Johnston L, Sawyer T, Ades A, Moussa A, Zenge J, Jung P, et al. Impact of Physician Training Level on Neonatal Tracheal Intubation Success Rates and Adverse Events: A Report from National Emergency Airway Registry for Neonates (NEAR4NEOS). Neonatology 2021; 118 4:434-42.
4. Lingappan K, Neveln N, Arnold JL, Fernandes CJ, Pammi M. Videolaryngoscopy versus direct laryngoscopy for tracheal intubation in neonates. Cochrane Database Syst Rev 2023; 5 5:Cd009975.
5. Hodgson KA, Owen LS, Kamlin COF, Roberts CT, Newman SE, Francis KL, et al. Nasal High-Flow Therapy during Neonatal Endotracheal Intubation. The New England journal of medicine 2022; 386 17:1627-37.
6. Bernhard M, Becker TK, Gries A, Knapp J, Wenzel V. The First Shot Is Often the Best Shot: First-Pass Intubation Success in Emergency Airway Management. Anesth Analg 2015; 121 5:1389-93.

The post EBNEO COMMENTARY: Impact of attending neonatologist presence on neonatal intubation success and adverse events: a cohort study appeared first on Evidence-Based Neonatology.

MANUSCRIPT CITATION

Kanaprach P, Michel-Macias C, Mazzarello M, Mir M, Rampakakis E, Wutthigate P, Simoneau J, Villegas D, Moore SS, Shemie SD, Brossard-Racine M, Dancea A, Bertolizio G, Wintermark P, Altit G. Cerebral Saturation and Fractional Tissue Oxygen Extraction Are Associated with Anterior Cerebral Artery Doppler Parameters in Neonates with Congenital Heart Defects. Neonatology 2025; 122(5):519-527. PMID: 40451174.

REVIEWED BY

Ashley L Lynch, MD (corresponding author)
University of Arkansas for Medical Sciences
Arkansas Children’s Hospital
Department of Pediatrics
Division of Neonatology
Allynch@uams.edu

Ethan L Gillett, MD
University of Arkansas for Medical Sciences
Arkansas Children’s Hospital
Department of Pediatrics
Division of Cardiology
ELgillett@uams.edu

TYPE OF INVESTIGATION

Diagnosis

QUESTION

In neonates born at greater than or equal to 35 weeks gestational age with congenital heart defect (CHD), what is the association between bedside measures of cerebral oxygen delivery and utilization and cerebral blood flow as assessed by anterior cerebral artery Doppler during the first week of life?

METHODS

• Design: Single-center prospective observational cohort study
• Allocation: Neonates with CHD born at >35 weeks gestational age and admitted to the study site’s neonatal intensive care unit within their first 7 days of postnatal life
• Blinding: Blinded data extraction for ultrasound Doppler evaluations; unblinded for bedside staff
• Follow-up period: Not applicable
• Setting: Single-center neonatal intensive care unit
• Patients: Neonates with CHD born at >35 weeks gestational age and admitted to a single-center neonatal intensive care unit within their first 7 days of post-natal life from November 2019 to December 2021, excluding those with a significant syndrome with more than one organ anomaly, including cerebral, pulmonary, airway, or intra-abdominal malformations.
• Intervention: Data from continuous cerebral oxygen saturation (CSat) [using near-infrared spectroscopy (NIRS)] and cerebral fractional tissue oxygen extraction (cFTOE) (using simultaneous NIRS and preductal SpO₂) monitoring was collected during the first week of life. Daily anterior cerebral artery (ACA) Doppler was obtained for resistive index (RI) and pulsatility index (PI) from day of life 1-7. When available, blood gas and hemoglobin levels were collected on the same day as the NIRS and ultrasound measurements. For daily transfontanellar cranial ultrasound with Doppler ACA readings, data were anonymized and masked to cardiac defect and NIRS values. The study focused only on the pre-surgical period, data were not collected after surgical intervention for the CHD.
• Outcomes: Relationship between CSat or cFTOE and RI/PI on ACA Doppler during the postnatal period of transitional physiology.
• Analysis and Sample Size: 34 neonates were enrolled, with 142 concomitant data measurements of NIRS and ultrasound Doppler. An average of the CSat values at the exact minute of Doppler ultrasound acquisition of the ACA was extracted, along with pre-ductal saturation for cFTOE calculation. Mixed-effects models evaluated the relationship between CSat/cFTOE and RI/PI-ACA, adjusting for time since birth, partial pressure of carbon dioxide (pCO₂), and hemoglobin levels.
• Patient follow-up: % included in analysis: Not applicable

MAIN RESULTS

The study included 142 concomitant measurements of NIRS and ultrasound parameters during first week of life collected in 34 neonates with various types of CHD. Most (79%) were inborn and had a prenatal diagnosis, and most (74%) received prostaglandins.

• 11 coarctation of aorta / aortic arch hypoplasia
• 7 dextro-transposition of the great arteries (d-TGA)
• 4 tetralogy of Fallot (ToF)
• 3 pulmonary atresia with intact ventricular septum (PAIVS)
• 2 tricuspid atresia
• 2 hypoplastic left heart syndrome (HLHS)
• 1 pulmonary atresia
• 1 congenitally corrected transposition of the great arteries (c-TGA)
• 1 double inlet left ventricle (DILV)
• 1 double outlet right ventricle (DORV)
• 1 with atrioventricular septal defect (AVSD)

Mixed effect models showed significant associations between CSat and cFTOE and the time-corresponding RI-ACA (p = 0.02 and 0.005) and PI-ACA (p = 0.006 and 0.002) values, respectively.

• A 0.1-point increase in RI was associated to a 2.3% decrease in CSat and a 3-point increase in cFTOE
• A 0.1-point increase in PI was associated to a 0.9% decrease in CSat and 1.1-point increase in cFTOE
• Regarding the effect of time, CSat values decreased over the 7-day period; cFTOE increased, mirroring the trends observed in RI and PI of the ACA which also increased over the time period.
• Accounting for confounders including pCO₂ and hemoglobin levels at the time of ultrasound did not alter the strength of the associations.

CONCLUSION

In neonates with CHD during their first week of life, doppler signs indicating increased cerebral blood flow resistance in the ACA correlated with lower CSat and higher cFTOE using NIRS. Given the inherent variations in arterial oxygen content in the CHD population, this provides insight into cerebral oxygen delivery and utilization. More research is needed to assess whether a multimodal bedside approach to assessing cerebrovascular hemodynamics could aid in prevention of brain injury and associated adverse neurodevelopmental outcomes by providing more timely detection of cerebral hypoperfusion.

COMMENTARY

The first week of postnatal life is a period of transition for both pulmonary and systemic vascular flow patterns. Owing to associated shunts and altered systemic/pulmonary blood flow, neonates with congenital heart defect (CHD) are at particular risk for disrupted end-organ perfusion and oxygen delivery, including that of the brain. Near-infrared spectroscopy (NIRS) measures venous-weighted cerebral oxygen saturation (CSat) at the frontal cortex, serving as an indirect reflection of cerebral blood flow. CSat is impacted by factors such as tissue perfusion, systemic oxygenation, regional oxygen extraction, and hemoglobin levels, all of which are affected by cardiac function and vascular supply [1, 2]. Cerebral fractional tissue oxygen extraction (cFTOE) reflects the balance between cerebral oxygen utilization and oxygen delivery, and it is operationally defined as (preductal SpO₂ – CSat) / preductal SpO₂. As such, cFTOE can provide insight into cerebral oxygen utilization. Increased cFTOE can be due to decreased oxygen delivery or increased oxygen consumption not met by associated increase in delivery. Likewise, decreased cFTOE can indicate that the brain is using less oxygen or that oxygen delivery has increased relative to utilization [3]. Data on CSat and cFTOE as cerebrovascular metrics in neonates with CHD during the period of postnatal adaptation are limited.

 

Elements of anterior cerebral artery (ACA) doppler such as resistive index (RI) and pulsatility index (PI) assess vascular resistance and flow characteristics in the frontal cortex, and have been shown to correspond to cerebral perfusion pressure [4]. Abnormal RI is a recognized indicator of such newborn pathologies as increased intracranial pressure, brain injury, and diastolic steal [5, 6, 7].

 

This study has made a notable contribution to the literature by applying these established bedside tools to a vulnerable and complex group of patients (neonates with CHD) during a time of critical transitional physiology (postnatal adaptation). The authors recruited 34 neonates with various types of CHD and analyzed 142 concomitant data measurements of NIRS and daily ultrasound doppler over the first 7 days of life. They used mixed-effects models to evaluate the relationship between CSat/cFTOE and RI/PI-ACA, adjusting for time since birth, pCO₂, and hemoglobin levels. Authors found a decline in CSat and rise in cFTOE throughout the first week of life in neonates with CHD, which aligns with findings from prior research [8]. RI and PI both increased over the time period, indicating increased resistance to flow velocities. Authors also reported statistically significant associations between CSat/cFTOE and simultaneous RI/PI values. The findings suggest progressive increase in oxygen extraction, possibly related to diminished blood flow, impaired oxygen delivery, or increased metabolic demand during postnatal transition. Authors theorize that this may be partly owing to altered adaptation due to shunts and abnormal anatomy. Despite the variability of the study population, findings supported consistent directional trends in NIRS and ultrasound. While these results are meaningful, an even greater impact will be gained in translating the findings to earlier detection/management of cerebral hypoperfusion in order to improve neurodevelopmental outcomes.

REFERENCES

1. Vesoulis ZA, Mintzer JP, Chock VY. Neonatal NIRS monitoring: recommendations for data capture and review of analytics. J Perinatol. 2021; 41:675-688.

2. Mulkey SB, Polglase GR. Cerebral oxygen saturation-a useful bedside vital sign for neonatal encephalopathy. J Perinatol. 2021; 41:2577-2579.

3. Schlatzer C, Schwaberger B, Bruckner M, Wolfsberger CH, Pichler G, Urlesberger B, et al. Cerebral fractional tissue oxygen extraction (cFTOE) during immediate fetal-to-neonatal transition: a systematic qualitative review of the literature. Eur J Pediatr. 2024; 183:3635-3645.

4. Robel-Tillig E, Möckel A, Vogtmann C. Normal Doppler ultrasound values of the anterior cerebral artery of premature and newborn infants with reference to cardiac function parameters and intestinal blood flow profile. Z Geburtshilfe Neonatol. 1999; 203:234-40.

5. Gerner GJ, Burton VJ, Poretti A, Bosemani T, Cristofalo E, Tekes A, et al. Transfontanellar duplex brain ultrasonography resistive indices as a prognostic tool in neonatal hypoxic-ischemic encephalopathy before and after treatment with therapeutic hypothermia. J Perinatol. 2016; 36:202-6.

6. Seibert JJ, McCowan TC, Chadduck WM, Adametz JR, Glasier CM, Williamson SL, et al. Duplex pulsed Doppler US versus intracranial pressure in the neonate: clinical and experimental studies. 1989; 171:155-9.

7. Ecury-Goossen GM, Raets MM, Camfferman FA, Vos RH, van Rosmalen J, Reiss IK, et al. Resistive indices of cerebral arteries in very preterm infants: values throughout stay in the neonatal intensive care unit and impact of patent ductus arteriosus. Pediatr Radiol. 2016; 46:1291-300.

8. Lynch JM, Ko T, Busch DR, Newland JJ, Winters ME, Mensah-Brown K, et al. Preoperative cerebral hemodynamics from birth to surgery in neonates with critical congenital heart disease. J Thorac Cardiovasc Surg. 2018; 156:1657-1664.

The post EBNEO COMMENTARY: Cerebral Saturation and Fractional Tissue Oxygen Extraction Are Associated with Anterior Cerebral Artery Doppler Parameters in Neonates with Congenital Heart Defects appeared first on Evidence-Based Neonatology.

The LAKANA Trial: Mass Administration of Azithromycin to Infants in Mali did not Reduce Mortality

MANUSCRIPT CITATION

Haidara FC, Adubra L, Abdou M, Alber D, Ashorn U, Cheung YB, et al. Mass Administration of Azithromycin to Infants in Mali to Reduce Mortality. N Engl J Med 2025; 395(15): 1498-1508. PMID 41092331.

REVIEWED BY

Maya I. Brasher, MD, FAAP
Assistant Professor of Pediatrics
Baylor College of Medicine
mbrasher@bcm.edu

Monika S. Patil, MD, FAAP
Associate Professor of Pediatrics
Baylor College of Medicine
Monika.patil@bcm.edu

TYPE OF INVESTIGATION

Prevention

QUESTION

Among children aged 1 to 11 months, does mass administration of azithromycin (2 doses versus 4 doses) administered over the first year of life result in decreased infant mortality when compared to placebo?

METHODS

• Design: Randomized control trial
• Allocation: Concealed
• Blinding: Yes
• Follow-up period: 2 years
• Setting: Villages in the Kayes, Kita, and Koulikoro regions (considered as nonurban, accessible, and safe regions) in Mali
• Patients: Infants aged 1 to 11 months (29 to 364 days) old, residing in a trial village, with a body weight of at least 3 kg, and with consent from the caregiver
• Intervention: Provision of a total of one to four doses of azithromycin or placebo, under direct observation with a dose of 20 mg per kilogram, depending on the infant’s age at enrollment and village’s randomization
• Outcomes: Death from any cause among infants 1 to 11 months of age
• Primary outcome: Mortality measured at 3-month time periods (interval between successive study visits), used to calculate person-years at risk
• Secondary outcomes: 1) All-cause mortality among children 12 to 59 months of age at the time of the village’s most recent drug distribution. 2) Assessment of whether infant characteristics (age, sex, weight-for-age z-score), seasonal factors (rainy or not rainy, exposure to seasonal malaria chemoprovention), logistics (order of mass administration, district of residence, distance from nearest health facility, and national outreach strategy), and socioeconomic factors (household asset index, WASH (water, sanitation, and hygiene) index) modified the effect of azithromycin on infant mortality.
• Analysis and Sample Size: 1170 villages were invited, of which 1151 were randomized. Villages were randomized in a 3:4:2 ratio as part of an adaptive trial design, to achieve adequate statistical power to test 3 distinct hypotheses: that twice-yearly azithromycin was more effective than placebo, quarterly administration was more effective than placebo, and quarterly administration was more effective than twice-yearly azithromycin at decreasing mortality in this patient population. Mortality outcomes were analyzed by intention-to-treat. Sample size was determined using simulations to obtain the power necessary to test the above hypotheses. An interim analysis was pre-specified to be performed once approximately 60% of total person-years were collected. Primary outcome was analyzed using one-sided hypothesis testing to estimate incidence rate ratios (IRR) with 95% confidence intervals (CI). Mixed-effect Poisson models with random intercepts for clusters (to account for similar outcomes among infants from the same village) and log-link function (with person-years as an offset variable) were used, and models were adjusted for the village size of <100 or 100+ infants (randomization stratification factor) as a fixed effect. Secondary outcomes were analyzed using two-sided tests, and effect modification was assessed using individual interaction terms to the mixed-effect Poisson models.
• Patient follow-up: Patients were followed-up through a systematic, house-to-house census performed every 3 months (+/-4 weeks) over a period of 2 years. Follow-up was recorded in units of person-years, to account for the fact that participants were followed for varying amounts of time.

MAIN RESULTS

In this study, also known as the LAKANA (Large-Scale Assessment of the Key Health-Promoting Activities of Two New Mass Drug Administration Regimens with Azithromycin) trial, 1151 villages were randomly assigned to the control (386), twice yearly azithromycin (511), or quarterly azithromycin (254) groups. Baseline characteristics were assessed at the initiation of mass distribution, and the villages comprising the three groups were found to be similar in the number of eligible infants per village and the distribution of infants by age, sex, and weight-for-age. Azithromycin administration was also timed to avoid overlap with the national malaria chemoprophylaxis program in the twice-yearly group. 9,085 visits were planned, with 7,831 (86.2%) completed on time, and 263 (2.9%) missed. In total, 285,227 households were registered, and a total of 149,090 infants received at least one dose of azithromycin or placebo, with 274,896 medication administrations and 82,600 person-years recorded. 968 deaths were documented over 82,600 person-years of follow-up. There was no statistically significant difference in the mortality rates of the three groups: mortality rate was 11.9 deaths 1000 person-years in the control group, 11.8 deaths per 1000 person-years in the twice-yearly group, and 11.3 deaths per 1000 person-years in the quarterly group. IRR for mortality was 1.00 (95% CI 0.83-1.19) in the twice-yearly group compared to the control group, 0.93 (95% CI 0.75-1.15) in the quarterly group compared to the control group, and 0.93 (95% CI 0.76-1.15) in the quarterly group compared to the twice-yearly group.

In assessing secondary outcomes, mortality among untreated children aged 12 to 59 months was similar regardless of age stratification and study group. Subgroup analyses indicated no significant difference in mortality of infants 1 to 11 months old, suggesting no apparent effect modification by infant characteristics, seasonal factors, study logistics, or socioeconomic factors examined.

CONCLUSION

Large-scale studies in Sub-Saharan Africa have demonstrated significant mortality reduction in children aged 1 to 59 months of age with twice yearly azithromycin administration. However, the World Health Organization recommends that if mass administration of azithromycin is implemented for child survival, it should target infants aged 1 to 11 months old to minimize risks of antimicrobial resistance while maximizing potential survival. In the LAKANA trial, no reduction in infant or child mortality was seen with mass administration of azithromycin, either two or four times per year, to infants between 1 and 11 months of age in Mali.

COMMENTARY

Under-5 mortality is highest in Sub-Saharan Africa at 68 per 1000 live births(1), with the infant mortality rate (IMR) comprising a significant portion of those deaths at 44 per 1000 live births(2). Recently, mass azithromycin administration has been studied to help decrease under-5 mortality. The MORDOR(3) and AVENIR(4) trials respectively showed 13.5% and 14% reductions in under-5 mortality across Malawi, Niger, and Tanzania. Based on these findings, the World Health Organization recommends(5) mass azithromycin administration limited to infants 1 to 11 months old in high-mortality regions, targeting highest-risk populations while minimizing antimicrobial resistance. The LAKANA trial(6) specifically studied the impact of mass azithromycin in infants in Mali, finding no reduction in IMR.

 

Study strengths include a thoughtful design and analysis plan, using simulations to generate sample size estimates for sufficient power based on prior available data, randomizing groups in a 3:4:2 ratio to allow for an adaptive model, and accounting for factors that may modify effect of azithromycin administration. Limitations include utilization of select sites in a single country; while simplifying study logistics, this limits generalizability to other countries/regions in Sub-Saharan Africa. The largest limitation, unfortunately, is that the trial encountered a lower-than-expected baseline mortality rate.

 

Based on recent census data from Mali, LAKANA trial authors used an infant mortality estimate of 60 to 70 deaths per 1000 live births for calculations of sample size and power. However, the control group had a mortality rate of ~12 deaths per 1000 person-years, corresponding to approximately 36 deaths per 1000 live births. This discrepancy, possibly attributed to a national decrease in infant mortality or Hawthorne effect (change in behavior by nature of being observed), may have decreased the study’s statistical power to detect smaller differences between groups and thus the study’s conclusion may be affected by Type II error (not finding a difference when one exists). Finally, the pathologies by which azithromycin administration may decrease under-5 mortality, such as malaria, pneumonia, and dysentery(3,7), may be less prevalent overall within the context of lower baseline mortality, resulting in decreased observed impact of this intervention.

 

Mass azithromycin administration is a relatively cost-effective(8) intervention with the potential to save a significant number of lives, but its effectiveness in decreasing mortality specifically among infants aged 1 to 11 months remains uncertain. Additionally, antimicrobial resistance has not been fully elucidated, but increased macrolide resistance among children treated as part of mass azithromycin administration efforts has been demonstrated(9). In this case, the LAKANA trial exemplifies the dangers in extrapolating data from other patient populations and sites. Reducing the IMR is paramount, but this study highlights the importance of rigorous testing across patient populations and sites to determine impact of interventions prior to development of generalized guidelines. Future studies are necessary to identify the target age range, with consideration of baseline mortality, for optimal mortality benefit from mass administration of azithromycin, better understand the potential community-level risks such as increased antimicrobial resistance, and track mortality trends to ensure maximal impact of interventions in areas with highest infant mortality.

REFERENCES

1. [Available from: https://data.worldbank.org/indicator/SH.DYN.MORT?locations=ZG.
2. [January 29, 2026]. Available from: https://data.worldbank.org/indicator/SP.DYN.IMRT.IN?locations=ZG.
3. Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, et al. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med 2018;378(17):1583-92.
4. O’Brien KS, Arzika AM, Amza A, Maliki R, Aichatou B, Bello IM, et al. Azithromycin to Reduce Mortality – An Adaptive Cluster-Randomized Trial. N Engl J Med 2024;391(8):699-709.
5. WHO Guideline on Mass Drug Administration of Azithromycin to Children under Five Years of Age to Promote Child Survival. WHO Guidelines Approved by the Guidelines Review Committee. Geneva: World Health Organization; 2020:viii-x. License: CC BY-NC-SA 3.0 IGO.
6. Haidara FC, Adubra L, Abdou M, Alber D, Ashorn U, Cheung YB, et al. Mass Administration of Azithromycin to Infants in Mali to Reduce Mortality. N Engl J Med 2025;393(15):1498-508.
7. Oldernburg CE, Ouattara M, Bountogo M, Boudo V, Ouedraogo T, Compaoré G, et al. Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial. JAMA 2024;331(6):482-490.
8. Brander RL, Weaver MR, Pavlinac PB, John-Stewart GC, Hawes SE, Walson JL. Projected impact and cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa. Clin Infect Dis 2020;74(3):375-86.
9. Doan T, Worden L, Hinterwirth A, Arzika AM, Maliki R, Abdou A, et al. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. N Engl J Med 2020;383(20):1941-50.

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Ojha S, Mitchell EJ, Johnson MJ, Gale C, McGuire W, Oddie S et al. Full exclusively enteral fluids from day 1 versus gradual feeding in preterm infants (FEED1): an open-label, parallel-group, multicentre, randomised, superiority trial. The Lancet Child & Adolescent Health. 2025 Dec 1;9(12):827-36. PMID 41115446

Reviewed By:

Dr. Kuldeep Singh, D.M
Assistant Professor, Department of Pediatrics, Maharishi Markandeshwar College of Medical Science & Research (MMCMSR), Ambala, Haryana, India- 134003
Email: kuldeepkk9@gmail.com

Type of Investigation:

Prevention

Question:

In infants born at 30 weeks and 0 days (30+⁰ weeks) to 32+⁶ weeks of gestation (P), does exclusively enteral fluids (I) (ie, full milk feeds) from day 1 compared with gradual feeding supplemented with intravenous fluids or parenteral nutrition (C) reduces the length of hospital stay (O)?

METHODS:

Design: Multi-centre, open, parallel group, randomized (1:1) controlled superiority trial
Allocation: The mothers were randomly assigned (1:1) via a secure web-based system to either the full milk group or the gradual milk group.
Blinding: Parents and the clinical team could not be masked, but investigators and data analysts were masked until after database lock
Follow-up period: Primary outcome assessed at the time of discharge
Setting: Recruitment was from 46 neonatal units in UK National Health Service hospitals across England, Scotland, and Wales.
Patients:
Inclusion criteria:
(i) Infants born at 30+0 to 32+6 weeks gestation (inclusive)
(ii) Infants < 3 h (180 min) old (since recorded time of birth)
Exclusion criteria:
(i) Infants with known congenital abnormalities of the gastrointestinal tract or other congenital conditions that make enteral feeding unsafe
(ii) Infants who were small for gestational age (SGA) (birth weight < 10th centile) and have evidence of reversed end-diastolic flow on antenatal umbilical artery Doppler ultrasound and
(iii) Mothers who had participated in the trial during a previous pregnancy.

Intervention:

For infants in the full milk group, milk feeds were started within 3 h of birth at 60–80 mL/kg per day via a gastric tube and continued milk feeds without intravenous fluids or parenteral nutrition. For those in the gradual feeding group, intravenous fluids or parenteral nutrition and small volumes of milk feeds (maximum of 30 mL/kg per day on day 1) were started according to local standard practice.

Outcomes:

Primary outcome: The primary outcome was length of hospital stay, which included the total duration in any neonatal unit measured from day of birth to the day of discharge home.
Secondary outcomes:
Key secondary outcomes were survival, incidence of necrotising enterocolitis (defined as Bell’s stage 2 or 3), incidence of microbiologically confirmed or clinically suspected late-onset sepsis, hypoglycaemia, and breastfeeding own mother’s milk up to hospital discharge.
Analysis and Sample Size: Analysis was intention-to-treat and sample size was 2088 (1047 full milk feeds, 1041 gradual feeding)
Patient follow-up: 100% included in intention-to-treat analysis

MAIN RESULTS:

Between Oct 15, 2019, and July 14, 2024, 2088 infants (1047 full milk feeds, 1041 gradual feeding) were enrolled. Mean gestational age was 31·7 weeks (SD 0·8), which was the same in both groups, and mean birthweight was 1626·0 g (301·8) in the full milk feeds group and 1617·1 (295·2) in the gradual feeding group. Primary outcome data were missing for 18 infants in each group. There was no difference in the length of hospital stay (32·4 days [SD 13·3] in the full milk group vs 32·1 days [13·5] in the gradual feeding group; adjusted difference between means –0·02 days [95% CI –1·07 to 1·03]; p=0·97). Survival to discharge (1030 [99·6%] of 1034 vs 1027 [99·6%] of 1031; –0·004 [95% CI –0·54 to 0·53]), presence of necrotising enterocolitis (4 [0·4%] of 1030 vs 6 [0·6%] of 1027; –0·19 [–0·80 to 0·41]), and mean number of blood glucose tests <2·2 mmol/L (0·6 [SD 1·0] vs 0·5 [0·7]) were similar. Serious adverse events were similar in both groups (eight [0·8%] of 1047 infants in the full milk group vs ten [1·0%] of 1041 infants in the gradual feeding group), all were unrelated to trial intervention.

CONCLUSION:

In infants born at 30+⁰ weeks to 32+⁶ weeks of gestation, full milk feeds from day 1 does not alter length of hospital stay. It does not increase the risk of necrotising enterocolitis or hypoglycaemia.

COMMENTARY:

The FEED1 Trial: When Process Improvement Doesn’t Equal Faster Discharge

The FEED1 trial by Ojha and colleagues represents a major contribution to neonatal research, reporting the largest randomized controlled trial of early full enteral feeding in preterm infants to date, with 2088 infants enrolled across 46 UK neonatal units.1 Though the primary outcome—length of hospital stay—was not reduced, findings challenge how we define clinical “success” and illuminate the multifactorial determinants of discharge in preterm neonates.

A Paradox That Reveals the Truth

The trial demonstrates a striking paradox: infants receiving full milk feeds reached full enteral nutrition 68% faster, required 1.5 fewer days of parenteral nutrition, had fewer invasive procedures, and spent one day less in intensive care—yet hospital length of stay remained unchanged (32.3 vs 32.1 days).1 This disconnect is telling. Even “time to objective discharge criteria” (23 days in both groups) revealed substantial discordance with actual discharge, representing a 9-day gap.1
What the trial inadvertently measured was not feeding practices’ effect on discharge readiness, but institutional discharge practices’ immutability. In the UK NHS context, social, logistical, or administrative factors—not medical readiness—predominantly determine discharge timing for stable moderate-to-late preterm infants.2 The feeding intervention successfully changed medical care but couldn’t overcome non-medical barriers to discharge.

The Challenge of Intervention Fidelity

The pragmatic design, whilst enhancing generalizability, introduces caveats about what was actually tested. Only 61.5% of infants allocated to full milk feeds received ≤24 hours of intravenous fluids, and merely 20.4% were truly exclusively enterally fed from birth.1 Non-adherence reached 39%, primarily due to perceived “feed intolerance” (12.4%)—a subjective assessment in an unmasked trial.
This raises a critical question: Did the trial compare full versus gradual feeding, or “attempted full feeding with frequent deviation to gradual feeding” versus gradual feeding? Substantial non-adherence likely underestimates the true effect of successfully implemented exclusive enteral nutrition.

Redefining Success in Neonatal Care

Should we consider FEED1 a “negative trial”? Absolutely not. The secondary outcomes reveal clinically meaningful benefits. Reduction in central line days (-0.87 days, ~40%) and parenteral nutrition duration (-1.52 days ~56%) represent substantial decreases in invasive interventions, costs, and infection risk exposure.1 Infants also transitioned out of intensive care one day earlier.

 

These findings suggest that early full enteral feeding improves neonatal care quality through reduced medicalization, even without shortening total hospital stay.

 

The subgroup analysis of 242 small-for-gestational-age infants revealed zero necrotizing enterocolitis cases in those receiving full milk feeds.1 While possibly chance in an underpowered group, it contradicts traditional concerns about aggressive feeding in growth-restricted infants and merits dedicated investigation.3

 

Critical questions remain unanswered: What is the optimal strategy for the 39% who did not tolerate full feeds? Can standardized feed intolerance criteria improved intervention fidelity? Does this approach benefit infants <30weeks or <1000g, who face higher NEC risk but might gain more from avoiding parenteral nutrition?4,5

The Path Forward

Rather than viewing FEED1 trial’s null primary outcome as disappointing, we should recognize it as paradigm-shifting evidence that feeding practices are not rate-limiting step for hospital discharge in this population. The path forward requires identifying and addressing true barriers to timely discharge, valuing de-medicalization as important outcomes, and refining protocols for infants who do not tolerate aggressive feeding.

 

The awaited 24-month neurodevelopmental follow-up and health economics analyses will be critical comprehensive interpretation. Meanwhile, FEED1 provides high-quality evidence that stable moderate-to-late preterm infants can be safely fed full milk feeds from birth, with meaningful reductions in medical intervention—an achievement worthy of celebration, even if babies don’t go home faster.

References:

1. Ojha S, Mitchell EJ, Johnson MJ, et al. Full exclusively enteral fluids from day 1 versus gradual feeding in preterm infants (FEED1): an open-label, parallel-group, multicentre, randomized, superiority trial. Lancet Child Adolesc Health 2025; published online Oct 17. doi: 10.1016/S2352-4642(25)00271-8
2. Seaton SE, Barker L, Draper ES, et al. Estimating neonatal length of stay for babies born very preterm. Arch Dis Child Fetal Neonatal Ed. 2019; 104:F182-F186. doi:10.1136/archdischild-2017-314405
3. Battersby C, Longford N, Mandalia S, Costeloe K, Modi N; UK Neonatal Collaborative Necrotising Enterocolitis (UKNC-NEC) study group. Incidence and enteral feed antecedents of severe neonatal necrotising enterocolitis across neonatal networks in England, 2012-13: a whole-population surveillance study. Lancet Gastroenterol Hepatol. 2017; 2:43-51. doi:10.1016/S2468-1253(16)30117-0
4. Dorling J, Abbott J, Berrington J, et al. Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants. N Engl J Med. 2019; 381:1434-43. doi:10.1056/NEJMoa1816654
5. Walsh V, Brown JVE, Copperthwaite BR, Oddie SJ, McGuire W. Early full enteral feeding for preterm or low birth weight infants. Cochrane Database Syst Rev. 2020; 12:CD013542. doi: 10.1002/14651858.CD013542.pub2

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Ojha S, Mitchell E, Johnson M, Gale Christopher, McGuire W, Oddie S, Hall S, Meakin G, Anderson J, P C, Su Y, Johnson S, Walker K, Ogollah R, Mistry H, Naghdi S, Montgomery A, Dorling, J, & Mcintyre J, Hartung R. Full exclusively enteral fluids from day 1 versus gradual feeding in preterm infants (FEED1): a open-label, parallel-group, multicentre, randomised, superiority trial. Lancet Child Adolesc Health 2025; 9:827-36
PMID: 41115446

REVIEWED BY

Johanna Baker and Harsha Gowda
University Hospitals Birmingham
Johanna.baker@nhs.net

CORRESPONDING AUTHOR

Name: Johanna Baker
Email johanna.baker@nhs.net
Telephone 07986285456

TYPE OF INVESTIGATION

Treatment: full enteral feeds versus gradual increase in enteral feeds, a multicentre, randomised controlled trial

QUESTION

In preterm infants between 30+0 and 32+6 weeks gestation (Population), does introducing full enteral feeds from first day of life (intervention) versus gradual increase in enteral feeds (comparison) lead to shorter hospital stay (outcome)?

METHODS

• Design: Multicentre, parallel group, randomised controlled trial in United Kingdom
• Allocation: Mothers allocated randomly using web-based randomisation software with minimization algorithm with random element to ensure balance of key factors
• Blinding: Parents and clinicians non-blinded; investigators and data analysts blinded.
• Follow-up period: 24 months (ongoing)
• Setting: Multicentre randomised controlled trial across 46 neonatal units in UK
• Patients: Preterm infants between 30+0 and 32+6 weeks gestational age within 3 hours of birth who were clinically stable. Infants were excluded if they had a congenital abnormality which made enteral feeding unsafe or were small for gestational age with reversed end diastolic flow on doppler.
• Intervention: Full enteral feeds on first day of life at 60-80ml/kg/day as compared to gradual increase over first days of life with maximum 30ml//kg/day enteral feeds on first day of life with remaining fluids as intravenus fluids or parenteral nutrition.
• Outcomes:
• Primary outcome: Length of Hospital stay
• Secondary outcomes: Survival to discharge, incidence of hypoglycaemia, necrotising enterocolitis, late onset sepsis and rates of breastfeeding at discharge and 6 weeks
• Analysis and Sample Size: A total of 2088 infants were enrolled to the study; 1047 in the full milk feeds group and 1041 in gradual feeding arm
• Patient follow-up: Primary outcome data was missing for 18 infants in each group (due to withdrawal from study or death; 1 record missing in each group), so 98.3% of enrolled infants were included in final analysis.

MAIN RESULTS

2088 infants were enrolled, with a mean gestational age of 31.7 weeks (SD 0.8) and mean birthweight of 1621g (SD 298). Baseline characteristics including sex, birthweight, gestation, birthweight, multiple birth, ethnicity, clinical condition, use of intravenous fluids prior to randomisation (within first 3 hours of birth), method of delivery, and use antenatal steroid and magnesium sulphate were similar across the two groups. In the full milk feeds group, 644 infants (61.5%) received no or less than 24 hours of intravenous fluids or parenteral nutrition from birth; the reason for non-adherence was reported in 387 (27%), and included failure to tolerate enteral feeds, abdominal concerns, hypoglycaemia, and escalation of respiratory support necessitating change in feeds.

The primary outcome studied was length of hospital stay, and results showed no significant difference between the 2 groups, with mean stays of 32.4 days [SD 13.3] and 32.1 days [13.5], with difference of -0.02 days [95% confidence interval -1.07 to 1.03]. Subgroup analysis showed that there remained no significant difference across different gestational ages, or for infants who were small for gestational age.

There was no significant difference noted in any of the safety secondary outcomes studied: survival to discharge (99.6% in both groups with adjusted risk ratio 1.00 [95% CI 0.99 to 1.01]), rates of hypoglycaemia (0.6 and 0.5 in full milk and gradual feeding arms), necrotising enterocolitis (0.4% and 0.6% in full milk and gradual feeding arms respectively, with adjusted risk ratio of 0.67 [95% CI 0.19 to 2.35], microbiologically confirmed or clinically suspected late-onset sepsis, or rates of breastfeeding at discharge or 6 weeks. Infants in the full milk feeds arm reached full enteral feeds quicker, had fewer days of intravenous fluids or parenteral nutrition, and had fewer incidents of peripheral and central access, and all of these outcomes reached statistical significance.

Outcome Full milk feeds group (n=1047) Gradual feeding group (n=1041) Adjusted risk ratio Hazard ratio 95% confidence interval

Survival to discharge 1030/1034 (99.6%) 1027/1031 (99.6%) 1.00 0.99 to 1.01

Necrotising enterocolitis (Bell stage 2 or 3) 4/1030 (0.4%) 6/1027 (0.6%) 0.67 – 0.19 to 2.35

Late onset sepsis 32/1031 (3.1%) 25/1026 (2.4%) 1.27 – 0.76 to 2.13

Any breastfeeding at discharge 447/1026 (43.6%) 434/1021 (42.5%) 1.04 – 0.94 to 1.14

Exclusive breastfeeding at discharge 109/1026 (10.6%) 117/1021 (11.5%) 0.95 – 0.74 to 1.2

Mothers breast milk at 6 weeks 301/697 (43.2%) 276/657 (43.0%) – – –

Number of glucose tests <2.2mmol/L before full enteral feeds (average) 0.6 0.5 – – – Time to full enteral feeds (days) 7.0 (SD 3.5) 7.9 (SD 3.9) – 2.35 1.91 to 2.89 Time with central line until discharge (days) 1.0 (SD 3.4). n= 1029 2.1 (SD 7.0) n= 1022 – -0.87 -1.31 to -0.42 Peripheral cannula until full milk feeding (days) 4.3 (SD 3.0). n=1019 5.3 (SD 2.9) n=1015 – -1.4 -1.29 to -0.78 CONCLUSION This study showed no significant difference in length of hospital stay, survival to discharge, or incidence of hypoglycaemia, necrotising enterocolitis or late-onset sepsis in infants over 30 weeks gestation who were commenced on full enteral milk feeds from the first day of life compared to those who received gradual increase in enteral feeds, but a statistically significant reduction in time taken to reach full enteral feeds, days of intravenous fluids or parenteral nutrition, and incidence of central and peripheral venous access.

COMMENTARY

Much of neonatal care of very preterm infants in the first days of life focuses around advancement of enteral feeding, with a need to balance the advancement of enteral feeds with minimising the risk of associated complications, such as feed intolerance and necrotising enterocolitis (NEC).1 The traditional approach has been one of caution, advocating slow advancement of enteral feeds to mitigate the risk of NEC.2 This cautious approach must be balanced against the need for optimum nutrition, particularly in infants who receive intravenous fluids for the remainder of their fluid volume, and the desire to reduce hospital stay. Adequate nutrition is of vital importance in preterm infants in order to optimise brain development. 3 Additionally, delay in introduction of enteral feeds is associated with problems with functional adaptation of the gastrointestinal tract and disruption in normal gut microbiome. 4

 

Previous smaller randomised controlled trials (RCTs) comparing early full milk feeds to gradual increase suggested that introduction of early full enteral feeds may reduce the length of hospital stay. 5, 6, 7 Of note, 2 of these 3 single-centre RCTs included infants of lower gestational ages, from 28+0 or 29+0 weeks. There was no significant difference in rates of NEC or spontaneous intestinal perforation between these groups, but numbers in this study were low and the studies were underpowered.

 

This current study by Ojha et al is a large, multicentre, randomised controlled study across 46 neonatal units in the United Kingdom. The study was well designed and appropriately powered to answer the primary outcome (length of hospital stay) and other important outcomes for both safety and clinical significance. Randomisation was stratified to ensure that key baseline characteristics were similar across the groups. Whilst it was not possible to blind parents or clinicians, data analysts were blinded to the allocation group. All babies were accounted for, including 1 in each group whose data were lost, and the authors showed >98% follow up of participants to discharge.

 

Contrary to previous studies, this study did not find any reduction in length of hospital stay in the full milk feed arm compared to the gradual feeding arm. However, secondary outcome data for safety parameters including incidence of NEC, late onset sepsis and hypoglycaemia was reassuring. Survival to discharge and breast feeding at discharge were similar in both groups.

 

Therefore, despite showing non-superiority in primary outcome of reduction in length of hospital stay, this study demonstrates that in preterm infants of 30+0 to 32+6 weeks gestation, in the absence of antenatal findings of both small for gestational age and reversed end diastolic flow, it is safe to introduce full enteral feeds from the first day of life. This is important because it justifies a change in clinical practice, and demonstrates that it is safe to commence enteral feeds in infants of this gestation without an initial period of trophic feeds.Introducing full enteral feeds from the first day of life reduces the need for parenteral nutrition or intravenous fluids and confers many advantages, including fewer invasive procedures, improved nutrition for those who would alternatively be receiving intravenous fluids, and reduced costs associated with administration of parenteral nutrition.

 

Future studies focusing on lowering the gestation at birth to 28+0 weeks, in line with the single-centre RCTs,5,7 and faster increment of feeds to achieve full nutritional requirement needs investigation.

REFERENCES

1. Kwok TC, Dorling J, Gale C. Early enteral feeding in preterm infants. Semin Perinatol. 2019; 43(7):151159.
2. Salas, A.A.; Ojha, S. Exclusive enteral nutrition in preterm infants: How early is too early? Semin. Fetal Neonatal Med. 2025; 30:101631.
3. Keunen K, van Elburg RM, van Bel F, Benders MJ. Impact of nutrition on brain development and its neuroprotective implications following preterm birth. Pediatr Res. 2015 Jan;77(1-2):148-55.
4. The SIFT Investigators Group Early enteral feeding strategies for very preterm infants: current evidence from Cochrane reviews Archives of Disease in Childhood – Fetal and Neonatal Edition 2013;98:F470-F472.
5. Razzaghy J, Shukla VV, Gunawan E, Reeves A, Nguyen K, Salas AA. Early and exclusive enteral nutrition in infants born very preterm. Arch Dis Child Fetal Neonatal Ed 2024; 109: 378–83.
6. Alshaikh BN, Hassan O, Alburaki W, et al. Early exclusive enteral feeding in 30–33 weeks gestation infants: a randomized controlled trial. J Perinatol 2025; 45: 628–34
7. Jajoo M, Singh A, Arora N et al. Early total versus gradually advanced enteral nutrition in stable very-low-birth-weight preterm neonates: a randomized, controlled trial Indian J Pediatr. 2022; 89:25-30

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Deferred Cord Clamping With High Oxygen in Extremely Preterm Infants: A Randomized Clinical Trial. Katheria et al., JAMA Pediatrics 2025 Sep 1;179(9):971-978. doi: 10.1001/jamapediatrics.2025.2128. PMID 40690234

Reviewed By:

 Simone Pratesi

University of Florence

Careggi University Hospital

Florence, Italy

simone.pratesi@unifi.it

Design:

Double-blinded, multicenter randomized clinical trial.
Allocation: Infants were randomized to receive either 100% oxygen (high oxygen group) or 30% oxygen (low oxygen group) during deferred cord clamping (DCC), using a concealed oxygen blender.

Blinding:

Blinding was maintained for both clinical teams and parents by covering the oxygen blender settings. Treatment assignment was concealed until after randomization.
Follow-up Period: Primary outcomes assessed at 5 minutes of life; exploratory outcomes followed through NICU stay and up to 40 weeks postmenstrual age.

Setting:

Three hospital centers in California: two university hospitals and one private medical center.

Patients (Inclusion/Exclusion Criteria):

Inclusion:
• Infants born at 22 to 28 weeks’ gestational age
• Parental consent obtained before delivery

Exclusion:
• Rupture of membranes before 20 weeks
• Monochorionic twins with twin-to-twin transfusion syndrome
• Placenta accreta
• Major congenital anomalies

Intervention:

During DCC (90 seconds), infants received CPAP or PPV via face mask with either 100% or 30% oxygen. After cord clamping, all infants were resuscitated per standard guidelines starting at 30% oxygen.

Primary Outcome:

Proportion of infants achieving SpO₂ ≥80% by 5 minutes of life

Main Exploratory Outcomes:
• Peripheral oxygen saturation (SpO₂) at 5 minutes
• Heart rate measurements during the first 10 minutes
• Delivery room interventions (intubation, surfactant, epinephrine)
• Cerebral oxygenation and blood pressure in the first 24 hours
• Intraventricular hemorrhage (IVH)
• Mortality before 40 weeks PMA
• Bronchopulmonary dysplasia (BPD)
.
Analysis and Sample Size:
Sample size:140 infants (70 per group);

Power:
80% to detect a 20% absolute a 20% absolute reduction in the incidence of oxygen saturation <80% at 5 minutes after birth

Statistical methods:
Chi-square, Fisher’s exact test, t-test, Mann-Whitney U, logistic regression, generalized estimating equations (GEE)

Patient Follow-up (% Included in Analysis):
100% of randomized infants were included in the intention-to-treat analysis.

MAIN RESULTS:

• 69% of infants in the high oxygen group achieved SpO₂ ≥80% by 5 minutes vs. 39% in the low oxygen group (adjusted OR 3.74; 95% CI, 1.80–7.79; P < .001)
• No significant differences in severe IVH, mortality, or other adverse outcomes
• Time to reach target SpO₂ was shorter in the high oxygen group
• No increase in systemic or cerebral hyperoxia observed

CONCLUSION:

Administering 100% oxygen during DCC significantly reduced early hypoxemia in extremely preterm infants without increasing morbidity. These findings support reconsideration of oxygen strategies during DCC and warrant larger trials to assess long-term outcomes.

COMMENTARY

This is a very interesting and well-designed trial with several strengths. Deferred cord clamping (DCC) for at least 120 seconds is associated with the highest likelihood of reducing mortality in preterm newborns (1). However, such prolonged DCC is feasible only when the newborn does not require respiratory support within the first minute of life.

 

Recently, three randomized controlled trials have compared resuscitation with an intact cord (lasting 2 to 6 minutes) to either deferred cord clamping (30–60 seconds) or umbilical cord milking (2-4). All three trials failed to show an improvement in the primary outcome. This raises an important question: why does intact cord resuscitation not improve outcomes in preterm infants compared to resuscitation after DCC or milking?

 

Possible explanations include reduced resuscitation quality at the bedside (with greater hypothermia), technical difficulty and variable expertise (5), and persistent early hypoxia, with low oxygen saturation at 5 minutes of life linked to adverse outcomes in very preterm infants (6).

 

Recent animal studies provide new physiological insights (7,8). In preterm lambs, brief ventilation with 100% oxygen while the umbilical cord remains intact promotes an increase in pulmonary blood flow without inducing systemic hyperoxia (7). This probably occurs because the newborn reduces oxygen uptake across the placenta, and when oxygen levels exceed fetal needs, the mother effectively acts as an ‘oxygen sink’ (8).

 

In the current trial, a peripheral oxygen saturation of 80% at 5 minutes was achieved more frequently (69% vs. 39%) when preterm infants were resuscitated on the cord with 100% oxygen for up to 90 seconds, compared to 30 seconds. This may reflect the beneficial role of 100% oxygen in enhancing pulmonary vasodilation and blood flow, as seen in lambs, and potentially in facilitating glottic opening and pulmonary ventilation. However, the similar rates of positive pressure ventilation (PPV) before and after cord clamping, along with comparable intubation rates between the low‑ and high‑oxygen groups, indicate that the beneficial effects of oxygenation on the initiation of spontaneous breathing or glottic opening do not appear to translate into clinical advantages. The two following considerations could at least partially explain this result. The paper fails to indicate how many infants were not breathing after birth, and this subgroup might have benefited more from receiving 100% oxygen. This is a critical consideration, especially since the Vent First trial (2) reported a high proportion (48%) of infants who were not breathing adequately at birth, and this subgroup appeared to benefit more from intact cord resuscitation with 30% oxygen. Moreover, it should be kept in mind that clinicians often underestimate spontaneous breathing and are frequently quick to initiate PPV in preterm infants, which makes it more difficult to detect differences in PPV rates between groups (9).

 

Administering 100% oxygen with the cord intact improves early oxygenation in preterm infants without increasing the risk of short-term morbidity. Future larger trials on intact cord resuscitation, conducted in centers with established expertise in this procedure, should incorporate the short-term use of 100% oxygen into their study design. This may help demonstrate improved outcomes in infants resuscitated with an intact cord.

REFERENCES

1) Seidler AL, Libesman S, Hunter KE, Barba A, Aberoumand M, Williams JG, Shrestha N, Aagerup J, Sotiropoulos JX, Montgomery AA, Gyte GML, Duley L, Askie LM; iCOMP Collaborators. Short, medium, and long deferral of umbilical cord clamping compared with umbilical cord milking and immediate clamping at preterm birth: a systematic review and network meta-analysis with individual participant data. Lancet. 2023 Dec 9;402(10418):2223-2234. doi: 10.1016/S0140-6736(23)02469-8.
2) Fairchild KD, Petroni GR, Varhegyi NE, et al. Ventilatory assistance before umbilical cord
clamping in extremely preterm infants: a randomized clinical trial. JAMA Netw Open.
2024;7(5):e2411140. doi:10.1001/jamanetworkopen. 2024.11140
3) Pratesi S, Ciarcià M, Boni L, et al. Resuscitation with placental circulation intact compared with cord milking: a randomized clinical trial. JAMA Netw Open. 2024;7(12):e2450476. doi:10.1001/jamanetworkopen.2024.50476
4) Knol R, Brouwer E, van den Akker T, et al. Physiological versus time based cord clampingin very preterm infants (ABC3): a parallel-group, multicentre, randomised, controlled superiority trial. Lancet Reg Health Eur. 2025;48:101146. doi:10.1016/j.lanepe.2024.101146
5) Knol R, Vermeulen MJ, de Boode WP, et al; ABC3 Research group. Experience with physiological based cord clamping is associated with increased effect size: a post-hoc analysis of the ABC3 trial. Resuscitation. 2025 Dec 17:110921. doi: 10.1016/j.resuscitation.2025.110921.
6) Oei JL, Finer NN, Saugstad OD, Wright IM, Rabi Y, Tarnow-Mordi W, Rich W, Kapadia V, Rook D, Smyth JP, Lui K, Vento M. Outcomes of oxygen saturation targeting during delivery room stabilisation of preterm infants. Arch Dis Child Fetal Neonatal Ed. 2018 Sep;103(5):F446-F454. doi: 10.1136/archdischild-2016-312366
7) Lakshminrusimha S, Vali P, Chandrasekharan P, Rich W, Katheria A. Differential Alveolar and Systemic Oxygenation during Preterm Resuscitation with 100% Oxygen during Delayed Cord Clamping. Am J Perinatol. 2023 Apr;40(6):630-637. doi: 10.1055/s-0041-1730362.
8) Cannata ER, Dekker J, Hooper SB, et al. Transplacental oxygen transfer during physiological-based cord clamping in preterm lambs. J Appl Physiol (1985). 2025 Dec 1;139(6):1517-1526. doi: 10.1152/japplphysiol.00641.2025.
9) Diggikar S, Ramaswamy VV, Koo J, et al. Positive Pressure Ventilation in Preterm Infants in the Delivery Room: A Review of Current Practices, Challenges, and Emerging Technologies. Neonatology. 2024;121(3):288-297. doi: 10.1159/000537800.

The post EBNEO Commentary: Does high oxygen intact cord ventilation improve early oxygenation in preterm infants? appeared first on Evidence-Based Neonatology.

Salas AA, Gunawan E, Jeffcoat S, Nguyen K. Early full enteral nutrition with fortified milk in very preterm infants: a randomized clinical trial. Am J of Clin Nutr 2025; 121(5):1117-1123. PMID 39986385.

REVIEWED BY

Kaitlin Hannan, MD
Emory University School of Medicine
Children’s Healthcare of Atlanta
Khannan@emory.edu

Kera McNelis, MD, MS
Emory University School of Medicine
Children’s Healthcare of Atlanta
Kmmcnel@emory.edu

TYPE OF INVESTIGATION

Treatment

QUESTION

In infants born at 29 0/7 weeks to 33 6/7 weeks gestation (Population), does enteral feeding fortification at 4-7 days (Intervention) vs. 7-10 days of life (Comparison) lead to improved free-fat mass z-scores (Outcome) at ~ 21 days postnatal age (Timeframe)?

METHODS

• Design: Randomized controlled trial.
• Allocation: Participants were allocated in a 1:1 ratio.
• Blinding: Unmasked.
• Follow-up period: Infants were followed through 36 weeks post menstrual age (PMA) or until discharge if this occurred prior to 36 weeks PMA.
• Setting: Conducted at a single center level IV NICU between November 2022 and November 2023.
• Patients: 80 infants.
o Inclusion criteria: Infants born between 29 0/7 and 33 6/7 weeks gestation with birthweight <1800g who received feeding volumes 60-80 mL/kg/d within the first 36 hours after birth
o Exclusion criteria: Birth weight <5th percentile for gestational age, major chromosomal or congenital anomalies, terminal illness.
• Intervention: Enteral feeds of human milk were fortified at days 4-7 of life (intervention) or days 10-14 of life (control). Feeding practices otherwise followed unit protocol with enteral advancement to target ≥150mL/kg/day. Infants <1500g received parenteral dextrose with amino acids and infants >1500g received dextrose containing fluids in combination with enteral nutrition to meet daily total fluid goal.
• Outcomes: Body composition and growth data was collected at ~21 days of life and at 36 weeks or discharge.
o Primary outcome: Free-fat mass (FFM) z-score on ~ day of life 21 obtained utilizing air-displacement plethysmography.
o Secondary outcomes: Weight, length, and head circumference measurements and z-scores were collected at birth, at the time of FFM assessment, and at 36 weeks PMA or discharge. Rates of necrotizing enterocolitis (NEC), spontaneous intestinal perforation, death, and feeding intolerance were also collected.
• Analysis and Sample Size: To detect a 0.5 difference in FFM z-score at a 0.05 significant level and 80%, 72 patients were required. 80 patients were recruited to account for attrition. Differences in FFM z-scores were calculated in means and 95% confidence intervals and then compared with an unadjusted t-test. Secondary efficacy endpoints were compared with t-tests or Wilcoxon tests, depending on normality of distribution. Relative risk with 95% confidence interval calculations were utilized for categorical variables. Chi-square test or Fisher’s exact test were applied to assess differences in categorical efficacy and safety outcomes.
• Patient follow-up: Of the 80 randomized infants, 96% were included in the statistical analysis.

MAIN RESULTS

There were no statistically significant differences between the two groups’ nutritional practices, such as duration of parenteral nutrition, aside from timing of fortification and feeding volume at time of fortification.

Z-score group comparisons for all growth parameters were not statistically significant at any time throughout the study period.

CONCLUSION

The authors concluded that earlier enteral fortification does not lead to improved FFM z-scores at ~21 days of life. However, there was a statistically significant difference with better length growth (reported in cm) at multiple time points, including 36 weeks corrected or discharge, for infants who had received earlier fortification.

COMMENTARY

This trial, Early full enteral nutrition with fortified milk in very preterm infants: a randomized clinical trial, assessed the impact of early human milk fortification on fat-free mass z-scores. A previous study by these investigators demonstrated benefit to early and exclusive enteral feeding, with reduction or avoidance of intravenous fluid, a novel strategy in high resource settings .[1] However, unfortified human milk does not contain sufficient protein and other nutrients to meet the needs of a growing neonate or match fetal accretion.[2] This trial assesses the practice of early fortification in the context of early enteral feeding. With earlier and possibly more prolonged use of unfortified human milk, the greater the cumulative nutrient deficit accrues. In fact, this cumulative deficit is visually depicted in Figure 2. Sufficient nutrition is needed to promote growth, health and improved outcomes. The investigators of this study likely chose their primary outcome of increased fat-free mass (FFM) z-score because it reflects the link between promoting growth and neurodevelopment. Greater accrual of FFM has been associated with larger brain size and improved neurocognition [3].

 

Despite the potential benefits of fortification, there are reservations by clinicians about tolerance and safety. Feeding intolerance may have nonspecific clinical signs, and there is worry for the risk of NEC. There might have been a reduced anticipated effect size if clinicians had reservations about early fortification, as the intervention was unmasked. The transiently lower feeding volume in the intervention (early fortification) group and smaller than expected differences in fortification timing may have reduced the effect size. The differences in days of feeding fortification were not different between the groups.

 

Ultimately, this study did not find a difference in the primary outcome of FFM z-score and it also didn’t find a difference in other outcomes. Although the effect size challenges in this study were important, there are other possibilities. A limitation of this trial is that it did not report the proportion or volumes of donor human milk (DHM) used in each group. This was indirectly described in Figure 2, where DHM and maternal milk were assigned different assumed macronutrient content. However, there are hormonal and bioactive differences in human milk beyond macronutrient content that are only beginning to be understood.[4] Earlier feeding advancement requires a greater volume of human milk provision earlier after preterm birth. There may be physiologic limitations to milk expression that lead to insufficient supply by the preterm parent and reliance on DHM supplementation. Certain parental comorbidities are a known risk for delayed lactogenesis, and infants of those parents may receive more DHM supplementation.[5] Twelve of the subjects were infants of diabetic mothers. Other comorbidities associated with delayed lactogenesis, such as obesity and thyroid dysfunction, were not reported in this trial.

 

Ultimately, this single-center trial was well done and chose an important primary outcome of FFM instead of a less specific growth goal. [6] A larger multicenter trial may be powered to detect differences in outcomes with fortification interventions. There may be population-based differences in environment and social determinants of health that have an interaction effect between nutrition and growth outcomes. Continuing to refine best nutrition practices with future research efforts initial enteral feeding selection and the rate of advancement towards full fortified feeding could ultimately improve preterm infant outcomes.

REFERENCES

1. Razzaghy J, et al. Early and exclusive enteral nutrition in infants born very preterm. Arch Dis Child Fetal Neonatal Ed 2024; 109(4): 378-83.
2. Koletzko B, et al. Defining Nutritional Needs of Preterm Infants. World Rev Nutr Diet 2021; 122: 5-11.
3. Viswanathan S, et al. Body Composition in Preterm Infants: Current Insights and Emerging Perspectives. Children 2025; 12(1): 53.
4. Marousez L, et al. Metabolic hormones in human breast milk are preserved by high hydrostatic pressure processing but reduced by Holder pasteurization. Food Chem 2022; 377: 131957.
5. Farah E, et al. Impaired Lactation: Review of Delayed Lactogenesis and Insufficient Lactation. Journal of Midwifery & Women’s Health 2021; 66(5): 631-40.
6. Fenton TR, Merlino Barr S, Elmrayed S, Alshaikh B. Expected and Desirable Preterm and Small Infant Growth Patterns. Advances in Nutrition. 2024/06/01/ 2024;15(6):100220. doi:https://doi.org/10.1016/j.advnut.2024.100220

The post EBNEO Commentary: Association Between Early Fortification and Body Composition in Very Preterm Infants appeared first on Evidence-Based Neonatology.

Teofili L, Papacci P, Pellegrino C, Molisso R, et al. Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial (BORN trial). eClinicalMedicine. 2025;87:103426. doi:10.1016/j.eclinm.2025.103426. PMID 40838199

REVIEWED BY

Mahmud Benoune, MBChB, MRCPCH
Neonatal Registrar, NHS
Email: mahmmoudbenoun@gmail.com

TYPE OF INVESTIGATION

Treatment / Prevention

QUESTION

In extremely preterm infants (24–27⁶ weeks’ gestation), do red blood cell transfusions derived from cord blood (CB-RBCs), compared with adult donor RBCs (A-RBCs), reduce the risk or severity of retinopathy of prematurity (ROP)?

METHODS

Design: Multicenter, double-blind, randomized controlled trial (Italy, 2021–2024).
Allocation: 1:1 randomization, concealed.
Blinding: Investigators, clinicians, and parents blinded to allocation.
Follow-up: Until 40 weeks’ postmenstrual age or discharge.
Setting: Eight tertiary NICUs.
Patients: Infants 24–27⁶ weeks GA, <32 weeks PMA, transfusion-naïve at enrolment. Excluded if congenital anomalies or severe early sepsis. Intervention: Transfusions with leukodepleted, irradiated, HbF-rich cord blood RBCs.
Comparison: Standard adult donor RBCs.
Primary Outcome: Severe ROP (stage ≥ 3 or plus disease).
Secondary Outcomes: ROP needing treatment, BPD, NEC, mortality, transfusion efficacy, and safety.
Analysis / Sample size: 142 infants randomized (73 control, 69 intervention). ITT and per-protocol analyses; study powered for 50% ROP reduction.
Patient follow-up: >95% included in final analyses.

MAIN RESULTS

– Neonates receiving cord RBC transfusions had significantly lower rates of severe ROP progression compared to controls.
– The need for rescue interventions (laser/anti-VEGF) was reduced in the cord RBC group.
– No excess in adverse events, mortality, or systemic morbidity was reported in the intervention group.
– Findings support biological plausibility, as cord RBCs contain higher fetal hemoglobin levels, potentially reducing oxidative stress.

CONCLUSION

Cord blood RBC transfusions were feasible and safe. In per-protocol analysis, they were associated with reduced severe ROP and BPD, suggesting a protective role of fetal hemoglobin (HbF). Findings require confirmation in larger, adequately powered studies.

COMMENTARY

This multicenter randomized trial explores an innovative approach to transfusion in preterm neonates—preserving fetal hemoglobin (HbF) via cord blood–derived RBCs to mitigate oxidative complications such as ROP and BPD. The investigators deserve recognition for demonstrating both feasibility and safety of cord blood transfusions in ELGANs, addressing a major logistical challenge in neonatal transfusion medicine.

 

Methodologically, the study was robust—randomized, blinded, and multicenter—with clinically meaningful endpoints. The biological rationale is sound: HbF’s high oxygen affinity may reduce retinal hyperoxia and free radical–mediated injury. The results are promising—no severe ROP or BPD among infants who received only cord blood—but interpretation must remain cautious.

 

Nearly half of the intervention group received mixed transfusions due to unit shortages, severely limiting statistical power in the ITT analysis. The striking benefit in the per-protocol subgroup, though compelling, was based on only 17 infants and is therefore hypothesis-generating rather than definitive. Additionally, logistical and cost barriers—cord collection, processing, and inventory constraints—would currently prevent large-scale adoption.

 

This trial aligns with previous observational data linking lower HbF levels to higher ROP and BPD risk (1,2). It adds randomized evidence supporting a potential causal mechanism but falls short of establishing clinical efficacy. Future studies should ensure adequate HbF exposure, standardized transfusion thresholds, and long-term visual and neurodevelopmental follow-up.

 

The clinical message is that cord-derived transfusions may hold protective potential, but the evidence remains preliminary. Neonatal units should continue to follow existing restrictive transfusion guidelines while further multicenter trials clarify the role of HbF-preserving strategies.

 

REFERENCES

1. Aher SM, Ohlsson A. Early versus late erythrocyte transfusion for preterm infants. Cochrane Database Syst Rev. 2020;2:CD005090.
2. Dani C, et al. Low fetal hemoglobin levels and risk of retinopathy of prematurity. Pediatr Res. 2021;90:1242–8.
3. Teofili L, et al. eClinicalMedicine. 2025;87:103426.
4. Stutchfield CJ, et al. Transfusion thresholds and outcomes in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2022;107:F72–F79.

The post EBNEO Commentary: Cord Blood Red Cell Transfusions and Severe Retinopathy of Prematurity in Preterm Neonates appeared first on Evidence-Based Neonatology.

Peña-Moreno A, Fernández-Monteagudo B, Gómez-Montes E, Tebar-Cuesta MI, Martín-Arriscado-Arroba C, Alba-Raya N, Moral-Pumarega MT, Pallás-Alonso CR, Piris-Borregas S. Immediate Kangaroo Mother Care Was More Feasible for Preterm Infants After Vaginal Than Caesarean Deliveries in a Spanish Neonatal Unit. Acta Paediatr. 2025 Jun 14;114(9):2397–9. doi: 10.1111/apa.70172. Epub ahead of print. PMID: 40515612; PMCID: PMC12336942.

REVIEWED BY

Le Khac Linh
College of Health Sciences, VinUniversity, Hanoi, Vietnam
Dr.linhkhac@gmail.com

Apoorva S Sachidanand
Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Apoorvaasachi@gmail.com

Phan Vinh Nghi
Department of Obstetrics and Gynecology Nam Can Tho University, Can Tho City, Vietnam
Pvnghi1994@gmail.com

Nguyen Tien Huy
Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
School of Medicine and Pharmacy, Duy Tan University, Da Nang, Vietnam
Nguyentienhuy4@duytan.edu.vn

TYPE OF INVESTIGATION

Quality improvement.

QUESTION

Among preterm infants born at ≥28 weeks’ gestation, is immediate Kangaroo Mother Care (KMC) feasible and safe compared to routine incubator-based stabilization, and does feasibility differ between vaginal and Caesarean deliveries?

METHODS

• Design: Single-center quality improvement study.
• Allocation: Non-randomized, based on feasibility and clinical condition.
• Blinding: Not applicable.
• Follow-up period: Immediate postnatal stabilization up to NICU transfer.
• Setting: Tertiary-level NICU, 12 de Octubre University Hospital, Madrid, Spain.
• Patients: Preterm infants born 28–36 weeks (n=96 eligible; 47 received KMC). Excluded if FiO₂ >40%, need for intubation, congenital malformations, triplets, maternal instability, or general anesthesia.
• Intervention: Immediate skin-to-skin KMC (median initiation 10 min after birth; up to 2 hrs vaginal, max 30 min Caesarean).
• Outcomes: Primary – feasibility of immediate KMC; Secondary – interruptions, safety (temperature, respiratory stability), transfer mode.
• Analysis & Sample Size: Descriptive comparison; subgroup analysis <30 weeks or <1000 g.
• Patient follow-up: 47 infants (49% of candidates) were included in analysis.

MAIN RESULTS

• Median gestation: 33+1 weeks; median birth weight: 1600 g.
• KMC initiated at median of 10 minutes after birth.
• Early interruption (<20 min): 8.5%, none due to respiratory deterioration.
• Caesarean birth significantly associated with shorter KMC duration (median 25 min vs 30 min, p=0.02).
• 66.7% transferred via KMC (mostly with father); 33.3% in incubator.
• Temperatures remained stable; colostrum collected in 15.6%.

CONCLUSION

Immediate KMC for preterm infants ≥28 weeks is feasible and safe, but more limited after Caesarean deliveries due to operating theatre logistics and maternal transfer requirements

COMMENTARY

This study conducted in a Spanish tertiary NICU aimed to evaluate the feasibility of immediate Kangaroo Mother Care (iKMC) for preterm infants born at 28 weeks’ gestation or later. The authors reported that iKMC for preterm infants ≥28 weeks is feasible and safe, but more limited after Caesarean deliveries due to operating theatre logistics and maternal transfer requirements; This pioneering effort provides important insights while also highlighting areas where further clarification and development would strengthen the evidence base.

 

First, additional detail on how parental consent was obtained would enhance transparency. Because preterm infants are very fragile and care protocols have been changed for research, clarifying the consent process would be valuable for both ethical considerations and reproducibility.

 

Second, 49 out of 96 infants (51.04%) were excluded from analysis. The high exclusion rate introduces potential selection bias and complicates the applicability of the results in other contexts, particularly in low- and middle-income nations where the newborn care system may be significantly different in structure and staffing.

 

Third, the authors reported that iKMC was more practicable following vaginal deliveries. The shorter iKMC sessions after C-sections, were mostly because of regulations at the hospital and not enough staff or training in the post-anesthesia care unit. Although these findings reflect local contextual barriers, they underscore the importance of training, staffing, and perioperative adaptations to make iKMC equally feasible after both vaginal and Cesarean deliveries. The conclusion that iKMC was more feasible following vaginal births is also not well supported by the data for the group of under 30 weeks’ gestation, as only 2 of the 10 infants in this subgroup were delivered vaginally. A larger sample would be needed to substantiate this observation.

 

The study would be strengthened by a clearer definition of what was meant by “feasibility”—whether it referred the duration of iKMC sessions, the infant’s physiological stability, staff compliance, or parental involvement. Establishing a clear definition is essential for comparing studies and drawing policy-relevant conclusions. The reduced iKMC durations following Caesarean deliveries seem to indicate institutional barriers rather than general problems. Similarly, while the study focused on short-term safety outcomes (e.g., temperature and oxygen stability), future investigations could expand such as neurodevelopment, infection rates, or breastfeeding success; It also did not compare neonates receiving iKMC with those placed in incubators, which would have provided additional insight into the relative advantages and disadvantages of both approaches.

 

Another noteworthy finding is fathers did 73.1% of iKMC transfers, but the study did not report whether the type of caregiver affected the infant’s stability, bonding, or the mother’s recovery. This was a missed chance to learn more about how fathers can help care for newborns.

 

In summary, this study provides valuable early evidence that iKMC can be implemented safely in preterm infants from 28 weeks’ gestation onwards. At the same time, it highlights practical considerations—consent processes, staffing, perioperative adaptations, and consistent definitions of feasibility—that will be crucial for broader adoption. Future research should continue to expand inclusion criteria, measure both short- and long-term outcomes, and address staffing and training barriers to ensure equitable access to iKMC across all delivery settings.

REFERENCES

None

FUNDING

None

CONFLICTS OF INTEREST

None

The post EBNEO Commentary: Immediate Kangaroo Care Feasible for Preterm Infants After Vaginal Rather Than Caesarean Deliveries appeared first on Evidence-Based Neonatology.