In recent years, the medical research community has long acknowledged a troubling disparity in neonatal outcomes: the male disadvantage in bronchopulmonary dysplasia (BPD). This chronic lung condition, primarily afflicting premature infants who require oxygen therapy or mechanical ventilation, has been consistently linked with worse prognoses for male newborns compared to females. However, the newest study published by Dassios and Roehr, titled “Reconsidering the male disadvantage in bronchopulmonary dysplasia: three exceptions,” challenges this prevailing narrative by meticulously dissecting instances where the typical gender-related vulnerability is not observed. This groundbreaking work compels a reassessment of gender biases in neonatal pulmonary biology and paves the way for more nuanced therapeutic approaches.
Classically, bronchopulmonary dysplasia develops as a multifactorial pathology where the interplay of premature birth, mechanical ventilation, oxygen toxicity, and inflammation culminates in disrupted alveolar and vascular development. Male infants have repeatedly been reported to experience more severe disease progression, attributed to factors such as delayed lung maturation, hormonal influences, and differing immune responses. However, Dassios and Roehr’s exploration suggests that these patterns are not universally applicable, as they identify three distinct clinical and biological contexts in which female infants may instead bear equal or greater susceptibility to BPD-related complications.
The first exception concerns the gestational age bracket of extremely preterm infants born before 28 weeks’ gestation. The authors observe that within this subgroup, the severity and incidence of bronchopulmonary dysplasia appear less skewed by sex. Advanced statistical analyses of large neonatal cohorts reveal overlapping outcome distributions for males and females when meticulously controlling for confounders such as birthweight, antenatal steroid administration, and perinatal infection rates. This suggests that at the threshold of viability, the pathophysiologic insults overwhelm subtle sex-related differences, equalizing risk profiles.
Next, Dassios and Roehr highlight environmental and iatrogenic factors as modulators capable of neutralizing male vulnerability. In neonatal intensive care units adhering strictly to lung-protective ventilation strategies and employing non-invasive respiratory support, the incidence disparity between sexes diminishes. The authors hypothesize that optimal clinical interventions may buffer male infants from their otherwise inherent biological disadvantages, underscoring the importance of uniform evidence-based care protocols. This insight has practical ramifications for neonatal management, potentially guiding resource allocation and intervention timing to minimize overall lung injury.
A particularly surprising third exception is noted in the subset of infants exhibiting specific genetic polymorphisms implicated in inflammation and tissue remodeling pathways. Through genomic and transcriptomic profiling, the study identifies rare genetic variants that predispose female preterm neonates to heightened inflammatory responses, accelerating lung tissue damage and fibrosis typical of BPD. These findings complicate the simplistic sex dichotomy and accentuate individualized medicine’s imperative in neonatal care. Future research into genotype-phenotype correlations may thus enable tailored treatment regimens, attenuating the male bias by addressing female-specific vulnerabilities.
Underlying these exceptions is a broader reconsideration of the biological mechanisms differentiating male and female lung development. The authors delve into the nuanced roles of sex hormones, particularly estradiol and testosterone, in modulating pulmonary vascular growth, surfactant production, and immune cell activation. Notably, testosterone’s immunosuppressive effects might paradoxically limit inflammation-induced injury, although it concurrently delays lung maturation. Conversely, estrogen signaling exerts generally protective effects but can amplify pro-inflammatory cascades under certain pathological stimuli, potentially explaining some of the female exceptions observed.
Furthermore, epigenetic influences emerge as critical contributors to the complex sex-dependent phenotypes in BPD. Environmental exposures in the perinatal period induce lasting changes in DNA methylation and histone modification patterns, which differ subtly between sexes and govern gene expression dynamics relevant to lung repair and inflammation. Such epigenetic landscapes, together with transcriptomic signatures detailed in the paper, provide a rich substrate for future therapeutic exploitation. Pharmacologic agents targeting epigenetic regulators could modulate disease trajectories asymmetrically by sex, heralding a new era of precision neonatology.
The authors also call attention to the heterogeneity in inflammatory biomarkers and immune cell profiles in the preterm lung. Males and females exhibit differential leukocyte infiltration, cytokine secretion profiles, and macrophage polarization patterns following injurious stimuli. These immunological disparities likely influence the progression and resolution of lung injury. By dissecting these pathways, Dassios and Roehr open the door to innovative anti-inflammatory and immunomodulatory therapies, potentially capable of rebalancing sex-specific susceptibilities.
Importantly, the study questions the reliance on population-level epidemiological data to formulate care guidelines. The identification of three exceptions encourages a stratified approach rather than a blanket application of sex-based risk assumptions. This recalibration is vital for clinical decision-making, as it encourages vigilance for female infants who might otherwise be overlooked under the “male disadvantage” paradigm, ensuring equitable vigilance and intervention.
Moreover, the authors emphasize the dynamic interplay between prenatal exposures—such as maternal smoking, infection, and corticosteroid use—and neonatal sex in shaping BPD risk. These prenatal factors interact differently with male and female fetal lung development, influencing susceptibility windows and lesion characteristics. Understanding these interactions not only broadens the scope of prevention strategies but also facilitates the design of targeted maternal-fetal interventions that holistically consider sex-specific trajectories.
Dassios and Roehr’s findings also shed light on long-term pulmonary outcomes beyond the neonatal intensive care unit. Bronchopulmonary dysplasia survivors face a spectrum of chronic respiratory morbidities, including asthma-like symptoms, reduced lung function, and pulmonary hypertension. The nuanced sex differences illuminated by this study may parallel divergent life-course trajectories, necessitating sex-aware monitoring and rehabilitation programs. This continuum of care perspective underscores the importance of early risk profiling in optimizing long-term health.
From a methodological standpoint, this research utilizes cutting-edge statistical modeling, including machine learning algorithms applied to large multinational datasets, enabling the recognition of subtle sex-based patterns masked in smaller or less complex analyses. The integration of clinical, genomic, epigenetic, and immunologic data exemplifies the multidisciplinary approaches now essential for elucidating complex neonatal diseases. Such comprehensive frameworks will likely become the standard in perinatal research.
The challenge now lies in translating these paradigm-shifting insights into practice. The authors advocate for clinical trials incorporating sex as a key stratification variable, ensuring that emerging therapies address sex-specific needs. Moreover, the potential for genetic screening at birth, guided by the polymorphisms identified, introduces ethical and logistic considerations that must be navigated carefully to balance benefits against risks of overmedicalization.
In conclusion, Dassios and Roehr’s study represents a landmark reconsideration of the “male disadvantage” in bronchopulmonary dysplasia, revealing important exceptions that disrupt previously accepted dogma. Their work advocates for a more sophisticated appreciation of sex differences, one that incorporates genetic, epigenetic, hormonal, and environmental complexity. By doing so, this research not only improves our understanding of neonatal lung disease pathophysiology but also charts a course toward personalized neonatal care that optimizes outcomes for all infants, regardless of sex.
As neonatal medicine evolves, this novel perspective may catalyze further investigations into sex-specific pathways in other preterm complications, fostering a holistic reexamination of perinatal health disparities. Ultimately, the promise of precision neonatology—with therapies tailored to the unique biology of each newborn—edges closer to reality through studies such as this, which insistently challenge established assumptions and expand the frontiers of pediatric respiratory research.
Subject of Research: Bronchopulmonary dysplasia (BPD) sex disparities in premature infants and exceptions to male disadvantage
Article Title: Reconsidering the male disadvantage in bronchopulmonary dysplasia: three exceptions
Article References:
Dassios, T., Roehr, C.C. Reconsidering the male disadvantage in bronchopulmonary dysplasia: three exceptions.
Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04238-z
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