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Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition)

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 11480

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Dr. Fumihiko Namba

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Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan
Interests: bronchopulmonary dysplasia; patent ductus arteriosus; preterm infants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In light of the remarkable advancements in perinatal and neonatal care, we have witnessed a significant reduction in neonatal and infant mortality rates. Yet, challenges persist, as some infants grapple with neurological, respiratory, gastrointestinal, and other complications despite receiving standard treatments. While fetal therapy, cell therapy, therapeutic medical gases, and therapeutic monoclonal antibodies have emerged as promising avenues for addressing neonatal diseases, there remains a pressing need for a deeper comprehension of the underlying pathophysiology and the development of novel treatment modalities tailored to this intricate landscape.

We invite distinguished researchers to contribute their original research and comprehensive review articles that delve into the recent breakthroughs in understanding the pathophysiology of neonatal diseases. Additionally, we are eager to receive submissions that shed light on innovative therapeutic approaches and their profound impact on the well-being of afflicted children. We also extend an invitation to researchers exploring the molecular mechanisms underpinning pharmacological interventions in neonatal care.

We earnestly seek original, high-quality contributions that have not been previously published elsewhere nor are currently under review by other esteemed journals or peer-reviewed conferences. Your expertise and insights will undoubtedly enrich the discourse surrounding neonatal healthcare and ultimately pave the way for improved outcomes in neonatal medicine.

We look forward to receiving your valuable contributions and fostering a platform for exchanging knowledge that will undoubtedly shape the future of neonatal care.

Dr. Fumihiko Namba
Guest Editor

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Keywords

fetal therapy
neonatal diseases
pathophysiology
innovative therapeutic approaches

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Published Papers (8 papers)

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Research

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16 pages, 1190 KB

Open AccessArticle

Neuropsychomotor Development of Children Exposed to SARS-CoV-2 in Utero During COVID-19 Pandemic

by Felipe Motta, Maria Eduarda Canellas-de-Castro, Geraldo Magela Fernandes, Lizandra Moura Paravidine Sasaki, David Alves de Araújo Júnior, Alberto Moreno Zaconeta, Ângelo Pereira da Silva, Ciro Martins Gomes, Cleandro Pires Albuquerque, Ismael Artur Costa-Rocha, Janaina Araújo Teixeira Santos, José Alfredo Lacerda De Jesus, Karina Nascimento Costa, Laila Salmen Espindola, Licia Maria Henrique da Mota, Lucas Lauand, Luiz Cláudio Gonçalves de Castro, Marcelo Antônio Pascoal Xavier, Jordana Grazziela Alves Coelho-dos-Reis, Otávio Toledo Nóbrega, Pabline Cavalcante da Silva, Rodrigo de Resende Nery, Wanessa Tavares Santos, Rosana Maria Tristão, Caroline Oliveira Alves, Olindo Assis Martins-Filho and Alexandre Anderson de Sousa Munhoz Soares Show full author list Hide full author list

Biomedicines 2025, 13(9), 2256; https://doi.org/10.3390/biomedicines13092256 - 12 Sep 2025

Viewed by 705

Abstract

Introduction: Little is known about the effects of intrauterine exposure to SARS-CoV-2, especially on growth and neurodevelopment in children. Objective: We wished to verify the effect of intrauterine exposure to SARS-CoV-2 on neurological development in children. Methods: Infants born to mothers presenting with SARS-CoV-2 infection during pregnancy were enrolled in a prospective descriptive–analytical study involving outpatient appointments performed 6 and 12 months after birth. Their neurological development was assessed using the Bayley-III Scale, using a score of >85 as the cutoff threshold for identifying developmental delay. Differences between groups were assessed through an ANOVA, using Bonferroni correction for multiple comparisons. Regression models were employed to examine the associations between the Bayley-III scores and maternal features. Results: Two hundred and sixty-nine infants were evaluated, most of whom were born full-term and with birth weights appropriate for gestational age at delivery. Developmental delays were observed in 26% of the infants in at least one of the Bayley-III domains. The language domain was particularly affected, with impairments observed in children exposed to SARS-CoV-2 closer to the time of delivery. These findings were statistically significant (p < 0.05). Conclusions: Infants born to mothers presenting with SARS-CoV-2 infection during pregnancy presented developmental delays at 6 and 12 months, particularly in the language domain. These findings reinforce the relevance of long-term clinical follow-ups of newborns exposed to SARS-CoV-2 infection during pregnancy. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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14 pages, 637 KB

Open AccessArticle

Impact of Pulmonary Hypertension and Patent Ductus Arteriosus in Preterm Infants with Presumed Pulmonary Hypoplasia

by Sol Kim, Yumi Seo, Moon-Yeon Oh, Min Soo Kim and Sook Kyung Yum

Biomedicines 2025, 13(7), 1725; https://doi.org/10.3390/biomedicines13071725 - 15 Jul 2025

Viewed by 638

Abstract

Objectives: Pulmonary hypertension and hemodynamically significant PDA (hsPDA) involve seemingly opposite physiological features—decreased pulmonary blood flow and pulmonary overcirculation, respectively—but the literature demonstrates variable respiratory consequences in association with each of these morbidities. The aim of this study is to evaluate whether the two factors representing pulmonary circulation provide different contributions to respiratory outcomes in preterm infants with and without pulmonary hypoplasia. Methods: The medical records of preterm very low birth weight (VLBW) infants admitted to our unit during the study period from January 2013 to December 2020 were retrospectively reviewed. Preterm VLBW infants were divided into groups according to the presence of presumed pulmonary hypoplasia (PPH). Multivariable logistic regression analysis was performed to assess the association of PPH and pulmonary hypertension or delayed PDA closure with in-hospital outcomes. Results: Postnatal age at final treatment for PDA was significantly later [median 33 vs. 19 days, p = 0.025] in the PPH group. Multivariable analysis indicated that early pulmonary hypertension was significantly associated with neonatal death [aOR (95%CI) 11.575 (2.988–44.833) for no-PPH vs. 9.981 (1.334–74.647) for PPH]. Delayed PDA closure was associated with increased odds of adverse respiratory and composite outcomes [aOR (95%CI) 4.929 (1.613–15.055) and 3.320 (1.048–10.515), respectively] but decreased odds of neonatal death in the no-PPH group. However, Cox proportional hazards models did not demonstrate statistically significant associations for PPH, early pulmonary hypertension, or delayed PDA closure with mortality, likely due to time-varying effects and the absence of death events in the subgroup of infants with both PPH and delayed PDA closure. Conclusions: PPH is associated with a higher prevalence of air leak syndrome and pulmonary hypertension. Delayed PDA closure exerts different effects on respiratory outcomes in preterm VLBW infants with and without PPH. Although early pulmonary hypertension appears to be a key circulatory factor contributing to neonatal death, its effect may vary over time. These findings underscore the importance of accounting for time-dependent effects when interpreting pulmonary circulatory risk factors in clinical practice. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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16 pages, 849 KB

Open AccessArticle

Fetal Hemoglobin as a Predictive Biomarker for Retinopathy of Prematurity: A Prospective Multicenter Cohort Study in Portugal

by Mariza Fevereiro-Martins, Laura Aguiar, Ângela Inácio, Carlos Cardoso, Ana Carolina Santos, Carlos Marques-Neves, Hercília Guimarães, Rui Pinto and Manuel Bicho

Biomedicines 2025, 13(1), 110; https://doi.org/10.3390/biomedicines13010110 - 6 Jan 2025

Cited by 5 | Viewed by 1547

Abstract

Background/Objectives: Retinopathy of prematurity (ROP) is a leading cause of vision impairment in preterm infants, with its pathogenesis linked to oxygen exposure. Red blood cell (RBC) transfusions, commonly performed in neonatal intensive care units (NICUs), reduce fetal hemoglobin (HbF) fraction, altering oxygen dynamics and potentially contributing to ROP. We aimed to investigate the relationship between RBC transfusions, HbF percentage, and ROP, evaluating HbF as a potential predictive biomarker. Methods: A multicenter, prospective study was conducted across eight Portuguese NICUs, involving infants born at <32 weeks gestational age (GA) or <1500 g. ROP staging followed the International Classification of ROP (ICROP2). Clinical data were collected during hospitalization, and HbF fractions were measured from blood samples in the first four weeks of life using standardized methods. Infants were stratified by ROP presence and treatment requirement. Statistical analysis was performed using SPSS 28.0, with p < 0.05. Results: Eighty-two infants (mean GA: 28.1 ± 2.1 weeks, birth weight: 1055.8 ± 258.3 g) were included. Among them, 29 (35.4%) presented ROP and 4 (4.9%) required treatment. Infants with ROP had more RBC transfusions and lower HbF percentages than those without ROP (p < 0.05). Lower HbF was associated with more RBC transfusions (p < 0.001). Kaplan–Meier survival curves showed a higher ROP risk in infants with reduced HbF (p < 0.05). Conclusions: Low HbF percentage in the first four weeks of life may increase ROP risk in preterm infants. HbF could serve as a biomarker for ROP prediction. Interventions preserving HbF may reduce ROP risk. Further studies are needed to validate HbF as a biomarker and refine prevention strategies. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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19 pages, 13088 KB

Open AccessArticle

Structural Disruption of Cilia and Increased Cytoplasmic Tubulin in Biliary Atresia—An Exploratory Study Focusing on Early Postoperative Prognosis Following Portoenterostomy

by Patrícia Quelhas, Rui Oliveira, Carlos Kieling, Sandra Vieira and Jorge dos Santos

Biomedicines 2025, 13(1), 87; https://doi.org/10.3390/biomedicines13010087 - 1 Jan 2025

Cited by 1 | Viewed by 1430

Abstract

Introduction: Biliary atresia (BA) is a progressive hepatobiliary disease in infants, leading to liver failure and the need for transplantation. While its etiopathogenesis remains unclear, recent studies suggest primary cilia (PC) disruption plays a role. This study investigates correlations between PC and cytoplasmic tubulin (TUBA4A) alterations with hypoxia in patients with the isolated form of BA, focusing on native liver survival. Methods: Using qualitative and quantitative digital image analysis of immunofluorescence-stained liver samples, we assessed PC and TUBA4A features correlating these findings with HIF-1α nuclear positivity, clinical–laboratory data, and early native liver survival. Liver samples from fourteen BA patients and six controls with another liver disease were analyzed by digital image analysis, with data evaluated using Spearman’s correlation and independent t-tests. Results: HIF-1α positivity in cholangiocytes was observed in 42.8% of BA patients. While the PC ratio per biliary structure (cilia ratio status, CRs) was similar between BA patients and controls, PC length was decreased in BA patients. Cytoplasmic TUBA4A levels were elevated in BA patients. CRs positively correlated with lower cytoplasmic TUBA4A expression and was higher in patients without HIF-1α nuclear positivity. Reduced cilia length correlated with higher bilirubin levels at portoenterostomy. Predictors of early poor prognosis (death or need for transplantation until 1 year of life) included HIF-1α positivity, elevated direct bilirubin levels, decreased cilia length, PC bending, and increased TUBA4A expression. Conclusions: Reduced PC length, PC bending, and increased intensity of cytoplasmic TUBA4A expression occur in the isolated BA clinical type and negatively impact the early prognosis after post-portoenterostomy. These findings suggest the existence of a disruption in the tubulin transport between cytoplasm and PC. The detrimental effect of HIF-1alpha pathway activation over early native liver survival was confirmed, although independently from PC or cytoplasmic tubulin features. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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10 pages, 1022 KB

Open AccessArticle

Early Transpyloric Tube Feeding in Preventing Adverse Respiratory Events in Extremely Low Birth Weight Infants

by Shinya Tanaka, Fumihiko Namba, Ken Nagaya, Naohiro Yonemoto, Shinya Hirano, Itaru Yanagihara, Hiroyuki Kitajima and Masanori Fujimura

Biomedicines 2024, 12(12), 2799; https://doi.org/10.3390/biomedicines12122799 - 10 Dec 2024

Cited by 2 | Viewed by 1458

Abstract

Background: It has been demonstrated that aspiration during endotracheal intubation in preterm infants with gastroesophageal reflux is a contributing factor in the worsening of lung diseases and the development of bronchopulmonary dysplasia (BPD). This study aims to compare the safety and efficacy of early transpyloric (TP) tube feeding with that of nasogastric (NG) tube feeding in relation to BPD. Methods: The study population consisted of 39 extremely low birth weight infants (ELBWIs) with mechanical ventilation and an enteral feeding volume of 50 mL/kg/day, which were randomly assigned to different groups based on the method of tube feeding. The primary outcome was the incidence of adverse events. Results: The hazard ratio for primary adverse events was significantly lower in the TP group. The TP group had a median time of 34 days (range 24–85) and the NG group 24 days (range 13–70). In general, neither group exhibited severe intestinal complications or poor growth. Conclusions: Early TP tube feeding may be a safer alternative method of NG tube feeding for intubated ELBWIs and has been shown to reduce the frequency of adverse respiratory events. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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Review

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17 pages, 6323 KB

Open AccessReview

Persistent Pulmonary Hypertension of the Newborn: A Pragmatic Review of Pathophysiology, Diagnosis, and Advances in Management

by Karolina Chojnacka, Yogen Singh, Sheen Gahlaut, Witold Blaz, Agata Jerzak and Tomasz Szczapa

Biomedicines 2025, 13(10), 2332; https://doi.org/10.3390/biomedicines13102332 - 24 Sep 2025

Viewed by 1057

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) results from disrupted fetal–neonatal circulatory transition, characterized by elevated pulmonary vascular resistance (PVR), right-to-left shunting, and refractory hypoxemia. Despite improved perinatal care, PPHN remains a major source of neonatal morbidity and mortality. This review details PPHN phenotypes, pathophysiology, etiology, diagnostics including echocardiography and biomarkers like B-type Natriuretic Peptide (BNP) or N-terminal pro-B-type Natriuretic Peptide (NT-proBNP), and current therapeutic modalities, from lung recruitment and surfactant to targeted vasodilator therapy (iNO, sildenafil, milrinone, bosentan) and extracorporeal membrane oxygenation (ECMO). We emphasize the role of endothelial and molecular mechanisms in precision therapy and outline guidelines for clinical decision-making in diverse care settings. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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16 pages, 1832 KB

Open AccessReview

Insights into the Global and Mexican Context of Placental-Derived Pregnancy Complications

by Erika Chavira-Suárez

Biomedicines 2025, 13(3), 595; https://doi.org/10.3390/biomedicines13030595 - 1 Mar 2025

Viewed by 3084

Abstract

Placental-derived pregnancy complications encompass a range of disorders that hinder optimal fetal development, significantly impacting maternal and neonatal health outcomes. Key conditions include placental insufficiency, preeclampsia, fetal growth restriction (FGR) or intrauterine growth restriction (IUGR), fetal overgrowth, and gestational diabetes mellitus (GDM), which together contribute to a heightened risk of preterm birth, perinatal mortality, and long-term developmental challenges in affected infants. These complications are particularly notable because they generate approximately 80% of pregnancy disorders and pose significant public health concerns across diverse global contexts. Their management continues to face challenges, including a lack of consensus on diagnostic criteria and varied implementation of care standards. While imaging techniques like magnetic resonance imaging (MRI) and Doppler ultrasound have emerged as critical tools in clinical assessment, disparities in access to such technologies exacerbate existing inequalities in maternal and fetal health outcomes. Maternal and pregnancy care is a broad range of services aimed at promoting the well-being of women throughout the perinatal period. However, access to these services is often limited by economic, geographical, and sociocultural barriers, particularly for marginalized groups and women in low- and middle-income countries (LMICs). The implementation of targeted interventions designed to address specific obstacles faced by disadvantaged populations is a crucial component of bridging the gap in health equity in maternal care. Public health authorities and policymakers strive to develop evidence-based strategies that address the interplay between healthcare access, socioeconomic factors, and effective interventions in order to mitigate the adverse effects of placental-derived pregnancy complications. Continued research and data collection are essential to inform future policies and practices to improve outcomes for mothers and infants. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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Other

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21 pages, 1067 KB

Open AccessSystematic Review

Antenatal Sildenafil for Congenital Diaphragmatic Hernia: A Systematic Review and Bayesian Meta-Analysis of Preclinical Studies

by Tamara M. Hundscheid, Ilaria Amodeo, Giacomo Cavallaro, Carlijn R. Hooijmans, František Bartoš and Eduardo Villamor

Biomedicines 2025, 13(9), 2274; https://doi.org/10.3390/biomedicines13092274 - 16 Sep 2025

Viewed by 399

Abstract

Background: In congenital diaphragmatic hernia (CDH), pulmonary hypoplasia and pulmonary hypertension are major causes of morbidity and mortality. Antenatal treatment with sildenafil has shown some promising protective effects in experimental CDH, but no systematic review has yet evaluated the preclinical evidence on this topic. Methods: PubMed and EMBASE databases were searched for studies using antenatal sildenafil in animal models of CDH. Bayesian model-averaged (BMA) meta-analysis was used to calculate Bayes factors (BFs). The BF₁₀ is the ratio of the probability of the data under the alternative hypothesis (presence of effect) over the probability of the data under the null hypothesis (absence of effect). Risk of bias was assessed by the SYRCLE tool. Results: We included 18 studies (14 nitrofen and 4 surgical CDH). The BMA analysis showed inconclusive evidence (BF₁₀ between 0.33 and 3) for the presence of an effect of sildenafil in fetal survival (7 studies, BF₁₀ = 1.25) or in lung hypoplasia as assessed by the lung-to-body weight ratio (16 studies, BF₁₀ = 2.04). In contrast, the BMA analysis showed conclusive evidence (BF₁₀ > 3) in favor of a positive effect of sildenafil on small pulmonary arteries medial wall thickness (12 studies, BF₁₀ = 1499), radial alveolar count (6 studies, BF₁₀ = 167.57), interalveolar septa thickness (4 studies, BF₁₀ = 56.86), distal airway complexity (3 studies, BF₁₀ = 7.95), mean saccular airspace diameter (2 studies, BF₁₀ = 7.61), total lung capacity (2 studies, BF₁₀ = 6.91), lung compliance (2 studies, BF₁₀ = 5.19), and VEGF expression (5 studies, BF₁₀ = 10.62). Conclusions: In preclinical models of CDH, antenatal sildenafil rescues pulmonary vascular remodeling and airway/airspace morphometric alterations. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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