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Biomedicines
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Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches
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Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 15265

Special Issue Editor

Dr. Fumihiko Namba

E-Mail Website
Guest Editor
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,

Significant advances in perinatology and neonatology in the last decade have resulted in the increased survival of extremely premature infants, leading to a lower threshold for their resuscitation. Because these extremely premature infants who can survive easily develop life-threatening diseases, such as bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP), the rates of prematurity-related morbidities either have not been changing or have been increasing. Furthermore, because neonates who are affected by these illnesses have been getting more and more immature over the past couple of decades, the pathophysiology of these morbidities has been changing with time. Therefore, under such circumstances, prematurity-related morbidities have been poorly understood in terms of pathophysiology and lack effective treatments.

We invite investigators to contribute original research as well as review articles addressing recent advances in aspects regarding the pathophysiology of prematurity-related morbidities and in novel therapies and their effects, not only on short-term but also on long-term outcomes in children born extremely prematurely. At the same time, research regarding the understanding of the molecular mechanisms based on pharmacological treatments is welcome. Original, high-quality contributions that are not yet published or that are not currently under review by other journals or peer-reviewed conferences are sought.

Dr. Fumihiko Namba
Guest Editor

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Published Papers (7 papers)

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11 pages, 1011 KiB  
Article
Contribution of Fetal Inflammatory Response Syndrome (FIRS) with or without Maternal-Fetal Inflammation in The Placenta to Increased Risk of Respiratory and Other Complications in Preterm Neonates
by Makoto Nomiyama, Takuya Nakagawa, Fumio Yamasaki, Nami Hisamoto, Natsumi Yamashita, Ayane Harai, Kanako Gondo, Masazumi Ikeda, Satoko Tsuda, Masato Ishimatsu, Yuko Oshima, Takeshi Ono, Yutaka Kozuma and Keisuke Tsumura
Biomedicines 2023, 11(2), 611; https://doi.org/10.3390/biomedicines11020611 - 18 Feb 2023
Cited by 3 | Viewed by 1784
Abstract
This study classifies fetal inflammatory response syndrome (FIRS) based on the presence or absence of maternal-fetal inflammation in the placenta and clarifies the association of FIRS with neonatal morbidities. Women (330) who delivered at gestational ages of 22w0d-33w6d were enrolled and grouped into [...] Read more.
This study classifies fetal inflammatory response syndrome (FIRS) based on the presence or absence of maternal-fetal inflammation in the placenta and clarifies the association of FIRS with neonatal morbidities. Women (330) who delivered at gestational ages of 22w0d-33w6d were enrolled and grouped into four based on FIRS and maternal/fetal inflammatory response (MIR/FIR) statuses: Group A: without FIRS and MIR/FIR (reference group); Group B: MIR/FIR alone; Group C: FIRS and MIR/FIR; and Group D: FIRS without MIR/FIR. The associations between bronchopulmonary dysplasia (BPD), adverse neonatal outcomes, extremely low gestational age and Groups B, C, and D were investigated after adjustment for potential confounders. Among patients with FIRS, 29% were in Group D. The risk of BPD was increased in Groups C (adjusted odds ratio (aOR): 3.36; 95% confidence interval (CI): 1.14–9.89) and D (aOR: 4.17; 95% CI: 1.03–16.9), as was the risk of adverse neonatal outcomes (Group C: aOR: 7.17; 95% CI: 2.56–20.1; Group D: aOR: 6.84; 95% CI: 1.85–25.2). The risk of extremely low gestational age was increased in Group D (aOR: 3.85; 95% CI: 1.56–9.52). Therefore, FIRS without MIR/FIR is not rare and may be associated with neonatal morbidities more than FIRS and MIR/FIR. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
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21 pages, 473 KiB  
Article
Bronchopulmonary Dysplasia in Extremely Premature Infants: A Scoping Review for Identifying Risk Factors
by Masato Ito, Shin Kato, Makoto Saito, Naoyuki Miyahara, Hirokazu Arai, Fumihiko Namba, Erika Ota and Hidehiko Nakanishi
Biomedicines 2023, 11(2), 553; https://doi.org/10.3390/biomedicines11020553 - 14 Feb 2023
Cited by 4 | Viewed by 2679
Abstract
Background: Over the years, bronchopulmonary dysplasia (BPD) affects the pulmonary function of infants, resulting in chronic health burdens for infants and their families. The aim of this scoping review was to screen available evidence regarding perinatal risk factors associated with the development and [...] Read more.
Background: Over the years, bronchopulmonary dysplasia (BPD) affects the pulmonary function of infants, resulting in chronic health burdens for infants and their families. The aim of this scoping review was to screen available evidence regarding perinatal risk factors associated with the development and severity of BPD. Methods: The eligibility criteria of the studies were year of publication between 2016 and 2021; setting of a developed country; English or Japanese as the study language; and randomized controlled, cohort, or case-control design. The titles and abstracts of the studies were screened by independent reviewers. Results: Of 8189 eligible studies, 3 were included for severe BPD and 26 were included for moderate BPD. The risk factors for severe BPD were male sex, iatrogenic preterm birth, maternal hypertensive disorders of pregnancy (HDP), low gestational age, small-for-gestational-age (SGA) birth weight, mechanical ventilation on day 1, and need for patent ductus arteriosus (PDA) management. The risk factors for moderate or severe BPD included male sex, premature rupture of membranes, clinical chorioamnionitis, maternal HDP, SGA birth weight, bubbly/cystic appearance on X-ray, and PDA management. Conclusions: We identified several risk factors for BPD. We plan to confirm the validity of the new classification using the existing dataset. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
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6 pages, 221 KiB  
Communication
Longitudinal Measurement of Histidine-Rich Glycoprotein Levels in Bronchopulmonary Dysplasia: A Pilot Study
by Daisaku Morimoto, Yosuke Washio, Kei Tamai, Takeshi Sato, Tomoka Okamura, Hirokazu Watanabe, Yu Fukushima, Junko Yoshimoto, Misao Kageyama, Kenji Baba and Hirokazu Tsukahara
Biomedicines 2023, 11(1), 212; https://doi.org/10.3390/biomedicines11010212 - 14 Jan 2023
Viewed by 1443
Abstract
Histidine-rich glycoprotein (HRG) has been reported to inhibit signaling leading to the release of high mobility group box 1 protein, a damage-associated molecular pattern. The present study aimed to determine the longitudinal change in HRG levels in extremely preterm infants and assess whether [...] Read more.
Histidine-rich glycoprotein (HRG) has been reported to inhibit signaling leading to the release of high mobility group box 1 protein, a damage-associated molecular pattern. The present study aimed to determine the longitudinal change in HRG levels in extremely preterm infants and assess whether complications such as bronchopulmonary dysplasia (BPD) were associated with differences in HRG levels. In this multicenter, prospective, observational study, we measured serum HRG levels every 2 weeks from birth to 8 weeks of age. Serum HRG was measured using an enzyme-linked immunosorbent assay. We included 19 extremely preterm infants in the study and 74 samples were analyzed. The median gestational age was 26.0 weeks, and the median birth weight was 858 g. Serum HRG levels showed a significant upward trend after birth (p < 0.001); median HRG concentrations at birth and at 2, 4, 6, and 8 weeks of age were 1.07, 1.11, 2.86, 6.05, and 7.49 µg/mL, respectively. Onset of BPD was not associated with differences in serum HRG levels. Further, the serum HRG levels increased significantly after birth in extremely preterm infants. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
11 pages, 1795 KiB  
Article
Sex Differences in Microglia Activation in a Rodent Model of Preterm Hypoxic Ischemic Injury with Caffeine Treatment
by Ruth Mae McLeod, Ted S. Rosenkrantz, Roslyn Holly Fitch and Rachel R. Koski
Biomedicines 2023, 11(1), 185; https://doi.org/10.3390/biomedicines11010185 - 11 Jan 2023
Cited by 4 | Viewed by 2082
Abstract
Preterm infants are often treated with caffeine as a respiratory stimulant. However, follow-up data shows caffeine may also have neuroprotective potential. There are several theories as to how caffeine might protect the brain, but none have been proven. This study looked at caffeine [...] Read more.
Preterm infants are often treated with caffeine as a respiratory stimulant. However, follow-up data shows caffeine may also have neuroprotective potential. There are several theories as to how caffeine might protect the brain, but none have been proven. This study looked at caffeine effects on microglial activation in rodent brains post hypoxic ischemic (HI) injury. Rat pups underwent either sham or HI surgery on P6, followed by treatment with either caffeine or saline. Forty-eight hours post-injury, brains were collected and underwent paraffin embedding and sectioning followed by immunofluorescence staining. Ionized calcium binding adaptor molecule 1 (Iba-1) was used to label microglia, and 4′,6-diamindino-2-phenylindole (DAPI) was used to label DNA. Cell size measurements of microglia were obtained to gauge microglia activation, and chromatin condensation (DAPI optical density) was used as an index of neuronal cell death. Results suggest that caffeine does offer protective effects, based on significantly increased levels of cell death in HI-saline animals not seen in caffeine-treated HI males and females. However, the mechanism of action may be different. Male HI animals showed marginally reduced microglial activation following caffeine treatment, whereas females did not. Results indicate that though caffeine may act protectively in both sexes by reducing cell death, the benefits may be mediated by different mechanisms. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
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10 pages, 501 KiB  
Article
Conservative Management of Patent Ductus Arteriosus Is Feasible in the Peri-Viable Infants at 22–25 Gestational Weeks
by Misun Yang, Yun Sil Chang, So Yoon Ahn, Se In Sung, Heui Seung Jo and Won Soon Park
Biomedicines 2023, 11(1), 78; https://doi.org/10.3390/biomedicines11010078 - 28 Dec 2022
Cited by 1 | Viewed by 1822
Abstract
The purpose of this study was to determine the natural course of hemodynamically significant (HS) patent ductus arteriosus (PDA) with conservative management and whether the presence or prolonged duration of HS PDA affected mortality/morbidities in infants at 22–25 weeks estimated gestational age (EGA). [...] Read more.
The purpose of this study was to determine the natural course of hemodynamically significant (HS) patent ductus arteriosus (PDA) with conservative management and whether the presence or prolonged duration of HS PDA affected mortality/morbidities in infants at 22–25 weeks estimated gestational age (EGA). We retrospectively reviewed the medical records of 77 infants born at 22–25 weeks EGA, stratified into 22–23 weeks (n = 21) and 24–25 weeks EGA (n = 56). HS PDA was present in 77%, 76%, and 77%, and open ductus at discharge was 12%, 13%, and 12% in the total and at 22–23 and 24–25 weeks EGA infants, respectively. For backup rescue treatment, 7% and 5% of the infants received oral ibuprofen and device closure, respectively. A mortality rate of 9% was found in the HS PDA (+) infants, significantly lower than the 28% in HS PDA (−) infants. There are no significant differences in morbidities. In multivariate analyses, the presence and/or prolonged duration of HS PDA was not associated with increased mortality or morbidity. Spontaneous closure of HS PDA was achieved through conservative management in the peri-viable infants at 22–25 weeks EGA. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
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18 pages, 2955 KiB  
Article
Hyperoxia Induced Hypomyelination
by Weilin Song, George Hoppe, Demiana Hanna, Tara M. DeSilva and Jonathan E. Sears
Biomedicines 2023, 11(1), 37; https://doi.org/10.3390/biomedicines11010037 - 23 Dec 2022
Cited by 4 | Viewed by 1775
Abstract
We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus [...] Read more.
We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified. Density of corpus callosal capillaries were measured after lectin staining and hypoxia measured by Hypoxyprobe. Numbers of oligodendrocytes were quantified by immunohistochemistry. We next used hypoxiamimesis as a surrogate to hypoxia by comparing cerebral hypoxia inducible factor (HIF) stabilization to hepatic HIF stabilization. Hyperoxia induced hypomyelination and a reduction of corpus callosal capillaries. Hyperoxia decreased numbers of oligodendrocytes with an increase in corpus callosal fibrosis and apoptosis. Cerebral hypoxiamimesis induced hypomyelination whereas hepatic hypoxiamimesis alone increased myelination, oligodendrocyte numbers, and corpus callosal capillary density. Hepatic HIF-1 dependence on myelination was confirmed using the cre/lox hepatic HIF-1 knockout. These findings suggest that hyperoxia can induce hypomyelination through vasoobliteration and subsequent ischemia, adding a potential oxygen induced mechanism to the diverse causes of periventricular leukomalacia of the severely preterm infant. Targeting hepatic HIF-1 alone led to increased myelination. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
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18 pages, 507 KiB  
Systematic Review
Is Spontaneous Preterm Prelabor of Membrane Rupture Irreversible? A Review of Potentially Curative Approaches
by Bianca Mihaela Danciu, Marina Ruxandra Oţelea, Marian Augustin Marincaş, Maria Niţescu and Anca Angela Simionescu
Biomedicines 2023, 11(7), 1900; https://doi.org/10.3390/biomedicines11071900 - 4 Jul 2023
Cited by 1 | Viewed by 2416
Abstract
There is still no curative treatment for the spontaneous preterm prelabor rupture of membranes (sPPROM), the main cause of premature birth. Here, we summarize the most recent methods and materials used for sealing membranes after sPPROM. A literature search was conducted between 2013 [...] Read more.
There is still no curative treatment for the spontaneous preterm prelabor rupture of membranes (sPPROM), the main cause of premature birth. Here, we summarize the most recent methods and materials used for sealing membranes after sPPROM. A literature search was conducted between 2013 and 2023 on reported newborns after membranes were sealed or on animal or tissue culture models. Fourteen studies describing the outcomes after using an amniopatch, an immunologic sealant, or a mechanical cervical adapter were included. According to these studies, an increase in the volume of amniotic fluid and the lack of chorioamnionitis demonstrate a favorable neonatal outcome, with a lower incidence of respiratory distress syndrome and early neonatal sepsis, even if sealing is not complete and stable. In vivo and in vitro models demonstrated that amniotic stem cells, in combination with amniocytes, can spontaneously repair small defects; because of the heterogenicity of the data, it is too early to draw a thoughtful conclusion. Future therapies should focus on materials and methods for sealing fetal membranes that are biocompatible, absorbable, available, easy to apply, and easily adherent to the fetal membrane. Full article
(This article belongs to the Special Issue Prematurity-Related Morbidities in Neonates: From Pathophysiology to Novel Therapeutic Approaches)
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