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Developmental Dynamics : An Official... Mar 2022The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling... (Review)
Review
The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.
Topics: Animals; Disease Models, Animal; Ductus Arteriosus; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Infant, Premature; Mice
PubMed: 34350653
DOI: 10.1002/dvdy.408 -
Pediatric Cardiology 2000Our hypotheses were that the following factors influenced closure of atrial septal defects (ASDs) detected in neonates: estimated gestational age (EGA), the presence of... (Comparative Study)
Comparative Study
Our hypotheses were that the following factors influenced closure of atrial septal defects (ASDs) detected in neonates: estimated gestational age (EGA), the presence of a persistent ductus arteriosus (PDA), severity of pulmonary disease, gender, and the initial size of the ASD. Our population consisted of 82 newborns (38 premature and 44 term) who were found before the age of 1 month to have an ASD. Closure of ASDs was analyzed using both Kaplan-Meier survival analysis and the Cox proportional hazards model, each with the five covariates. The hazard ratio (or ratio of instantaneous closure rates) of term vs preterm infants was 3.60 (95% CI = 1.80-7.20), whereas the hazard ratio for infants with a PDA (compared to infants with no PDA) was 2.41 (95% CI = 1.28-4.54). Multivariate analysis showed that each of these terms (PDA and EGA) were independent predictors of ASD closure. The hazard ratio of ASD closure for each of four levels of pulmonary disease was 0.632 [95% CI = 0.453-0.881]. We conclude that the majority of neonatal ASDs will close, with EGA and PDA acting as important influences on closure.
Topics: Chi-Square Distribution; Ductus Arteriosus, Patent; Female; Heart Septal Defects, Atrial; Heart Septum; Humans; Infant, Newborn; Infant, Premature; Male; Proportional Hazards Models; Remission, Spontaneous; Respiratory Distress Syndrome, Newborn; Survival Analysis; Ultrasonography, Doppler, Color
PubMed: 10754082
DOI: 10.1007/s002469910020 -
Seminars in Perinatology Jun 2010Premature birth and disruption of the normal maturation process leave the immature ductus arteriosus unable to respond to postnatal cues for closure. Strategies that... (Review)
Review
Premature birth and disruption of the normal maturation process leave the immature ductus arteriosus unable to respond to postnatal cues for closure. Strategies that advocate conservative management of the patent ductus arteriosus (PDA) in premature infants are dependent on identification of the symptomatic PDA and understanding the risk factors that predispose to PDA. Exposure of premature infants to unintended vasodilatory stimuli may be one of the risk factors for PDA that is under recognized. In this article, we summarize the clinical factors that are associated with PDA and review commonly used neonatal drugs for their vasodilatory properties. Data demonstrating relaxation of the ductus arteriosus by gentamicin and other aminoglycoside antibiotics, by cimetidine and other H2 receptor antagonists, and by heparin are provided as examples of neonatal therapies that have unanticipated effects that may promote PDA.
Topics: Animals; Cimetidine; Ductus Arteriosus; Ductus Arteriosus, Patent; Gentamicins; Heparin; Histamine H2 Antagonists; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Nitric Oxide; Prostaglandins; Risk Factors; Vasodilation; Vasodilator Agents
PubMed: 20494739
DOI: 10.1053/j.semperi.2010.02.007 -
Taiwanese Journal of Obstetrics &... Jul 2021Spina bifida (SB) is a congenital birth defect defined as a failure of the neural tube formation during the embryonic development phase. Fetoscopic repair of SB is a... (Review)
Review
OBJECTIVE
Spina bifida (SB) is a congenital birth defect defined as a failure of the neural tube formation during the embryonic development phase. Fetoscopic repair of SB is a novel treatment technique that allows to close spinal defect early and prevent potential neurological and psychomotor complications.
CASE REPORT
We present a case report of a 32-year-old-multigravida whose fetus was diagnosed with lumbosacral myelomeningocele at 23rd week. Fetoscopic closure of MMC was performed at 26 weeks. At 32 weeks, due to premature amniorrhexis and placental abruption, an emergency C-section was performed. Newborn's psychomotor development was within normal limits.
CONCLUSION
Although intrauterine treatment has an increased risk of premature labor, placental abruption, prenatal closure is associated with improved postnatal psychomotor development. Prenatal surgery decreases the risk of Arnold-Chiari II malformation development and walking disability. Fetoscopic closure of SB is becoming a choice for treatment with beneficial outcomes for mother and fetus.
Topics: Abruptio Placentae; Adult; Cesarean Section; Female; Fetal Membranes, Premature Rupture; Fetoscopy; Humans; Infant, Newborn; Lumbosacral Region; Meningomyelocele; Pregnancy; Pregnancy Trimester, Second; Spinal Dysraphism
PubMed: 34247822
DOI: 10.1016/j.tjog.2021.05.032 -
Arquivos Brasileiros de Cardiologia Sep 2022The presence of patent ductus arteriosus can be as high as 50% in preterm babies. Hemodynamically significant patent ductus arteriosus is a common cause of delayed...
BACKGROUND
The presence of patent ductus arteriosus can be as high as 50% in preterm babies. Hemodynamically significant patent ductus arteriosus is a common cause of delayed weaning of respiratory support and an important risk factor of necrotizing enterocolitis, intraventricular hemorrhage, and bronchopulmonary dysplasia in this population.
OBJECTIVE
The aim of this study is to describe an initial experience of percutaneous closure of the ductus arteriosus in preterm infants weighing less than 2 kg.
METHODS
This was a prospective study, comprised of 14 consecutive patients submitted to percutaneous closure of ductus arteriosus between March 2020 and February 2021 in 6 institutions in Brazil.
RESULTS
Mean gestational age was 28.45±3.14 weeks, mean age at the procedure was 38.85±17.35 days and mean weight was 1.41 ±0.41 kg; 79% of the patients were under mechanical ventilation, and 79% had been submitted, on average, to a 1.5 cycle of non-steroidal anti-inflammatory drugs. Most patients were weaned off of mechanical ventilation in a mean of 12.6 ±7.24 days after the procedure. Success rate was 100%. No procedure-related mortality was observed.
CONCLUSION
This study concluded that percutaneous closure of ductus arteriosus in premature babies below 2 kg has satisfactory results and a low complication rate in this study sample.
Topics: Brazil; Ductus Arteriosus; Ductus Arteriosus, Patent; Humans; Ibuprofen; Infant; Infant, Newborn; Infant, Premature; Prospective Studies
PubMed: 36074378
DOI: 10.36660/abc.20210818 -
Frontiers in Pediatrics 2021Patent ductus arteriosus (PDA) is common in preterm infants and contributes to morbidity and mortality. Several studies have shown the feasibility and safety of...
Patent ductus arteriosus (PDA) is common in preterm infants and contributes to morbidity and mortality. Several studies have shown the feasibility and safety of percutaneous PDA closure. Minimally invasive surgical ligation by anterior thoracotomy is an alternative, bedside technique for PDA closure in very low birth weight preterm infants. Our study aimed to compare short- and medium-term morbidity and mortality between anterior minithoracotomy and transcatheter PDA closure. From 2010 to 2020, 92 preterm infants <1,600 g underwent PDA closure in two centers: 44 surgical anterior minithoracotomies (center 1) and 48 transcatheter closures (center 2). Using a 1:1 propensity score match analysis, 22 patients in each group were included. The primary outcome was time to extubation after intervention. Preoperative characteristics were similar in both groups after propensity matching (mean weight at procedure, 1,171 ± 183 g; = 0.8). Mean time to extubation was similar: 10 ± 15 days in the surgical group vs. 9 ± 13 days in the transcatheter group ( = 0.9). Mean age at hospital discharge was 114 ± 29 days vs. 105 ± 19 days ( = 0.2). Two deaths occurred in the surgical group and one in the transcatheter group ( = 0.61). Five complications (pneumothorax = 2, chylothorax = 2, phrenic nerve injury = 1) occurred in three patients after surgery. Three complications (chylothorax = 1, endocarditis = 1, renal vein thrombosis = 1) occurred in two patients after percutaneous closure ( = 0.63). Equivalent efficiency and safety of surgical mini-invasive vs. transcatheter PDA closure in preterm infants <1,600 g are in favor of applying these alternative techniques according to centers' facilities and competences.
PubMed: 34869092
DOI: 10.3389/fped.2021.700284 -
Journal of Bone and Mineral Research :... Jul 2021The growth plates are key engines of skeletal development and growth and contain a top reserve zone followed by maturation zones of proliferating, prehypertrophic, and...
The growth plates are key engines of skeletal development and growth and contain a top reserve zone followed by maturation zones of proliferating, prehypertrophic, and hypertrophic/mineralizing chondrocytes. Trauma or drug treatment of certain disorders can derange the growth plates and cause accelerated maturation and premature closure, one example being anti-hedgehog drugs such as LDE225 (Sonidegib) used against pediatric brain malignancies. Here we tested whether such acceleration and closure in LDE225-treated mice could be prevented by co-administration of a selective retinoid antagonist, based on previous studies showing that retinoid antagonists can slow down chondrocyte maturation rates. Treatment of juvenile mice with an experimental dose of LDE225 for 2 days (100 mg/kg by gavage) initially caused a significant shortening of long bone growth plates, with concomitant decreases in chondrocyte proliferation; expression of Indian hedgehog, Sox9, and other key genes; and surprisingly, the number of reserve progenitors. Growth plate involution followed with time, leading to impaired long bone lengthening. Mechanistically, LDE225 treatment markedly decreased the expression of retinoid catabolic enzyme Cyp26b1 within growth plate, whereas it increased and broadened the expression of retinoid synthesizing enzyme Raldh3, thus subverting normal homeostatic retinoid circuitries and in turn accelerating maturation and closure. All such severe skeletal and molecular changes were prevented when LDE-treated mice were co-administered the selective retinoid antagonist CD2665 (1.5 mg/kg/d), a drug targeting retinoid acid receptor γ, which is most abundantly expressed in growth plate. When given alone, CD2665 elicited the expected maturation delay and growth plate expansion. In vitro data showed that LDE225 acted directly to dampen chondrogenic phenotypic expression, a response fully reversed by CD2665 co-treatment. In sum, our proof-of-principle data indicate that drug-induced premature growth plate closures can be prevented or delayed by targeting a separate phenotypic regulatory mechanism in chondrocytes. The translation applicability of the findings remains to be studied. © 2021 American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Antineoplastic Agents; Cell Differentiation; Child; Chondrocytes; Growth Plate; Hedgehog Proteins; Humans; Mice; Neoplasms; Retinoids
PubMed: 33724538
DOI: 10.1002/jbmr.4291 -
Human Molecular Genetics Nov 2018Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by...
Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.
Topics: Acrocephalosyndactylia; Animals; Core Binding Factor Alpha 1 Subunit; Cranial Sutures; Craniosynostoses; Disease Models, Animal; Female; Gain of Function Mutation; Gene Expression Regulation; Humans; Mice; Morphogenesis; NIMA-Interacting Peptidylprolyl Isomerase; Naphthoquinones; Osteoblasts; Pregnancy; Primary Cell Culture; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction
PubMed: 30007339
DOI: 10.1093/hmg/ddy252 -
Research Square Apr 2024Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 hours of birth....
INTRODUCTION
Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 hours of birth. However, this is not always possible in severely premature infants. Given the rarity of this patient population, we aimed to share our institutional experience and outcomes of severely premature infants with MMC.
METHODS
We performed a retrospective, observational review of premature infants (≤ 32 weeks gestational age) identified through our multidisciplinary spina bifida clinic (1995-2021) and surgical logs. Descriptive statistics were compiled about this sample including timing of MMC closure and incidence of adverse events such as sepsis, CSF diversion, meningitis, and death.
RESULTS
Eight patients were identified (50% male) with MMC who were born ≤ 32 weeks gestational age. Mean gestational age of the population was 27.3 weeks (SD 3.5). Median time to MMC closure was 1.5 days (IQR = 1 -80.8). Five patients were taken for surgery within the recommended 48 hours of birth; 2 patients underwent significantly delayed closure (107 and 139 days); and one patient's defect epithelized without surgical intervention. Six of eight patients required permanent cerebrospinal fluid (CSF) diversion (2 patients were treated with ventriculoperitoneal shunting (VPS), three were treated with endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) and 1 patient treated with ETV; mean of 3 years after birth, ranging from 1 day to 16 years). Two patients required more than one permanent CSF diversion procedure. Two patients developed sepsis (defined as meeting at least 2/4 SIRS criteria), and 2 patients had intraventricular hemorrhage (both grade III). No patients developed meningitis (defined as positive CSF cultures) prior to MMC closure. Median follow up duration was 9.7 years. During this time epoch, 3 patients died: Two before 2 years of age of causes unrelated to surgical intervention. One of the two patients with grade III IVH died within 24 hours of MMC closure.
CONCLUSIONS
In our institutional experience with premature infants with MMC, some patients underwent delayed MMC closure. The overall rate of meningitis, sepsis, and mortality for preterm children with MMC was similar to MMC patients born at term.
PubMed: 38645257
DOI: 10.21203/rs.3.rs-4158288/v1 -
Children (Basel, Switzerland) Jan 2021The identification of an optimal management strategy for the patent ductus arteriosus (PDA) in the context of extreme prematurity remains elusive. Observational studies... (Review)
Review
The identification of an optimal management strategy for the patent ductus arteriosus (PDA) in the context of extreme prematurity remains elusive. Observational studies have reported a persistent association between PDA and neonatal adverse outcomes, but by and large, no clinical trial, to date, has demonstrated that treating a PDA results in a reduction of those morbidities. This discrepancy has led many to assume that the PDA is an innocent bystander in the physiological mechanisms responsible for such complications and a reluctance to actively pursue shunt elimination. It would be remiss to discount the volume of evidence available clearly documenting a strong association between longstanding PDA exposure and negative outcomes. There needs to be a radical change in the design, patient selection and possible outcome assessment in any further trials addressing the PDA. The purpose of this review is to explore the reasons that preclude existing clinical trials from definitively ascribing a causal relationship between PDA patency and adverse outcomes in the context of extreme prematurity, why previous studies have failed to demonstrate significant beneficial effects following PDA treatment and how future research may be conducted to allow us to draw concrete conclusions regarding the potential merits of ductal closure.
PubMed: 33467401
DOI: 10.3390/children8010047