Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model.

Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O2) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.

Bridging Gaps and Understanding Disparities in Gestational Diabetes Mellitus to Improve Perinatal Outcomes.

IN BRIEF For a woman who is facing financial, cultural, psychological, or social challenges, discovering that she has gestational diabetes mellitus (GDM) represents a significant burden. By better understanding challenges underserved women with GDM face, multidisciplinary clinical teams can make essential changes in health care delivery to optimize outcomes not just during pregnancy, but also, equally importantly, beyond pregnancy to prevent long-term disease.

Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants.

Importance: Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation. Objective: To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping. Design, Setting, and Participants: Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks' gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018. Interventions: Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238). Main Outcomes and Measures: The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin. Results: Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, -2% to 9%]; P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%]; P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks' gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%]; P = .002). Conclusions and Relevance: In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks' gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulting post hoc nature of the analyses preclude definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT03019367.

Delayed Cord Clamping in Newborns Born at Term at Risk for Resuscitation: A Feasibility Randomized Clinical Trial.

Infants may benefit if resuscitation could be provided with an intact umbilical cord. Infants identified at risk for resuscitation were randomized to 1- or 5-minute cord clamping. The 5-minute group had greater cerebral oxygenation and blood pressure. Studies are needed to determine whether this translates into improved outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02827409.

Moderate hyperoxia induces extracellular matrix remodeling by human fetal airway smooth muscle cells.

BACKGROUND: Premature infants are at increased risk for airway diseases, such as wheezing and asthma, because of early exposure to risk factors including hyperoxia. As in adult asthma, airway remodeling and increased extracellular matrix (ECM) deposition is involved. METHODS: We assessed the impact of 24-72 h of moderate hyperoxia (50%) on human fetal airway smooth muscle (fASM) ECM deposition through western blot, modified in-cell western, and zymography techniques. RESULTS: Hyperoxia exposure significantly increased collagen I and collagen III deposition, increased pro- and cleaved matrix metalloproteinase 9 (MMP9) activity, and decreased endogenous MMP inhibitor, TIMP1, expression. Hyperoxia-induced change in caveolin-1 (CAV1) expression was assessed as a potential mechanism for the changes in ECM deposition. CAV1 expression was decreased following hyperoxia. Supplementation of CAV1 activity with caveolar scaffolding domain (CSD) peptide abrogated the hyperoxia-mediated ECM changes. CONCLUSION: These results demonstrate that moderate hyperoxia enhances ECM deposition in developing airways by altering the balance between MMPs and their inhibitors (TIMPs), and by increasing collagen deposition. These effects are partly mediated by a hyperoxia-induced decrease in CAV1 expression. In conjunction with prior data demonstrating increased fASM proliferation with hyperoxia, these data further demonstrate that hyperoxia is an important instigator of remodeling in developing airways.

TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells.

Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll-like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-κB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma.

Effects of antenatal lipopolysaccharide and postnatal hyperoxia on airway reactivity and remodeling in a neonatal mouse model.

BACKGROUND: Antenatal inflammation and preterm birth are associated with the development of airway diseases such as wheezing and asthma. Utilizing a newborn mouse model, we assessed the effects of maternal inflammation and postnatal hyperoxia on the neonatal airway. METHODS: Pregnant C57/Bl6 dams were injected with lipopolysaccharide (LPS) or saline on embryonic day 16. Offspring were placed in room air or hyperoxia (50% O2) for 7 d and then returned to normoxia. Airway mechanics, histology, and laser capture micro-dissection (LCM) were performed. RESULTS: At postnatal day 21, maternal LPS- and 50% O2-exposed pups exhibited increased resistance and decreased compliance compared to 21% O2 pups; however their effects were not synergistic. LPS and hyperoxia each increased the thickness of airway smooth muscle (ASM), but not the airway epithelial layer. Structural changes were largely limited to the conducting airways. Upregulation of inflammatory markers in the lung was observed at birth. LCM revealed increased collagen-3, transforming growth factor ß, and connective tissue growth factor expression with LPS and hyperoxia within the ASM layer. CONCLUSION: These novel studies provide functional, structural, and molecular evidence that antenatal inflammation is detrimental to the developing airway. Exposure to moderate hyperoxia does not exacerbate LPS effects on the airway.

Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells.

Asthma in the pediatric population remains a significant contributor to morbidity and increasing healthcare costs. Vitamin D3 insufficiency and deficiency have been associated with development of asthma. Recent studies in models of adult airway diseases suggest that the bioactive Vitamin D3 metabolite, calcitriol (1,25-dihydroxyvitamin D3 ; 1,25(OH)2 D3 ), modulates responses to inflammation; however, this concept has not been explored in developing airways in the context of pediatric asthma. We used human fetal airway smooth muscle (ASM) cells as a model of the early postnatal airway to explore how calcitriol modulates remodeling induced by pro-inflammatory cytokines. Cells were pre-treated with calcitriol and then exposed to TNFα or TGFß for up to 72 h. Matrix metalloproteinase (MMP) activity, production of extracellular matrix (ECM), and cell proliferation were assessed. Calcitriol attenuated TNFα enhancement of MMP-9 expression and activity. Additionally, calcitriol attenuated TNFα and TGFß-induced collagen III expression and deposition, and separately, inhibited proliferation of fetal ASM cells induced by either inflammatory mediator. Analysis of signaling pathways suggested that calcitriol effects in fetal ASM involve ERK signaling, but not other major inflammatory pathways. Overall, our data demonstrate that calcitriol can blunt multiple effects of TNFα and TGFß in developing airway, and point to a potentially novel approach to alleviating structural changes in inflammatory airway diseases of childhood.

Challenging the 4- to 5-minute rule: from perimortem cesarean to resuscitative hysterotomy.

Although perimortem delivery has been recorded in the medical literature for millennia, the procedural intent has evolved to the current fetocentric approach, predicating timing of delivery following maternal cardiopulmonary arrest to optimize neonatal outcome. We suggest a call to action to reinforce the concept that if the uterus is palpable at or above the umbilicus, preparations for delivery should be made simultaneous with initiation of maternal resuscitative efforts; if maternal condition is not rapidly reversible, hysterotomy with delivery should be performed regardless of fetal viability or elapsed time since arrest. Cognizant of the difficulty in determining precise timing of arrest in clinical practice, if fetal status is already compromised further delay while attempting to assess fetal heart rate, locating optimal surgical equipment, or transporting to an operating room will result in unnecessary worsening of both maternal and fetal condition. Even if intrauterine demise has already occurred, maternal resuscitative efforts will typically be markedly improved following delivery with uterine decompression. Consequently we suggest that perimortem cesarean delivery be renamed "resuscitative hysterotomy" to reflect the mutual optimization of resuscitation efforts that would potentially provide earlier and more substantial benefit to both mother and baby.

Perinatal oxygen in the developing lung.

Lung diseases, such as bronchopulmonary dysplasia (BPD), wheezing, and asthma, remain significant causes of morbidity and mortality in the pediatric population, particularly in the setting of premature birth. Pulmonary outcomes in these infants are highly influenced by perinatal exposures including prenatal inflammation, postnatal intensive care unit interventions, and environmental agents. Here, there is strong evidence that perinatal supplemental oxygen administration has significant effects on pulmonary development and health. This is of particular importance in the preterm lung, where premature exposure to room air represents a hyperoxic insult that may cause harm to a lung primed to develop in a hypoxic environment. Preterm infants are also subject to increased episodes of hypoxia, which may also result in pulmonary damage and disease. Here, we summarize the current understanding of the effects of oxygen on the developing lung and how low vs. high oxygen may predispose to pulmonary disease that may extend even into adulthood. Better understanding of the underlying mechanisms will help lead to improved care and outcomes in this vulnerable population.

Self-Reported Medication Use Across Racial and Rural or Urban Subgroups of People Who Are Pregnant in the United States: Decentralized App-Based Cohort Study.

BACKGROUND: Maternal health outcomes have been underresearched due to people who are pregnant being underrepresented or excluded from studies based on their status as a vulnerable study population. Based on the available evidence, Black people who are pregnant have dramatically higher maternal morbidity and mortality rates compared to other racial and ethnic groups. However, insights into prenatal care-including the use of medications, immunizations, and prenatal vitamins-are not well understood for pregnant populations, particularly those that are underrepresented in biomedical research. Medication use has been particularly understudied in people who are pregnant; even though it has been shown that up to 95% of people who are pregnant take at least 1 or more medications. Understanding gaps in use could help identify ways to reduce maternal disparities and optimize maternal health outcomes. OBJECTIVE: We aimed to characterize and compare the use of prenatal vitamins, immunizations, and commonly used over-the-counter and prescription medications among people who are pregnant, those self-identifying as Black versus non-Black, and those living in rural versus urban regions in the United States. METHODS: We conducted a prospective, decentralized study of 4130 pregnant study participants who answered survey questionnaires using a mobile research app that was only available on iOS (Apple Inc) devices. All people who were pregnant, living in the United States, and comfortable with reading and writing in English were eligible. The study was conducted in a decentralized fashion with the use of a research app to facilitate enrollment using an eConsent and self-reported data collection. RESULTS: Within the study population, the use of prenatal vitamins, antiemetics, antidepressants, and pain medication varied significantly among different subpopulations underrepresented in biomedical research. Black participants reported significantly lower frequencies of prenatal vitamin use compared to non-Black participants (P<.001). The frequency of participants who were currently receiving treatment for anxiety and depression was also lower among Black and rural groups compared to their non-Black and urban counterparts, respectively. There was significantly lower use of antidepressants (P=.002) and antiemetics (P=.02) among Black compared to non-Black participants. While prenatal vitamin use was lower among participants in rural areas, the difference between rural and urban groups did not reach statistical significance (P=.08). There were no significant differences in vaccine uptake for influenza or tetanus-diphtheria-pertussis (TDaP) across race, ethnicity, rural, or urban status. CONCLUSIONS: A prospective, decentralized app-based study demonstrated significantly lower use of prenatal vitamins, antiemetics, and antidepressants among Black pregnant participants. Additionally, significantly fewer Black and rural participants reported receiving treatment for anxiety and depression during pregnancy. Future research dedicated to identifying the root mechanisms of these differences can help improve maternal health outcomes, specifically for diverse communities.

Preterm premature rupture of membranes ≥ 32 weeks' gestation: impact of revised practice guidelines.

OBJECTIVE: The purpose of this study was to determine the perinatal impact of the 2007 American College of Obstetricians and Gynecologists Practice Bulletin on preterm premature membrane rupture. STUDY DESIGN: Perinatal outcomes were compared in women who had experienced preterm membrane rupture in the 3 years before the 2007 Practice Bulletin to similar women who experienced preterm premature rupture of membranes in the 3 years after the issue and implementation of the guideline. RESULTS: After adjustment for gestational age at membrane rupture and steroids, composite severe morbidity (death, respiratory distress syndrome, assisted ventilation for ≥ 6 hours, sepsis, pneumonia, grade 3 or 4 intraventricular hemorrhage, or necrotizing enterocolitis) was similar by group. Infants in the "after" group experienced less pneumonia and sepsis, similar respiratory morbidity, but more labor inductions and postpartum hemorrhage. CONCLUSION: The new guideline significantly decreases severe neonatal infections but is associated with more frequent labor induction and postpartum hemorrhage.

Acceptability of Bedside Resuscitation With Intact Umbilical Cord to Clinicians and Patients' Families in the United States.

BACKGROUND: While delayed umbilical cord clamping in preterm infants has shown to improve long-term neurological outcomes, infants who are thought to need resuscitation do not receive delayed cord clamping even though they may benefit the most. A mobile resuscitation platform allows infants to be resuscitated at the mother's bedside with the cord intact. The newborn is supplied with placental blood during the resuscitation in view of the mother. The objective of the study is to assess the usability and acceptability of mobile resuscitation platform, LifeStart trolley, among the infants' parents and perinatal providers. METHODS: A resuscitation platform was present during every delivery that required advanced neonatal providers for high-risk deliveries. Perinatal providers and parents of the infants were given a questionnaire shortly after the delivery. RESULTS: 60 neonatal subjects were placed on the trolley. The majority of deliveries were high risk for meconium-stained amniotic fluid (43%), and non-reassuring fetal heart rate (45%). About 50% of neonatal providers felt that there were some concerns regarding access to the baby. No parents were uncomfortable with the bedside neonatal interventions, and most parents perceived that communication was improved because of the proximity to the care team. CONCLUSION: Bedside resuscitation with umbilical cord intact through the use of a mobile resuscitation trolley is feasible, safe, and effective, but about half of the perinatal providers expressed concerns. Logistical issues such as improved space management and/or delivery setup should be considered in centers planning to perform neonatal resuscitation with an intact cord.

Pregnancy in Desmin-Related Cardiomyopathy.

The course of desmin-related restrictive cardiomyopathy (DRCM) during pregnancy has not been described previously because of the rarity of the condition. Following an episode of heart failure antecedent to conception, a 28-year-old primigravida with DRCM presented to establish prenatal care during the first trimester. Prenatal management consisted of ß-blocker and diuretic therapy, with serial echocardiography to monitor cardiac function. Spontaneous labor ensued at 39 weeks' gestation, and vacuum-assisted delivery was performed for fetal indication. Postpartum blood transfusion was required for symptomatic anemia because of uterine atony, and subsequent maternal and neonatal courses were uncomplicated. Cardiac evaluation postpartum demonstrated stable maternal status. Pregnancy in women with controlled DRCM is not contraindicated, however, it requires careful planning and monitoring during the antenatal, intrapartum, and postpartum periods. On the basis of this report, pregnancy does not appear to exert a permanent deleterious effect on cardiac function in women with DRCM.

Persistent Notochord in a Fetus with COL2A1 Mutation.

Multiple anomalies including micromelia, poor mineralization of the vertebrae, and a persistent notochord were identified on second trimester ultrasound in a fetus with a COL2A1 mutation. To our knowledge, this represents the first case of a persistent notochord associated with a COL2A1 mutation in humans. In this case report, we describe ultrasound and postmortem findings and review the pathogenesis associated with a persistent notochord.

Perinatal factors in neonatal and pediatric lung diseases.

Wheezing and asthma are significant clinical problems for infants and young children, particularly following premature birth. Recurrent wheezing in infants can progress to persistent asthma. As in adults, altered airway structure (remodeling) and function (increased bronchoconstriction) are also important in neonatal and pediatric airway diseases. Accumulating evidence suggests that airway disease in children is influenced by perinatal factors including perturbations in normal fetal lung development, postnatal interventions in the intensive care unit (ICU) and environmental and other insults in the neonatal period. Here, in addition to genetics, maternal health, environmental processes, innate immunity and impaired lung development/function can all influence pathogenesis of airway disease in children. We summarize current understanding of how prenatal and postnatal factors can contribute to development of airway diseases in neonates and children. Understanding these mechanisms will help identify and develop novel therapies for childhood airway diseases.