Respiratory Support as a Source of Plasticizer Exposure in Premature Neonates.

Plasticizers like di-(2-ethylhexyl) phthalate (DEHP) are commonly used in medical devices to enhance plastic flexibility. DEHP is classified as a CMR1b substance due to its adverse effects on reproduction and fertility, and it has been linked to neurodevelopmental disorders such as ADHD, autism spectrum disorder, and learning disabilities. While DEHP is scheduled for phase-out by 2030, data on the developmental neurotoxicity (DNT) of alternative plasticizers remain scarce. We evaluated the DNT potential of DEHP and three alternative plasticizers: di-(2-ethylhexyl) terephthalate (DEHT), di-(2-ethylhexyl) adipate (DEHA), and tris-(2-ethylhexyl) trimellitate (TOTM), aiming to identify safer substitutes, particularly for neonates in neonatal intensive care units (NICUs). The human Neurosphere Assay was used to assess plasticizer effects on seven key neurodevelopmental processes: neural progenitor cell (NPC) proliferation, migration of radial glia, neurons, and oligodendrocytes, neurite outgrowth, and differentiation of neurons and oligodendrocytes. Concentration-response analyses provided benchmark concentrations (BMCs) and lowest observed adverse effect concentrations (LOAECs). Gene expression profiling provided mechanistic insights, and toxicity was ranked using the most sensitive endpoint (MSE) and ToxPi Tool. DEHP and TOTM showed the highest DNT potential, with NPC proliferation as the MSE. DEHT impacted oligodendrocyte differentiation, while no BMC was determined for DEHA within the tested concentrations. Considering an exposure scenario in NICUs, the estimated neonatal DEHP plasma levels exceeded the LOAEC for NPC proliferation, raising concerns for DNT. Overall, DEHA emerged as the least hazardous alternative for neurodevelopment, highlighting the value of combined human-relevant in vitro phenomics and human biomonitoring for DNT hazard evaluation.

One year respiratory and neurodevelopmental outcome of premature neonates after exposure to plasticizers in the neonatal intensive care unit - A prospective cohort study.

Introduction: In Nigeria, eighty two percent of the three leading causes of neonatal mortality may require respiratory support for their management, yet this is unavailable.Objective: To review the spectrum of respiratory disorders that were ventilated, their outcomes and the contribution of such support to survivalMethods: A data base of cases managed in the unit is maintained and reviewed regularly for enhancement of quality of care. Such prospectively documented information on babies who received respiratory support over the period 1st January to 31st June 2014 were analysed.Results: Five hundred and seventy six babies were admitted. Fortynine (8, 5%) received ventilator support. These comprised preterm (77.6%) and term (22.4%) babies with mean gestational age of 33.2 weeks (range 28-41). The spectrum of disorders supported were: respiratory distress syndrome (RDS) 55.1%, asphyxia 20.4%, sepsis12.3%, acute bilirubin encephalopathy (ABE) 8.2%, transient tachypnoea of the new-born (TTNB) 2% and neonatal tetanus (NT) 2%. They were non- invasive support (NIVRS) 33(67.3%) for respiratory distress; invasive support (IVRS) 16(32.7%) for respiratory failure. NIVRS was mostly for RDS (88.9%); ABE (100%) received invasive support. Mortality was: NIVRS7/33(21.2%); IVRS 11/16(68.75 %). Respiratory dysfunction contributed 25.4% of the total neonatal mortality of 123 per thousand. Survival was 63.3%.Conclusion: The morbidities were: asphyxia, prematurity, sepsis, ABE, and tetanus. Ventilator support was non-invasive with bubble CPAP and invasive with mechanical ventilation through endotracheal intubation. Survival was improved. There is the urgent need to commence and sustain basic non -invasive respiratory support in all neonatal units in Nigeria.Keywords: Spectrum; Neonatal diseases; Respiratory support

Di(2-ethylhexyl)phthalate leached from medical PVC devices serves as a substrate and inhibitor for the P-glycoprotein

The harmful effects of mechanical ventilation (MV) on the preterm lung are well established. Avoiding MV at birth and stabilization on continuous positive airway pressure (CPAP) decreases the composite outcome of death or bronchopulmonary dysplasia. Although preterm infants are increasingly being admitted to the neonatal intensive care unit on CPAP, centers differ in the ability to manage infants primarily on CPAP. Over the last decade, less invasive surfactant administration (LISA), a method of administering surfactant with a thin catheter, has been devised and has been shown to decrease the need for MV and improve outcomes compared to surfactant administration via an endotracheal tube following intubation. While LISA has been widely adopted in Europe and other countries, its use is not widespread in the United States. This article provides a summary of the existing evidence on LISA, and practical guidance for US units choosing to implement a change of practice incorporating optimization of CPAP and LISA.Impact The accumulated body of evidence for less invasive surfactant administration (LISA), a widespread practice in other countries, justifies its use as an alternative to intubation and surfactant administration in US neonatal units.This article summarizes the current evidence for LISA, identifies gaps in knowledge, and offers practical tips for the implementation of LISA as part of a comprehensive non-invasive respiratory support strategy.This article will help neonatal units in the US develop guidelines for LISA, provide optimal respiratory support for infants with respiratory distress syndrome, improve short- and long-term outcomes of preterm infants, and potentially decrease costs of NICU care.

Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, is a ubiquitous environmental contaminant and may act as an endocrine disruptor. Early life exposures to DEHP may result in anti-androgenic effects, impairing the development of the male reproductive tract. However, data on the long-lasting consequences of such DEHP exposures on adult male reproductive function are still rare and discrepant. Previously, we identified 2 novel plasticizers, 1,4-butanediol dibenzoate (BDB) and dioctyl succinate (DOS), as potential substitutes for DEHP that did not reproduce classically described endocrine disrupting phenotypes in prepubertal male offspring after maternal exposure. Here, we investigated the consequences of in utero and lactational exposure to BDB and DOS on adult male rat reproductive function in a comparative study with DEHP and a commercially available alternative plasticizer, 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). Timed pregnant Sprague Dawley rats were gavaged with vehicle or a test chemical (30 or 300 mg/kg/day) from gestation day 8 to postnatal day 21. While DEHP exposure (300 mg/kg/day) significantly increased epididymal weight in the adult, exposure to DINCH, BDB, or DOS did not affect reproductive organ weights, steroid levels, or sperm quality. Using a toxicogenomic microarray approach, we found that adult testicular gene expression was affected by exposure to the higher dose of DEHP; transcripts such as Nr5a2, Ltf, or Runx2 were significantly downregulated, suggesting that DEHP was targeting estrogen signaling. Lesser effects were observed after treatment with either DINCH or BDB. DOS exposure did not produce such effects, confirming its potential as a responsible substitute for DEHP.

Biomarkers of phthalates and alternative plasticizers in the Flemish Environment and Health Study (FLEHS IV): Time trends and exposure assessment.

ObjectiveTo identify the neonatal, pediatric and mixed (neonatal and pediatric) intensive care units in Brazil that use cuffed tracheal tubes in clinical practice and to describe the characteristics related to the use of protocols and monitoring.MethodsTo identify the intensive care units in Brazil, the Ministry of Health’s National Registry of Health Facilities was accessed, and information was collected on 693 registered intensive care units. This was an analytical cross-sectional survey conducted through electronic questionnaires sent to 298 neonatal, pediatric and mixed intensive care units in Brazil.ResultsThis study analyzed 146 questionnaires (49.3% from neonatal intensive care units, 35.6% from pediatric intensive care units and 15.1% from mixed pediatric intensive care units). Most of the participating units (78/146) used cuffed tracheal tubes, with a predominance of use in pediatric intensive care units (52/78). Most of the units that used cuffed tracheal tubes applied a cuff pressure monitoring protocol (45/78). The use of cuff monitoring protocols was observed in intensive care units with a physical therapy service exclusive to the unit (38/61) and in those with a physical therapist present 24 hours/day (25/45). The most frequent cause of extubation failure related to the use of cuffed tracheal tubes in pediatric intensive care units was upper airway obstruction.ConclusionIn this survey, the use of cuffed tracheal tubes and the application of a cuff pressure monitoring protocol was predominant in pediatric intensive care units. The use of a monitoring protocol was more common in intensive care units that had a physical therapist who was exclusive to the unit and was present 24 hours/day.

An adenovirus (Ad) type 8 outbreak was prospectively studied in a neonatal intensive care unit. Nasopharyngeal secretions were cultured weekly for viruses and clinical information was obtained daily in each infant. Eleven of 112 neonates were infected with Ad; 8 of 9 available isolates represented one variant of Ad 8. The median age at infection was 54 days and the median duration of virus shedding was 2 days. Seven of 11 infants had onset of new symptoms and/or required acute respiratory support; only 2 infants had eye disease. Maternal characteristics, race, gender, age at entry into study and respiratory distress syndrome at birth were similar for both groups. Ad-infected infants tended to have earlier gestations and lower birth weights. Ad-infected neonates stayed longer in the neonatal intensive care unit, required more days of respiratory support and were more likely to develop bronchopulmonary dysplasia. Thus an association was established between lung disease in premature neonates and Ad infection.

Di(2-ethylhexyl)phthalate (DEHP) is a reproductive and developmental toxicant in animals and a suspected endocrine modulator in humans. There is widespread exposure to DEHP in the general population. Patients can be additionally exposed through DEHP-containing medical devices. Toxicokinetic and metabolic knowledge on DEHP in humans is vital not only for the toxicological evaluation of DEHP but also for exposure assessments based on human biomonitoring data. Secondary oxidized DEHP metabolites like mono-(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono-[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) are most valuable biomarkers of DEHP exposure. They represent the major share of DEHP metabolites excreted in urine (about 70% for these four oxidized metabolites vs. about 6% for MEHP); they are immune to external contamination and possibly the ultimate developmental toxicants. Long half-times of elimination make 5cx-MEPP and 2cx-MMHP excellent parameters to measure the time-weighted body burden to DEHP. 5OH-MEHP and 5oxo-MEHP more reflect the short-term exposure. We calculated the daily DEHP intake for the general population (n = 85) and for children (n = 254). Children were significantly higher exposed to DEHP than adults. Exposures at the 95th percentile (21 and 25 microg/kg/day, respectively) scooped out limit values like the Reference Dose (RfD, 20 microg/kg/day) and the Tolerable Daily Intake (TDI, 20-48 microg/kg/day) to a considerable degree. Up to 20-fold oversteppings for some children give cause for concern. We also detected significant DEHP exposures for voluntary platelet donors (n = 12, 38 microg/kg/apheresis, dual-needle technique). Premature neonates (n = 45) were exposed to DEHP up to 100 times above the limit values depending on the intensity of medical care (median: 42 microg/kg/day; 95th percentile: 1,780 microg/kg/day).

BackgroundThere have been several reports on neonates with milk allergy in a neonatal ward. This type of allergy is mostly categorized as a non-IgE-mediated food allergy. Although most cases of milk allergy occur in the first few months of life, the differences in clinical characteristics between premature and full-term neonates are still unclear.ObjectiveThis study aimed to clarify the differences in clinical characteristics of milk allergy between premature and full-term neonates.MethodsWe retrospectively evaluated 2,116 neonates admitted to the Department of Neonatology, Chiba Kaihin Municipal Hospital, between 2001 and 2007.ResultsWe identified 24 neonates strongly suspected of having milk allergy because of symptoms, such as bloody stools, repeated vomiting, diminished sucking and abdominal distension, as well as objective laboratory findings of eosinophilia in stool cytology and/or positive results for a rectal milk challenge test. Twelve of these 24 neonates were premature (median gestational age, 31 ± 3 weeks; median birth weight, 1,656 ± 592 g) and the other 12 were full-term (median gestational age, 38 ± 1 weeks; median birth weight, 2,760 ± 560 g). There were no differences in symptoms and time to start of feeding between premature and full-term neonates, but there was a significant difference in the median postnatal age at onset (premature neonates: 23 days; vs. full-term neonates: 3.5 days; p < 0.01).ConclusionAll premature neonates developed a milk allergy after 32 weeks of corrected gestational age, suggesting that the development of milk allergy requires a certain degree of immunological maturation.

Surveillance of Multidrug-resistant Gram-negative Pathogens in High-risk Neonates—Does it Make a Difference?

Extremely preterm infants commonly suffer from respiratory distress syndrome. Ventilatory management of these infants starts from birth and includes decisions such as timing of respiratory support in relation to umbilical cord management, oxygenation targets, and options of positive pressure support. The approach of early intubation and surfactant administration through an endotracheal tube has been challenged in recent years by primary noninvasive respiratory support and newer methods of surfactant administration via thin catheters. Available data comparing the thin catheter method to endotracheal tube and delayed extubation in extremely preterm infants born before 28 weeks of gestation did not show differences in survival free of bronchopulmonary dysplasia. Data from numerous randomized trials comparing conventional ventilation with high‐frequency oscillatory ventilation did not show differences in meaningful outcomes. Among conventional modes of ventilation, there is good evidence to favor volume‐targeted ventilation over pressure‐limited ventilation. The former reduces the combined risk of bronchopulmonary dysplasia or death and several important secondary outcomes without an increase in adverse events. There are no evidence‐based guidelines to set positive end‐expiratory pressure in ventilated preterm infants. Recent research suggests that the forced oscillation technique may help to find the lowest positive end‐expiratory pressure at which lung recruitment is optimal. Benefits and risks of the various modes of noninvasive ventilation depend on the clinical setting, degree of prematurity, severity of lung disease, and competency of staff in treating associated complications. Respiratory care after discharge includes home oxygen therapy, lung function monitoring, weaning from medication started in the neonatal unit, and treatment of asthma‐like symptoms.

Exposure to environmental chemicals has adverse effects on the health and survival of humans. Emerging evidence supports the idea that exposure to endocrine-disrupting compounds (EDCs) can perturb an individual's physiological set point and as a result increase his/her propensity toward several diseases. The purpose of this review is to provide an update on di-(2-ethylhexyl) phthalate, the primary plasticizer found in plastic medical devices used in neonatal intensive care units, its effects on the fetus and newborn, epidemiological studies, pharmacokinetics, toxicity and epigenetic implications. We searched the PubMed databases to identify relevant studies. Phthalates are known EDCs that primarily are used to improve the flexibility of polyvinyl chloride plastic products and are called plasticizers in lay terms. Neonates and infants are particularly vulnerable to the effects of phthalates, beginning with maternal exposure and placental transfer during gestation and during infancy following birth. In line with the developmental origins of adult disease, a focus on the effects of environmental chemicals in utero or early childhood on the genesis of adult diseases through epigenome modulation is timely and important. The epigenetic effects of phthalates have not been fully elucidated, but accumulating evidence suggests that they may be associated with adverse health effects, some of which may be heritable. Phthalate exposure during pregnancy and the perinatal period is particularly worrisome in health-care settings. Although the clinical significance of phthalate exposure has been difficult to assess with epidemiologic studies, the evidence that physiological changes occur due to exposure to phthalates is growing and points toward the need for more investigation at a molecular, specifically epigenetic level.

Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult male