Exposure Of Premature Infants Research Articles

Early Life Stress, DNA Methylation of NR3C1 and HSD11B2 , and Oral Feeding Skill Development in Preterm Infants : A Pilot Study.

Early life stress exposure in preterm infants may alter DNA methylation of NR3C1 and HSD11B2 , disrupting neurobehaviors needed for oral feeding (PO) skill development. To (1) examine the feasibility of the study protocol; (2) describe early life stress, DNA methylation of NR3C1 and HSD11B2 , and PO skill development; and (3) explore the association between DNA methylation of NR3C1 and HSD11B2 and infant characteristics, early life stress, and PO skill development. We employed a longitudinal descriptive pilot study (N=10). Infant characteristics were collected from the infant's electronic medical record. Early life stress was assessed via the modified Neonatal Infant Stressor Scale. DNA methylation of NR3C1 exon 1F and HSD11B2 promoter regions was analyzed from the infant's buccal samples. PO skill development was evaluated using the Early Feeding Skills Assessment. Infants who experienced more acute and chronic stress during their neonatal intensive care unit hospitalization demonstrated higher DNA methylation at CpG 17 and 31 of the NR3C1 exon 1F and at CpG 4 and 28 of the HSD11B2 promoter regions. Infants with higher DNA methylation at these CpG sites also exhibited less optimal PO skill development and experienced longer transition from first to full PO. Our findings revealed relationships among early life stress, DNA methylation of NR3C1 and HSD11B2 , and PO skill development in preterm infants. Future research is warranted to examine the multiomics pathways whereby early life stress influences the phenotypes of infant outcomes.

Platelet-Derived Growth Factor Subunit A Strengthens the Neurovascular Unit and Inhibits Retinal Vascular Regression Under Hyperoxic Conditions.

Retinopathy of prematurity (ROP) is primarily caused by the exposure of preterm infants with underdeveloped blood vessels to high oxygen concentrations. This damages the astrocytes that promote normal vascular development, leading to avascularity, pathological neovascularization, and retinal detachment, and even blindness as the disease progresses. In this study, the aim was to investigate the differences in the characteristics of astrocytes and blood vessels between wild-type (WT) and genetically modified mice overexpressing platelet-derived growth factor subunit A (PDGF-A) in the retina immediately after high oxygen exposure, a protocol in the oxygen-induced retinopathy (OIR) model of ROP. Our results showed that PDGF-A mice exhibited an increased population of astrocytes and higher vascular density than WT mice and that PDGF-A strengthened the resistance to hyperoxic conditions. In the OIR model, PDGF-A mice had reduced avascular zone areas following hyperoxia exposure. Furthermore, immunostaining for NG2 and CD31 showed that pericytes tended to regress earlier than endothelial cells, particularly at the vessel edges in both WT and transgenic mice, indicating relatively higher susceptibility to hyperoxia-induced damage. These findings suggest that PDGF-A plays a crucial role in stabilizing retinal vessels and may serve as a novel therapeutic target for ROP, highlighting the potential significance of PDGF-A in the pathological mechanisms of retinal diseases.

Lead Exposure in Preterm Infants Receiving Packed Red Blood Cell Transfusions

Abstract Background The frequency of anemia is high in very low birth weight (VLBW) infants in the neonatal intensive care units (NICU). Blood transfusion has been associated with significant morbidity among which what is related to the increased lead content of blood. Aim of the Work To evaluate pre- and post-transfusion serum lead level in preterm neonates with birth weight of 1500 grams (VLBW) receiving packed red blood cells (PRBCs) transfusions and correlate these levels to lead concentrations in the transfused PRBCs and to evaluate effect of environmental prenatal maternal exposure to lead on neonatal serum lead level. Methods This a prospective cohort study and was conducted on 45 preterm infants who were admitted to NICUs of Ain Shams university hospitals. All selected neonates were subjected to full maternal, natal and postnatal history, full clinical evaluation, laboratory investigations including measurement of serum lead level, hemoglobin and hematocrit pre and post-transfusion. By using the 2010 Centers for Disease Control and Prevention (CDC) guidelines for identification of lead exposure in pregnant and lactating women, studied mothers who met one of these criteria (Living near lead mines, smelters or battery recycling plants, working with lead, use lead glazed ceramic pottery, renovating or remodeling older homes without lead hazard controls, using imported cosmetics or certain food may be contaminated with lead, eating nonfood substances (pica) contaminated with lead, and/or consumption of lead contaminated drinking water) were considered at risk of environmental exposure to lead Results Twenty-three of studied infants (51.1%) were females, and 22 (48.9%) were males. Their gestational ages were ranged between 27 to 33 weeks with mean ± SD: 29.91± 2.03 weeks and their weights ranged between 700 to 1500 grams with mean ± SD: 1228.4 ± 222.16 grams. Regarding pretransfusion hematological parameters, the mean hemoglobin (Hb) concentration was 7.2 ± 1.5 g/dl and the mean hematocrit (HCT) percent was 28.9 ± 5.05%. while, post-transfusion mean Hb concentration was 11.2 ± 1.3 g/dl and the mean HCT was 38.4 ± 4.8%. Pretransfusion serum leads levels ranged between 0.3 to 23 pg/L with median (IQR): 4.7 (0.71 - 1.8) pg/L. While post-transfusion lead levels ranged between 0.6 - 20 7 pg/L with median (IQR): 7 (0.89 - 2.4) pg/L. The post-transfusion lead level was significantly higher than the pre-transfusion lead levels with p-value: 0.009. There was a significant correlation between the increase in posttransfusion lead level and lead levels in transfused PRBCs. Regarding prenatal maternal lead exposure, 29 (64.4%) of mothers showed positive history of lead exposure (17 mothers were working in lead, 10 mothers were using cheap and unknow cosmetics, 10 were using Ceramic utensils) while 16 (35.6%) showed no history of lead exposure, there was no statistically significant difference between infants with history of environment prenatal maternal lead exposure and those without regarding gestational ages, weight, pre-transfusion Hb concentration, Hematocrit and serum lead levels. Conclusion Blood transfusions is a source of lead and therefore, it should be considered when administering blood transfusions to infants, particularly to very preterm babies.

Decreasing early invasive mechanical ventilation exposure in preterm infants: a quality improvement initiative.

To decrease invasive mechanical ventilation exposure in the neonatal intensive care unit (NICU) in the first week of life for preterm infants with the global aim of decreasing bronchopulmonary dysplasia (BPD). We created a quality improvement (QI) initiative to optimize early non-invasive respiratory support which launched in August 2021. Patients born at <32 weeks gestation and admitted to the NICU on non-invasive respiratory support were included. Invasive mechanical ventilation exposure decreased from 38 to 25% with evidence of special cause variation beginning in August 2022. Infants born at ≥26 weeks were most impacted, with a 50% reduction, from 34 to 17%. While BPD rates decreased, there has not yet been evidence of special cause variation. Invasive mechanical ventilation exposure for infants born at <32 weeks gestation decreased following the creation of a QI initiative focused on optimization and standardization of early non-invasive respiratory support.

Pre-post implementation study of chronic diuretic clinical practice guideline for bronchopulmonary dysplasia in preterm infants

Pre-post implementation study of chronic diuretic clinical practice guideline for bronchopulmonary dysplasia in preterm infants

The Detrimental Effects of Peripartum Antibiotics on Gut Proliferation and Formula Feeding Injury in Neonatal Mice Are Alleviated with Lactobacillus rhamnosus GG.

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined mechanisms by which peripartum antibiotics increase neonatal gut injury and evaluated whether probiotics protect against gut injury potentiated by peripartum antibiotics. To accomplish this objective, we administered broad-spectrum antibiotics or sterile water to pregnant C57BL6 mice and induced neonatal gut injury to their pups with formula feeding. We found that pups exposed to antibiotics had reduced villus height, crypt depth, and intestinal olfactomedin 4 and proliferating cell nuclear antigen compared to the controls, indicating that peripartum antibiotics impaired intestinal proliferation. When formula feeding was used to induce NEC-like injury, more severe intestinal injury and apoptosis were observed in the pups exposed to antibiotics compared to the controls. Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) reduced the severity of formula-induced gut injury potentiated by antibiotics. Increased intestinal proliferating cell nuclear antigen and activation of the Gpr81-Wnt pathway were noted in the pups supplemented with LGG, suggesting partial restoration of intestinal proliferation by probiotics. We conclude that peripartum antibiotics potentiate neonatal gut injury by inhibiting intestinal proliferation. LGG supplementation decreases gut injury by activating the Gpr81-Wnt pathway and restoring intestinal proliferation impaired by peripartum antibiotics. Our results suggest that postnatal probiotics may be effective in mitigating the increased risk of NEC associated with peripartum antibiotic exposure in preterm infants.

Duration of Neonatal Antibiotic Exposure in Preterm Infants in Association with Health and Developmental Outcomes in Early Childhood

Over 90% of preterm neonates are, often empirically, exposed to antibiotics as a potentially life-saving measure against sepsis. Long-term outcome in association with antibiotic exposure (NABE) has insufficiently been studied after preterm birth. We investigated the association of NABE-duration with early-childhood developmental and health outcomes in preterm-born children and additionally assessed the impact of GA on outcomes. Preterm children (GA &lt; 30 weeks) participating in a multicenter cohort study were approached for follow-up. General expert-reviewed health questionnaires on respiratory, atopic and gastrointestinal symptoms were sent to parents of children &gt; 24 months’ corrected age (CA). Growth and developmental assessments (Bayley Scales of Infant and Toddler Development (BSID) III) were part of standard care assessment at 24 months’ CA. Uni- and multivariate regressions were performed with NABE (per 5 days) and GA (per week) as independent variables. Odds ratios (OR) for health outcomes were adjusted (aOR) for confounders, where appropriate. Of 1079 infants whose parents were approached, 347 (32%) responded at a mean age of 4.6 years (SD 0.9). In children with NABE (97%), NABE duration decreased by 1.6 days (p &lt; 0.001) per week of gestation. Below-average gross-motor development (BSID-III gross-motor score &lt; 8) was associated with duration of NABE (aOR = 1.28; p = 0.04). The aOR for constipation was 0.81 (p = 0.04) per gestational week. Growth was inversely correlated with GA. Respiratory and atopic symptoms were not associated with NABE, nor GA. We observed that prolonged NABE after preterm birth was associated with below-average gross-motor development at 24 months’ CA, while a low GA was associated with lower weight and stature Z-scores and higher odds for constipation.

Scoping Review of Early Toxic Stress and Epigenetic Alterations in the Neonatal Intensive Care Unit.

Preterm infants are uniquely vulnerable to early toxic stress exposure while in the neonatal intensive care unit (NICU) and also being at risk for suboptimal neurodevelopmental outcomes. However, the complex biological mechanisms responsible for variations in preterm infants' neurodevelopmental outcomes because of early toxic stress exposure in the NICU remain unknown. Innovative preterm behavioral epigenetics research offers a possible mechanism and describes how early toxic stress exposure may lead to epigenetic alterations, potentially affecting short- and long-term outcomes. The aim of this study was to review the relationships between early toxic stress exposures in the NICU and epigenetic alterations in preterm infants. The measurement of early toxic stress exposure in the NICU and effect of epigenetic alterations on neurodevelopmental outcomes in preterm infants were also examined. We conducted a scoping review of the literature published between January 2011 and December 2021 using databases PubMed, CINAHL, Cochrance Library, PsycINFO, and Web of Science. Primary data-based research that examined epigenetics, stress, and preterm infants or NICU were included. A total of 13 articles from nine studies were included. DNA methylations of six specific genes were studied in relation to early toxic stress exposure in the NICU: SLC6A4, SLC6A3, OPRMI, NR3C1, HSD11B2, and PLAGL1. These genes are responsible for regulating serotonin, dopamine, and cortisol. Poorer neurodevelopmental outcomes were associated with alterations in DNA methylation of SLC6A4, NR3C1, and HSD11B2. Measurements of early toxic stress exposure in the NICU were inconsistent among the studies. Epigenetic alterations secondary to early toxic stress exposures in the NICU may be associated with future neurodevelopmental outcomes in preterm infants. Common data elements of toxic stress exposure in preterm infants are needed. Identification of the epigenome and mechanisms by which early toxic stress exposure leads to epigenetic alterations in this vulnerable population will provide evidence to design and test individualized intervention.

Low nephron endowment increases susceptibility to renal stress and chronic kidney disease.

Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated potentially novel mouse models with a 30%-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy, followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared with controls with normal nephron number. Mice with low nephron number had reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.

Invasive fungal infection is associated with antibiotic exposure in preterm infants: a multi-centre prospective case–control study

Previous antibiotic exposure is an important risk factor for invasive fungal infection (IFI). Antibiotic overexposure is common in lower-income countries; however, multi-centre studies concerning IFI in relation to antibiotic exposure are scarce. This prospective, multi-centre matched case-control study explored the correlation of IFI and antibiotic exposure in very preterm infants or very-low-birthweight infants admitted to 23 tertiary hospitals in China between 2018 and 2021. Using a 1:2 matched design for gestational age, birth weight and early-onset sepsis (yes/no), the risk factors between infants diagnosed with IFI and infection-free controls were compared. The antibiotic use rate (AUR) was calculated using calendar days of antibiotic therapy in the 4 weeks preceding IFI onset divided by onset day of IFI. In total, 6368 infants were included in the study, of which 90 (1.4%) were diagnosed with IFI. Median AUR, length of antibiotic therapy (LOT) and days of antibiotic therapy (DOT) within the 4 weeks preceding IFI onset were 0.90, 18 days and 30 days, respectively. Multi-variate analysis showed that a 10% increase in AUR, each additional day of DOT and LOT, and each additional day of third-generation cephalosporins and carbapenems were notably associated with IFI. Prolonged antibiotic therapy is common before the onset of IFI, and is an important risk factor, especially the use of third-generation cephalosporins and carbapenems. Antibiotic stewardship should be urgently developed and promoted for preterm infants in order to reduce IFI in lower-income countries such as China.

Prenatal tobacco smoke exposure and risk of brain abnormalities on magnetic resonance imaging at term in infants born very preterm

Prenatal tobacco smoke exposure and preterm birth are associated with abnormal brain and neurodevelopmental outcomes in infants. Studies that can disentangle indirect mediating effects from direct effects of prenatal tobacco smoke exposure on sensitive early brain magnetic resonance imaging biomarkers in very preterm infants are needed. This study aimed to determine whether prenatal tobacco smoke exposure in preterm infants posed any direct effects on magnetic resonance imaging-determined global brain abnormality score and secondary measures of brain abnormalities after removing any indirect mediating effects of preterm birth on neurostructural outcomes. We examined brain magnetic resonance imaging findings collected at 39 to 44 weeks postmenstrual age from a prospective cohort of 395 infants born very preterm (gestational age of ≤32 weeks). The primary outcome was global brain abnormality score, and the secondary outcomes were global efficiency of structural connectome, diffuse white matter abnormality volume, total brain tissue volume, total gray and white matter volumes, and cerebellar volume. Maternal reports of smoking during pregnancy were obtained. We performed multivariable linear regression analyses to examine the association between prenatal tobacco smoke exposure and our magnetic resonance imaging outcomes, controlling for prospectively collected confounders. Moreover, we performed a mediation analysis to estimate the direct effects of prenatal tobacco smoke exposure on brain abnormalities and any indirect effects through preterm birth. Overall, 12.6% of infants had prenatal tobacco smoke exposure. Infants with prenatal tobacco smoke exposure had a higher median global brain abnormality score than nonexposed infants (7 [interquartile range, 0-41] vs 5 [interquartile range, 0-34]; P≤.001); the findings remained significant (P<.001) after controlling for antenatal confounders. Global efficiency (P<.001), diffuse white matter volume (P=.037), and total brain tissue volume (P=.047) were significantly different between TSE groups in multivariable analyses. On mediation analysis, preterm birth mediated between 0% and 29% of the indirect effect of prenatal tobacco smoke exposure on several measures of brain abnormality outcomes. Thus, prenatal tobacco smoke exposure had a direct adverse effect between 71% and 100% on brain injury or abnormal development. Our study has identified multiple adverse effects of prenatal tobacco smoke exposure on sensitive and objective measures of neonatal brain injury and abnormal development; most cases seemed to be a direct effect of prenatal tobacco smoke exposure on fetal brain development. The results underscored the significant adverse neurostructural effects of prenatal tobacco smoke exposure to tobacco smoke pollutants.

565. Pilot Study of Prolonged Post-Discontinuation Antibiotic Exposure (PDAE) to Ampicillin Among Low Birthweight Preterm Infants

Abstract Background In the United States, 75% of preterm infants receive ampicillin after birth for evaluation of early onset sepsis. Excess antibiotic exposure in preterm infants is associated with morbidity and mortality. Pharmacokinetic (PK) simulations suggest that very low birthweight (&amp;lt; 1500g) infants receiving ampicillin may experience excess and prolonged therapeutic exposures to ampicillin after drug discontinuation, called post-discontinuation antibiotic exposures (PDAE). It is unknown if low birthweight ( &amp;gt; 1500g to &amp;lt; 2500g) infants that receive ampicillin experience prolonged PDAE. Methods We conducted a pilot prospective PK clinical trial at a single tertiary care center. We enrolled infants with gestational age (GA) &amp;lt; 36 weeks and birthweight (BW) &amp;gt; 1500g and &amp;lt; 2500g who received ampicillin 200 mg/kg/day per standard of care. All infants received 6 ampicillin 66mg/kg doses administered Q8H within 24 hours following birth. Post-discontinuation PK samples were collected between 8-120 hours after the last dose of ampicillin. We performed descriptive statistics on patient characteristics, and graphically displayed ampicillin plasma concentrations following discontinuation. We defined therapeutic exposures as concentrations above the minimum inhibitory concentration (MIC) for Group B Streptococcus (0.25mcg/mL). Results We analyzed 20 PK samples from 12 infants with median (IQR) GA of 32 weeks (31, 34) and BW of 1838g (1730, 2060). See Table 1 for clinical characteristics. All infants (N=8) with post-discontinuation samples collected within 48 hours of last dose had continued therapeutic ampicillin exposures, only 25% of infants had continued therapeutic exposures between 48 and 72 hours post last dose (N=4), and none had therapeutic ampicillin exposures beyond 72 hours post-dose (Figure 1). Samples (n=5) within 24 hours of last dose had median (IQR) ampicillin concentration of 13.2mcg/mL (9.2, 18.7); those within 25-48 hours (n=3) had median concentration of 0.9 mcg/mL (0.6, 2.2). TABLE 1.Enrolled Patient Characteristics and Plasma Ampicillin ConcentrationsFigure 1.Ampicillin Post-Discontinuation Antibiotic Exposures in Low Birthweight Infants (1500g-2500g)MIC = minimum inhibitory concentration. GBS = Group B Streptococcus. Each individual symbol represents one sample collected. MICs based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (8 for E. coli, 0.25mcg/mL for Group B Streptococcus). Conclusion In this small cohort of premature infants, exposures of ampicillin remained therapeutic for at least 24 hours post drug discontinuation and suggests that shorter duration of empirical ampicillin treatments may be warranted in this population. Disclosures Daniel Benjamin, Jr., MD PhD MPH, Allergan: Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant|Syneos Health: Advisor/Consultant Rachel Greenberg, MD, MB, MHS, Provepharm Inc: Advisor/Consultant|Tellus Therapeutics: Advisor/Consultant.

Breast Milk Exposure is Associated With Cortical Maturation in Preterm Infants.

Breast milk exposure is associated with improved neurocognitive outcomes following preterm birth but the neural substrates linking breast milk with outcome are uncertain. We tested the hypothesis that high versus low breast milk exposure in preterm infants results in cortical morphology that more closely resembles that of term-born infants. We studied 135 preterm (<32 weeks' gestation) and 77 term infants. Feeding data were collected from birth until hospital discharge and brain magnetic resonance imaging (MRI) was performed at term-equivalent age. Cortical indices (volume, thickness, surface area, gyrification index, sulcal depth, and curvature) and diffusion parameters (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], axial diffusivity [AD], neurite density index [NDI], and orientation dispersion index [ODI]) were compared between preterm infants who received exclusive breast milk for <75% of inpatient days, preterm infants who received exclusive breast milk for ≥75% of inpatient days and term-born controls. To investigate a dose response effect, we performed linear regression using breast milk exposure quartile weighted by propensity scores. In preterm infants, high breast milk exposure was associated with reduced cortical gray matter volume (d=0.47, 95% confidence interval [CI]=0.14 to 0.94, p=0.014), thickness (d=0.42, 95% CI=0.08 to 0.84, p=0.039), and RD (d=0.38, 95% CI=0.002 to 0.77, p=0.039), and increased FA (d=-0.38, 95% CI=-0.74 to -0.01, p=0.037) after adjustment for age at MRI, which was similar to the cortical phenotype observed in term-born controls. Breast milk exposure quartile was associated with cortical volume (ß=-0.192, 95% CI=-0.342 to -0.042, p=0.017), FA (ß=0.223, 95% CI=0.075 to 0.372, p=0.007), and RD (ß=-0.225, 95% CI=-0.373 to -0.076, p=0.007) following adjustment for age at birth, age at MRI, and weighted by propensity scores, suggesting a dose effect. High breast milk exposure following preterm birth is associated with a cortical imaging phenotype that more closely resembles the brain morphology of term-born infants and effects appear to be dose-dependent. ANN NEUROL 2023;93:591-603.

Association of necrotizing enterocolitis with antimicrobial exposure in preterm infants

Objective: To assess the risk of necrotizing enterocolitis (NEC) and explore the relationship between antibiotic overexposure and disease occurrence in a large prospective birth cohort. Methods: Based on a prospective birth cohort, the study collected hospitalization data of very preterm infants (VPIs) having gestational age of less than 32 weeks from January 1, 2018, to June 30, 2021 via the China Northern Neonatal Network. Infants diagnosed with NEC ≥ stage II were included in the case group, and each case was matched for GA and birth weight for the control group. Furthermore, the risk factors for NEC were determined by statistical analyses. Results: A total of 6425 VPIs were included in this study, and 167 (2.6%) of these subjects were diagnosed with NEC ≥ stage II. The study also included 984 extremely preterm infants (gestational age <28 weeks), including 50 (5.1%) infants diagnosed with NEC ≥ stage II. In the matched case-control study, subjects had a total of antibiotic days-of-therapy for 9015 days, of which broad-spectrum antibiotics (BSAs) accounted for 77%. The antibiotic spectrum index per antibiotic day in the case group was significantly higher and was an independent risk factor for the occurrence of NEC (p = 0.001, OR = 1.13). Conclusion: The cohort of VPIs was overexposed to antiboitics. Unreasonable combination of antibiotics and overexposure to BSAs may increase the risk of NEC in preterm infants.

Fentanyl Exposure in Preterm Infants: Five-Year Neurodevelopmental and Socioemotional Assessment.

ObjectiveTo evaluate the association between cumulative fentanyl dose during neonatal intensive care and 5-year neurodevelopmental and socioemotional outcomes in very preterm infants.Materials and MethodsPatient demographics and clinical factors during the perinatal and neonatal course were collected in 84 patients born between 23- and 30-weeks gestational age (GA). Cumulative fentanyl dose during neonatal intensive care was calculated. Developmental testing at age 5 years included the Wechsler Preschool and Primary Scale of Intelligence Full-Scale Intelligence Quotient, Third Edition, Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, Movement Assessment Battery for Children, Second Edition (MABC-2), and Shape School Assessment. Socioemotional outcomes were assessed via caregiver's responses on the Child Behavior Checklist/1.5-5 (CBCL/1.5-5.5) and Social Responsiveness Scale, Second Edition (SRS-2). Covariates were identified on bivariate analysis (p < 0.1). Linear regression models related outcome measures to the log of cumulative fentanyl dose adjusted for covariates.ResultsHigher cumulative fentanyl dose was associated with lower composite motor scores on bivariate analysis (p < 0.01). Cumulative fentanyl dose did not correlate with composite intelligence quotient, language, or executive function. The Clinical Risk Index for Babies score, log of mechanical ventilation, inotrope, and anesthesia duration, and log of cumulative midazolam and hydrocortisone dose were also associated with MABC-2 scores (p < 0.1). Cumulative fentanyl dose was not associated with composite MABC-2 scores on multiple linear regression. Higher cumulative fentanyl dose was associated with decreased socioemotional problems based on caregiver's response on CBCL/1.5-5.5 t-scores driven by fewer symptoms of depression. The McMaster Family Assessment Device general functioning scale score, maternal age, GA, log of total parenteral nutrition days, patent ductus arteriosus requiring treatment, and log of inotrope hours were also associated with CBCL/1.5-5.5 t-scores (p < 0.1). Cumulative fentanyl dose (p = 0.039) and family dysfunction score (p = 0.002) remained significant after controlling for covariates on multiple linear regression.ConclusionCumulative fentanyl dose during neonatal intensive care did not correlate with 5-year motor, cognitive, or language outcomes after controlling for other variables. Fentanyl dose was associated with caregiver reported total socioemotional problems on the CBCL/1.5-5.5 on multivariate modeling. Additional long-term studies are needed to fully elucidate the safety of fentanyl in very preterm neonates.

Exposure to perfluoroalkyl substances through human milk in preterm infants.

Perfluoroalkyl substances (PFASs) are environmental contaminants that have been shown to exert toxic effects, which are dependent upon concentration, in animals and humans. No specific data on the exposure of preterm infants to PFASs are available. We aimed to quantify the potential exposure of preterm infants to PFASs through human milk (HM), to be compared to the exposure data recently reported for infants by EFSA. The amount of PFASs in ten preterm (PHM) and ten donor HM (DHM) samples was evaluated, and the expected daily intake (EDI) at full enteral feeding was calculated. This EDI was compared to the mean and the 95th centile dietary exposure ranges at the lower bound for infants issued by EFSA. The calculated median EDI for total PFASs was 20.72 ng/kg/day (range 10.72-107.84) for PHM and 17.92 ng/kg/day (range 6.4-28.96) for DHM, which were both higher than mean exposure ranges reported for infants (2.4-12.2 ng/kg/day). The calculated EDI for DHM was far more similar to the 95th centile (4.5-27.9 ng/kg/day) dietary exposure ranges. For PHM samples, higher EDI values were obtained, with 4 out of 10 samples exceeding the upper limit of the 95th centile range.Conclusion: The exposure of preterm infants to PFASs through HM feeding might exceed reference values reported for older and healthier infants. Given the immunological and developmental vulnerability of preterm infants, the risks related to their exposure to PFASs should be further investigated, also focusing on how maternal exposure and subsequent transfer through HM feeding can be reduced. What is Known: • Perfluoroalkyl substances (PFASs) are environmental contaminants that have been shown to exert toxic effects, which are dependent upon concentration, in animals and humans. The EFSA has recently issued reference values for PFASs exposure for different age groups. • Infants might be exposed to PFASs prenatally, as these substances can cross the placenta, and postnatally, through breastfeeding. No specific data about exposure of preterm infants through human milk (HM) feeding are currently available. What is New: • The exposure of preterm infants to PFASs through HM feeding might exceed reference values reported for older and healthier infants. • Given the immunological and developmental vulnerability of preterm infants, the risks related to their exposure to PFASs deserve further investigation. As HM represents the optimal feeding for preterm infants, it will be fundamental to focus on how maternal exposure and subsequent transfer through HM feeding can be reduced.

Pathogenesis of necrotising enterocolitis: The impact of the altered gut microbiota and antibiotic exposure in preterm infants.

Necrotising enterocolitis (NEC) is a devastating condition with high morbidity and mortality seen predominately in preterm infants. Multiple factors are associated with the pathogenesis of NEC. The widespread use of antibiotics in the neonatal intensive care unit might play a role in the pathogenesis of NEC in preterm infants. This review provides a summary on the intestinal microbiota in preterm infants with a focus on how antibiotic exposure may reduce the biodiversity of the intestinal microbiota and may predispose preterm infants to NEC. CONCLUSION: Prolonged antibiotic therapy has been suggested as a risk factor for the development of NEC in preterm infants.

Antibiotics Effects on the Fecal Metabolome in Preterm Infants.

Within a randomized prospective pilot study of preterm infants born at less than 33 weeks’ gestation, weekly fecal samples from 19 infants were collected and metabolomic analysis was performed. The objective was to evaluate for differences in fecal metabolites in infants exposed to antibiotics vs. not exposed to antibiotics in the first 48 h after birth. Metabolomics analysis was performed on 123 stool samples. Significant differences were seen in the antibiotics vs. no antibiotics groups, including pathways related to vitamin biosynthesis, bile acids, amino acid metabolism, and neurotransmitters. Early antibiotic exposure in preterm infants may alter metabolites in the intestinal tract of preterm infants. Broader multi-omic studies that address mechanisms will guide more prudent antibiotic use in this population.

The bioavailability and maturing clearance of doxapram in preterm infants.

Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®). A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CLFORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CLDOXAPRAM OTHER ROUTES was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.

Effect of cumulative dexamethasone dose in preterm infants on neurodevelopmental and growth outcomes: a Western Australia experience

ObjectiveComparing the long-term neurodevelopmental and growth outcomes of lower and higher cumulative dexamethasone exposure in preterm infants ventilated for a minimum cumulative duration of 7 days.DesignA retrospective cohort medical chart...