Evaluation of Gastroesophageal Reflux in Symptomatic Young Infants Using Multichannel Intraluminal pH-Impedance Testing: A large Cohort Study from a Single Center.

OBJECTIVES: This study aimed to assess the use of combined multichannel intraluminal impedance and pH studies (MII-pH) in a large group of symptomatic young infants, to characterize the occurrence of gastroesophageal reflux disease (GERD), and to establish temporal association of the reflux behaviors with gastroesophageal reflux using symptom indices. STUDY DESIGN: This is a retrospective cohort study on 181 infants who underwent MII-pH studies for clinical behaviors that were suggestive of GERD. Symptom index (SI) and symptom association probability (SAP) were used to establish symptom association with reflux. More than 100 GER episodes in 24 hours or acid reflux index > 10% was considered pathological reflux. RESULTS: A total of 181 infants (median age: 60 days, interquartile range [IQR]: 34-108) underwent MII-pH studies with median study duration of 22.41 hours (IQR: 21.5-23.32). A total of 4,070 hours of data were analyzed, with 8,480 reflux events (2,996 [35%] acidic, 5,484 [65%] nonacidic). A total of 2,541 symptoms were noted, 894 (35%) were temporally related to reflux events. A total of 113 infants (62.4%) had positive symptom association with SI > 50% and/or SAP > 95% for at least one symptom. There was modest symptom association for choking and gagging, but apnea, bradycardia, and desaturations had poor symptom association. Only 29 infants (16%) had pathological reflux, and only 18 infants (10%) had both pathological reflux and positive symptom association. CONCLUSION: MII-pH can be used to characterize GERD in young infants, along with establishing temporal association with symptoms. Pathological reflux in symptomatic young infants is not common, but symptom association may occur without frequent or acidic reflux. KEY POINTS: · Gastroesophageal reflux (GER) disease can be studied in young infants using MII-pH, to characterize the frequency and nature of GER events.. · The probability of GER events being associated temporally with GER symptoms can also be determined using MII-pH in this population.. · Using frequency of GER events, reflux indices, and symptom association indices with MII-pH, infants having true GER disease can be identified, thereby reducing unnecessary therapy.. · Symptom association may occur even without frequent or severe acidic reflux..

Sex-Related Differences in the Severity of Neonatal Opioid Withdrawal Syndrome: A Single-Center, Retrospective Cohort Study.

OBJECTIVE: Factors associated with the development and expression of Neonatal Opioid Withdrawal Syndrome (NOWS) are poorly understood. There are conflicting data on the role of infant sex in NOWS. Some studies have suggested that infant sex predicts NOWS severity and adverse outcomes, with male infants being more vulnerable. This study aimed to analyze if infant sex is associated with the severity of NOWS among those who require pharmacologic treatment. STUDY DESIGN: This is a retrospective cohort study of term and late-preterm infants (≥35 weeks gestation) exposed to in utero opioids, born between September 2006 and August 2022, and required pharmacologic treatment for NOWS. Maternal and infant demographics were collected. Indicators of the severity of NOWS (duration of medical treatment (DOT), duration of hospitalization, maximum dose of opioid treatment, and use of secondary medications) were compared between male and female infants. Standard statistical tests and regression analysis were used to establish the differences in outcomes after accounting for confounders and baseline differences. RESULTS: Out of the 1,074 infants included in the study, 47.9% were female, and 52.1% were male. There was no significant difference in demographic and baseline clinical characteristics between groups except for anthropometry (birth weight, head circumference, and length) and Apgar score at 5 minutes. The median DOT (25 days [14, 39] vs. 23 days [13, 39], p = 0.57), length of hospital stay (31.5 days [20, 44] vs. 28 days [20, 44], p = 0.35), treatment with phenobarbital (24.7 vs. 26.3%, p = 0.56), and clonidine (3.9 vs. 3.8%, p = 0.9) were similar in both groups. The differences remained nonsignificant after adjusting for birth anthropometric measurements, gestational age, 5-minute Apgar score, small for gestational age status, and maternal exposure to benzodiazepines. CONCLUSION: In this cohort of neonates, sex-related differences were not identified to influence the severity of NOWS among those who required pharmacological treatment. KEY POINTS: · Vulnerability to NOWS is multifactorial.. · The role of infant sex in the severity of NOWS is not concrete.. · We noted that sex did not impact NOWS severity in those treated..

CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection.

The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.

Buprenorphine vs. morphine: impact on neonatal opioid withdrawal syndrome (NOWS) outcomes in a single center retrospective study.

OBJECTIVES: To compare clinical outcomes for infants with neonatal opioid withdrawal syndrome (NOWS) treated with buprenorphine or morphine. STUDY DESIGN: Retrospective study of infants born ≥35 weeks' gestation and admitted to the NICU for NOWS treatment between 2011 and 2022. Length of treatment, length of stay in the hospital, and the need for secondary medications were compared between buprenorphine and morphine treated neonates. Multiple regression analysis was performed, adjusting for baseline differences and confounders. RESULTS: 417 neonates were treated with morphine and 232 with buprenorphine. The buprenorphine group had shorter treatment days [-10.8 days; 95% CI: -8.08 to -13.53] and shorter hospital stay [-11.8 days; 95% CI: -8.83 to -14.78]. The buprenorphine group was no more likely to receive phenobarbital or clonidine (26% vs. 29%). CONCLUSION: In this large single-center study, buprenorphine was associated with shorter lengths of treatment and hospital stay in the treatment of NOWS compared to morphine.

IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro.

CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-α, we hypothesized that IL-17A would enhance TNF-α-induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-α in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-α and IL17A were greatly attenuated in Cxcl5(-/-) mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild-type mice. Bone marrow chimeras produced using Cxcl5(-/-) donors and recipients demonstrated that lung-resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-α-induced CXCL5 transcription and stabilized TNF-α-induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-κB, IL-17A did not increase TNF-α-induced NF-κB activation. Apical costimulation of IL-17A and TNF-α provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimulation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury.

Growth failure in infants with neonatal abstinence syndrome in the neonatal intensive care unit.

OBJECTIVE: To assess if infants with neonatal abstinence syndrome (NAS) are smaller at birth and have decreased growth parameters between birth and discharge from the neonatal intensive care unit (NICU). METHODS: Retrospective data analysis of term/late-preterm neonates with NAS at a single-center NICU between September 2006 and May 2018. Growth parameters (weight, length, HC) were measured at birth and discharge. Z scores and percentiles were calculated using WHO standard growth curves. RESULTS: A total of 864 infants ≥35 weeks were admitted for NAS. At birth, median percentiles were weight 30%, HC 23%, and length 37%; these decreased significantly (p < 0.001) at discharge to 12%, 6.5%, and 13%, respectively. The percentage of infants <3rd percentile increased significantly (p < 0.001) in all growth parameters from birth to discharge. CONCLUSION: Infants with NAS are smaller at birth and have significant growth retardation in all growth parameters at discharge. An ongoing long-term growth follow-up study will discern the impact of growth restriction in NAS infants.

Assessment of temporal variations in adherence to NRP using video recording in the delivery room.

INTRODUCTION: Video recording and video evaluation tools have been successfully used to evaluate neonatal resuscitation performance. The objective of our study was to evaluate differences in Neonatal Resuscitation Program (NRP) adherence at time of birth between three temporal resuscitative periods using scored video recordings. METHODS: This is a retrospective review of in-situ resuscitation video recordings from a level 3 perinatal center between 2017 and 2018. The modified Neonatal Resuscitation Assessment (mNRA) scoring tool was used as a surrogate marker to assess NRP adherence during daytime, evening, and nighttime hours. RESULTS: A total of 260 resuscitations, of which 258 were births via Cesarean section, were assessed. mNRA composite scores were 86.2% during daytime hours, 87% during evening hours, and 86.6% during nighttime hours. There were no significant differences in mNRA composite scores between any of the three time periods. Differences remained statistically similar after controlling for complexity of resuscitations with administration of positive pressure ventilation (PPV), intubation, or chest compressions. CONCLUSION: Overall adherence to NRP, as measured by composite mNRA scores as a surrogate marker, was high across all three daily resuscitative periods without significant differences between daytime, evening, and nighttime hours.

Prolonging gavage feeds for reduction of gastroesophageal reflux in infants.

OBJECTIVE: To determine if prolonging gavage feedings in infants for ≥60 min is associated with decreased gastroesophageal reflux (GER) compared with bolus feeding using multiple-channel intraluminal impedance with pH probe (MII-pH). STUDY DESIGN: Retrospective analysis of infants who underwent MII-pH between October 2009 and July 2018 and received gavage feedings. Infants were divided into two groups: bolus (<30 min) or prolonged (≥60 min). Symptoms, number of reflux events and percent time pH < 4 was compared. RESULT: Fifty-eight infants underwent evaluation. Thirty-one (54%) received bolus gavage feedings and 27 (46%) received prolonged feedings. Groups differed in postmenstrual age. Total reflux episodes were significantly lower with prolonged feeding (median 19 vs. 28 episodes, p = 0.015), with no difference in acid exposure time. There was no significant difference in GER symptoms between the two groups. CONCLUSION: Prolongation of gavage feedings was associated with decreased total numbers of GER events without reduction in GER symptoms.

A novel noninvasive approach for evaluating work of breathing indices in a developmental rat model using respiratory inductance plethysmography.

Pulmonary function testing (PFT) is an important component for evaluating the outcome of experimental rodent models of respiratory diseases. Respiratory inductance plethysmography (RIP) provides a noninvasive method of PFT requiring minimal cooperation. RIP measures work of breathing (WOB) indices including phase angle (Ф), percent rib cage (RC %), breaths per minute (BPM), and labored breathing index (LBI) on an iPad. The aim of this study was to evaluate the utility of a recently developed research instrument, pneuRIP, for evaluation of WOB indices in a developmental rat model. Sprague Dawley rats (2 months old) were commercially acquired and anaesthetised with isoflurane. The pneuRIP system uses two elastic bands: one band (RC) placed around the rib cage under the upper armpit and another band (AB) around the abdomen. The typical thoracoabdominal motion (TAM) plot showed the abdomen and rib cage motion in synchrony. The plots of phase angle and LBI as a function of data point number showed that values were within the range. The distribution for phase angle and LBI was within a narrow range. pneuRIP testing provided instantaneous PFT results. This study demonstrated the utility of RIP as a rapid, noninvasive approach for evaluating treatment interventions in the rodent model.

DNA Methylation Profile in Human Cord Blood Mononuclear Leukocytes From Term Neonates: Effects of Histological Chorioamnionitis.

Background: Histological chorioamnionitis (HCA) is an infection/inflammation of fetal membranes and complicates 5.2-28.5% of all live births. Exposure to HCA can have long-term consequences including abnormal neurodevelopment and an increased risk for allergic disorders and asthma later in childhood. HCA may incite epigenetic changes, which have the potential to modulate both the immune and neurological systems as well as increase the risk of related disorders later in life. However, there is limited data on the impact of HCA on epigenetics, in particular DNA methylation, and changes to immune and neurological systems in full-term human neonates. Objective: To determine differential DNA methylation in cord blood mononuclear leukocytes from neonates exposed to HCA. Methods: Cord blood was collected from 10 term neonates (5 with HCA and 5 controls without HCA) and mononuclear leukocytes were isolated. Genome-wide DNA methylation screening was performed on Genomic DNA extracted from mononuclear leukocytes. Results: Mononuclear leukocytes from cord blood of HCA-exposed neonates showed differential DNA methylation of 68 probe sets compared to the control group (44 hypermethylated, 24 hypomethylated) with a p ≤ 0.0001. Several genes involved in immune modulation and nervous system development were found to be differentially methylated. Important canonical pathways as revealed by Ingenuity Pathway Analysis (IPA) were CREB Signaling in Neurons, FcγRIIB Signaling in B Lymphocytes, Cell Cycle: G1/S Checkpoint Regulation, Interleukin-1, 2, 3, 6, 8, 10, 17, and 17A signaling, p53 signaling, dopamine degradation, and serotonin degradation. The diseases and disorders picked up by IPA were nervous system development and function, neurological disease, respiratory disease, immune cell trafficking, inflammatory response, and immunological disease. Conclusions: HCA induces differential DNA methylation in cord blood mononuclear leukocytes. The differentially methylated genes may contribute to inflammatory, immunological and neurodevelopmental disorders in neonates exposed to HCA.

Maternal breast milk feeding and length of treatment in infants with neonatal abstinence syndrome.

OBJECTIVE: The objective of this study is to assess whether infants with neonatal abstinence syndrome (NAS), who receive maternal breast milk (BM), have shorter pharmacological treatment durations and lengths of stay compared with formula-fed infants. STUDY DESIGN: Retrospective data analysis from Optum Neonatal Database for infants born between 1 January 2010 and 21 November 2016, who received treatment for NAS. Clinical characteristics and outcomes were compared between infants who received any amount of BM and those exclusively formula-fed. RESULT: Infants (1738) were analyzed. Median length of pharmacological treatment was significantly lower in infants who received any BM (14 days) compared with "no BM" group (17 days, p = 0.04). Similarly, median length of hospitalization was significantly reduced in "any BM" group (19 days vs. 20 days), which remained significant after adjustment for confounders (p = 0.01). There was no difference in hospital re-admission rates. CONCLUSION: Feeding any BM to infants with NAS was associated with both decreased lengths of pharmacological treatment and hospital stay compared with exclusively formula-fed infants.

Histological Chorioamnionitis Induces Differential Gene Expression in Human Cord Blood Mononuclear Leukocytes from Term Neonates.

Histological chorioamnionitis (HCA) is an infection of fetal membranes and complicates 5.2% to 28.5% of all live births. HCA is associated with increased mortality and morbidity in both premature and term neonates. Exposure to HCA may have long-term consequences, including an increased risk for allergic disorders and asthma later in childhood, the mechanism(s) of which are still not yet well understood. The objective of this study was to determine the mRNA transcriptome of cord blood mononuclear leukocytes from term neonates to identify key genes and pathways involved in HCA. We found 366 differentially expressed probe IDs with exposure to HCA (198 upregulated, 168 downregulated). These transcriptomes included novel genes and pathways associated with exposure to HCA. The differential gene expression included key genes regulating inflammatory, immune, respiratory and neurological pathways, which may contribute to disorders in those pathways in neonates exposed to HCA. Our data may lead to understanding of the role of key genes and pathways identified on the long-term sequelae related to exposure to HCA, as well as to identifying potential markers and therapies to prevent HCA-associated complications.