Evaluating the Effect of Maternal Opioid Maintenance Dose on the NOWS-COS Outcome Criteria: A Pilot Study.

This retrospective cohort study included 77 mother-infant dyads that delivered term pregnancies at a single tertiary care institution. The primary objective was to investigate whether maternal dose of opioid maintenance therapy during pregnancy affects infant outcomes. All infants had prenatal exposure to opioid maintenance therapies. Maternal dose was converted into morphine milligram equivalents (MMEs) and stratified into high- (MME >1000 mg) and low-dose groups (MME ≤1000 mg). Associations between infant outcomes and MME dosage were examined using Wilcoxon rank-sum and Fisher's Exact tests. Days to symptom control were significantly higher in the high MME group (5 days vs 2.8 days, P = .016). Rates of developmental delay at 24 months were higher in the high MME group (21.2% vs 4.5%, P = .0335). Maternal MME did not predict need for NOWS treatment. Higher MME-exposed infants should have optimized nonpharmacologic interventions for consolation and be increasingly observed for signs of developmental delay.

Placental pathology reports: A qualitative study in a US university hospital setting on perceived clinical utility and areas for improvement.

OBJECTIVE: To explore how placental pathology is currently used by clinicians and what placental information would be most useful in the immediate hours after delivery. STUDY DESIGN: We used a qualitative study design to conduct in-depth, semi-structured interviews with obstetric and neonatal clinicians who provide delivery or postpartum care at an academic medical center in the US (n = 19). Interviews were transcribed and analyzed using descriptive content analysis. RESULTS: Clinicians valued placental pathology information yet cited multiple barriers that prevent the consistent use of pathology. Four main themes were identified. First, the placenta is sent to pathology for consistent reasons, however, the pathology report is accessed by clinicians inconsistently due to key barriers: difficult to find in the electronic medical record, understand, and get quickly. Second, clinicians value placental pathology for explanatory capability as well as for contributions to current and future care, particularly when there is fetal growth restriction, stillbirth, or antibiotic use. Third, a rapid placental exam (specifically including placental weight, infection, infarction, and overall assessment) would be helpful in providing clinical care. Fourth, placental pathology reports that connect clinically relevant findings (similar to radiology) and that are written with plain, standardized language and that non-pathologists can more readily understand are preferred. CONCLUSION: Placental pathology is important to clinicians that care for mothers and newborns (particularly those that are critically ill) after birth, yet many problems stand in the way of its usefulness. Hospital administrators, perinatal pathologists, and clinicians should work together to improve access to and contents of reports. Support for new methods to provide quick placenta information is warranted.

Multiomics endotyping of preterm infants with bronchopulmonary dysplasia and pulmonary hypertension-A pilot study.

Pulmonary hypertension associated with bronchopulmonary dysplasia is a severe complication of preterm birth resulting in high mortality of up to 50% within the first 2 years of life. There is a direct relationship between bronchopulmonary dysplasia severity and incidence of associated pulmonary hypertension. However, it is challenging to clinically characterize severe bronchopulmonary dysplasia with and without pulmonary hypertension and there is need for better understanding of the two entities. Our main objective is to identify markers to help understand biological processes and characterize infants with pulmonary hypertension associated with bronchopulmonary dysplasia using tracheal aspirates. We conducted an unbiased multiomic analysis of tracheal aspirates via microRNA (miRNA) polymerase chain reaction arrays, RNA sequencing, and mass spectrometry proteomics in preterm infants with severe bronchopulmonary dysplasia with and without pulmonary hypertension (n = 46). Our pilot study analysis revealed 12 miRNAs (hsa-miR-29a, has-miR-542-3p, has-miR-624, has-miR-183, hsa-miR-501-3p, hsa-miR-101, hsa-miR-3131, hsa-miR-3683, hsa-miR-3193, hsa-miR-3672, hsa-miR-3128, and hsa-miR-1287), 6 transcripts (IL6, RPL35P5, HSD3B7, RNA5SP215, OR2A1-AS1, and RNVU1-19), and 5 proteins (CAPS, AAT, KRT5, SFTPB, and LGALS3BP) with significant differential expression in preterm infants with severe lung disease with pulmonary hypertension when compared with infants with severe lung disease but no pulmonary hypertension. Pathway analysis of the integrated multiomic expression signatures revealed NFkB, VEGF, SERPINA1, IL6, and ERK1/2 as target molecules and cellular development, cellular growth and proliferation, and cellular movement as key affected molecular functions. Our multiomic analysis of tracheal aspirates revealed a comprehensive thumbprint of miRNAs, mRNAs, and proteins that could help endotype infants with severe lung disease and pulmonary hypertension.

A scoping review of the opioid epidemic among U.S. Immigrants: Implications for treatment practices.

The purpose of this review was to identify knowledge gaps within the literature regarding the impact of opioid use disorder, specific to immigrants in the United States, by addressing the following questions: 1) What is presented in the literature about the impact of opioid use disorder (OUD) and the opioid epidemic on immigrants in the United States?; and 2) What role does culture play in the opioid use disorder experiences of immigrants in the United States? Nineteen research articles were uncovered that addressed immigrants in the U.S. and opioid use disorder. The following themes prevailed: 1) OUD comparisons, 2) OUD comorbidities, 3) disparate OUD treatment engagement, and 4) the role of country of origin. Limited review findings support the need for future research on the topic of opioid misuse among immigrants in the United States. The authors elaborated on additional issues that influence OUD rates and warrant further exploration. Matters related to the potential positive roles of religion and faith leaders, cultural perceptions and expectations about gender roles, immigration status, ethnically diverse needs among sub-groups of immigrants, the role of geographic location within the U.S., and the implications of COVID-19 on OUD among immigrants need to be addressed to alleviate the deleterious impact of opioid misuse among immigrants.

Early Salivary miRNA Expression in Extreme Low Gestational Age Newborns.

Background: MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression playing a key role in organogenesis. MiRNAs are studied in tracheal aspirates (TA) of preterm infants. However; this is difficult to obtain in infants who are not intubated. This study examines early salivary miRNA expression as non-invasive early biomarkers in extremely low gestational age newborns (ELGANs). Methods: Saliva was collected using DNA-genotek swabs, miRNAs were analyzed using RNA seq and RT PCR arrays. Salivary miRNA expression was compared to TA using RNA seq at 3 days of age, and longitudinal changes at 28 days of age were analyzed using RT PCR arrays in ELGANs. Results: Approximately 822 ng of RNA was extracted from saliva of 7 ELGANs; Of the 757 miRNAs isolated, 161 miRNAs had significant correlation in saliva and TA at 3 days of age (r = 0.97). Longitudinal miRNA analysis showed 29 miRNAs downregulated and 394 miRNAs upregulated at 28 days compared to 3 days of age (adjusted p < 0.1). Bioinformatic analysis (Ingenuity Pathway Analysis) of differentially expressed miRNAs identified organismal injury and abnormalities and cellular development as the top physiological system development and cellular function. Conclusion: Salivary miRNA expression are source for early biomarkers of underlying pathophysiology in ELGANs.

Risk Factors Associated with Perinatal Relapse to Opioid Use Disorder.

The recent opioid epidemic in the United States has led to rising prevalence of maternal opioid use disorder (OUD). First-line treatment for maternal OUD involves the use of opioid agonist pharmacotherapy, such as methadone or buprenorphine, in addition to cognitive behavioral therapy and counseling. The management of maternal OUD can become overwhelming for both patients and clinicians, especially during the early postpartum period. Therefore, it is imperative that clinicians understand the impact of additional stressors in caring for these patients. Maternal chronic opioid dependence can lead to neonatal opioid withdrawal syndrome after birth. This multisystem condition affects neonatal neurobehavioral functioning and has significant human and socioeconomic consequences. First-line treatment for this syndrome involves intensive nonpharmacologic comforting measures, with maternal presence and involvement being central to ensuring the success of such measures. In this review, we describe the factors that place pregnant and postpartum women with OUD at risk of returning to illicit opioid use. We evaluate these multifaceted personal, social, societal, and systemic factors to inform the development of future clinical care initiatives.

Effect of Coronavirus Disease-2019 on the Workload of Neonatologists.

OBJECTIVE: To describe the impact of coronavirus disease-2019 (COVID-19) on the neonatology workforce, focusing on professional and domestic workloads. STUDY DESIGN: We surveyed US neonatologists in December 2020 regarding the impact of COVID-19 on professional and domestic work during the pandemic. We estimated associations between changes in time spent on types of professional and domestic work and demographic variables with multivariable logistic regression analyses. RESULTS: Two-thirds (67.6%) of the 758 participants were women. Higher proportions of women than men were in the younger age group (63.3% vs 29.3%), held no leadership position (61.4% vs 46.3%), had dependents at home (68.8% vs 56.3%), did not have a partner or other adult at home (10.6% vs 3.2%), and had an employed partner (88.1% vs 64.6%) (P < .01 for all). A higher proportion of women than men reported a decrease in time spent on scholarly work (35.0% vs 29.0%; P = .02) and career development (44.2% vs 34.9%; P < .01). A higher proportion of women than men reported spending more time caring for children (74.2% vs 55.8%; P < .01). Reduced time spent on career development was associated with younger age (aOR, 2.21; 95% CI, 1.20-4.08) and number of dependents (aOR, 1.21; 95% CI, 1.01-1.45). Women were more likely to report an increase in time spent time doing domestic work (aOR, 1.53; 95% CI, 1.07-2.19) and a reduction in time on self-care (aOR, 0.49; 95% CI, 0.29-0.81). CONCLUSIONS: COVID-19 significantly impacts the neonatology workforce, disproportionately affecting younger, parent, and women physicians. Targeted interventions are needed to support postpandemic career recovery and advance physician contributions to the field.

MicroRNA Signatures Associated with Bronchopulmonary Dysplasia Severity in Tracheal Aspirates of Preterm Infants.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth, arrested fetal lung development, and inflammation. The incidence of BPD remains on the rise as a result of increasing survival of extremely preterm infants. Severe BPD contributes to significant health care costs and is associated with prolonged hospitalizations, respiratory infections, and neurodevelopmental deficits. In this study, we aimed to detect novel biomarkers of BPD severity. We collected tracheal aspirates (TAs) from preterm babies with mild/moderate (n = 8) and severe (n = 17) BPD, and we profiled the expression of 1048 miRNAs using a PCR array. Associations with biological pathways were determined with the Ingenuity Pathway Analysis (IPA) software. We found 31 miRNAs differentially expressed between the two disease groups (2-fold change, false discovery rate (FDR) < 0.05). Of these, 4 miRNAs displayed significantly higher expression levels, and 27 miRNAs had significantly lower expression levels in the severe BPD group when compared to the mild/moderate BPD group. IPA identified cell signaling and inflammation pathways associated with miRNA signatures. We conclude that TAs of extremely premature infants contain miRNA signatures associated with severe BPD. These may serve as potential biomarkers of disease severity in infants with BPD.

Clinical care of neonates undergoing opioid withdrawal in the immediate postpartum period.

As the opioid epidemic escalates in westernized countries around the world, chronic opioid use during pregnancy has become a growing public health issue. There are increasing concerns that chronic maternal opioid use might adversely affect the developing fetal brain. Furthermore, the sudden discontinuation of the trans-placental opioid supply at birth puts newborns at acute risk for neonatal opioid withdrawal syndrome (NOWS). NOWS is a multi-system disorder that has been identified in approximately 50-80% of neonates exposed to opioids due to chronic maternal use. Clinically, NOWS affects the central and autonomic nervous systems as well as the gastrointestinal and respiratory tracts. The clinical features of NOWS include hyperirritability, high-pitched crying, restlessness, tremors, poor sleep, agitation, seizures, sweating, fever, poor feeding, regurgitation, diarrhea, and tachypnea. NOWS is currently diagnosed using a clinical scoring tool followed by toxicological confirmation of the presence of opioids in meconium or tissue specimens. The first-line treatments for NOWS are non-pharmacologic comfort measures. If these measures fail, neonates may be treated with opioids and/or sedatives. Since the severity of NOWS can be highly variable, it is quite difficult to predict which opioid-exposed neonates will require pharmacotherapy and prolonged hospitalization. Factors associated with maternal polysubstance use, including the use of illicit substances and tobacco, have been associated with the increased severity and duration of NOWS. Since neonates with NOWS are at increased risk for long-term adverse neurodevelopmental outcomes, ongoing monitoring beyond the neonatal period is essential.

Tracheal aspirate transcriptomic and miRNA signatures of extreme premature birth with bronchopulmonary dysplasia.

OBJECTIVE: Extreme preterm infants are a growing population in neonatal intensive care units who carry a high mortality and morbidity. Multiple factors play a role in preterm birth, resulting in major impact on organogenesis leading to complications including bronchopulmonary dysplasia (BPD). The goal of this study was to identify biomarker signatures associated with prematurity and BPD. STUDY DESIGN: We analyzed miRNA and mRNA profiles in tracheal aspirates (TAs) from 55 infants receiving invasive mechanical ventilation. Twenty-eight infants were extremely preterm and diagnosed with BPD, and 27 were term babies receiving invasive mechanical ventilation for elective procedures. RESULT: We found 22 miRNAs and 33 genes differentially expressed (FDR < 0.05) in TAs of extreme preterm infants with BPD vs. term babies without BPD. Pathway analysis showed associations with inflammatory response, cellular growth/proliferation, and tissue development. CONCLUSIONS: Specific mRNA-miRNA signatures in TAs may serve as biomarkers for BPD pathogenesis, a consequence of extreme prematurity.

Management of newborns exposed to mothers with confirmed or suspected COVID-19.

There is limited information about newborns with confirmed or suspected COVID-19. Particularly in the hospital after delivery, clinicians have refined practices in order to prevent secondary infection. While guidance from international associations is continuously being updated, all facets of care of neonates born to women with confirmed or suspected COVID-19 are center-specific, given local customs, building infrastructure constraints, and availability of protective equipment. Based on anecdotal reports from institutions in the epicenter of the COVID-19 pandemic close to our hospital, together with our limited experience, in anticipation of increasing numbers of exposed newborns, we have developed a triage algorithm at the Penn State Hospital at Milton S. Hershey Medical Center that may be useful for other centers anticipating a similar surge. We discuss several care practices that have changed in the COVID-19 era including the use of antenatal steroids, delayed cord clamping (DCC), mother-newborn separation, and breastfeeding. Moreover, this paper provides comprehensive guidance on the most suitable respiratory support for newborns during the COVID-19 pandemic. We also present detailed recommendations about the discharge process and beyond, including providing scales and home phototherapy to families, parental teaching via telehealth and in-person education at the doors of the hospital, and telehealth newborn follow-up.

Term Neonate Presenting with the Combined Occurrence of Mucolipidosis Type II and Leigh Syndrome.

Mucolipidosis II α/beta (MLII) is an autosomal recessive disease in which a gene mutation leads to improper targeting of lysosomal enzymes with an end result of accumulation of lysosomes in the mitochondria resulting in a dysfunctional mitochondria. 1 Leigh syndrome (LS) is a rare progressive neurodegenerative disorder associated with dysfunctional mitochondria and oxidative phosphorylation. 4 Both disease processes typically present in infancy. 3 7 Herein, we present a case of an infant diagnosed with both mucolipidosis II and Leigh syndrome. Genetic analysis in this case revealed two mutations (NDUFA12 c.178C > T p.Arg60* and GNPTAB c.732_733delAA) on the long arm of chromosome 12 as the etiology of MLII and LS in this neonate, respectively. We are unaware of any previously published cases of the presence of these two diseases occurring in the same patient. The complex clinical presentation of this case led to a delay in the diagnosis, and we believe that the clinical phenotypes of these two conditions were likely worsened. The genetic alterations presented in this case occurred as a result of mutations on chromosome 12. We suggest further investigation into the potential overlap in the pathophysiology, specifically the inheritance pattern, linkage disequilibrium, mitochondrial-lysosomal interaction, or crosstalk contributing to both diseases.

Prenatal opioid exposure heightens sympathetic arousal and facial expressions of pain/distress in term neonates at 24-48 hours post birth.

Purpose: The rising issue of opioid use during pregnancy poses an increased risk of fetal exposure to opioids in-utero and the development of neonatal abstinence syndrome (NAS). The cessation of exposure to opioids upon birth causes elevated levels of norepinephrine in the circulation enhancing sympathetic arousal. Skin conductance (SC) detects sympathetic-mediated sweating while the Neonatal Facial Coding System (NFCS) depicts facial expressions of stress and pain. We hypothesize that there will be a direct correlation between SC and NFCS scores, such that neonates with prenatal opioid exposure will have higher SC and facial responses to pain/stress as compared with healthy neonates without prenatal opioid exposure.Objective: This study evaluates the utility of SC and the NFCS in the objective assessment of early postnatal pain response in opioid-exposed and non-opioid exposed neonates.Methods: This prospective, single-center, pilot study enrolled opioid-exposed term neonates (>37 weeks) and healthy controls. Subjects were observed within 24-48 hours post-birth (and prior to opioid withdrawal) for pain at baseline, during, and post-heel lance/squeeze (HLS) with simultaneously measured SC and videotaped facial expressions. SC data included electro-dermal responses over time (EDR/second) and the average amplitude of responses (mean of peaks [MP]). Video data were scored using the NFCS by two trained coders with inter-rater agreement >85%.Results: SC and NFCS scores were significantly associated with both groups. The opioid-exposed neonates had significantly higher skin conductance indices, EDR/sec for the HLS phase, and MP for HLS and post phases as compared with controls (p < .05). Opioid-exposed neonates demonstrated higher NFCS at baseline (p = .003).Conclusions: Prenatal opioid exposure was associated with heightened sympathetic arousal during both pain and recovery phases and higher facial expressions of pain/distress at baseline only. A multimodal system of assessment may be useful in understanding the complexity and severity of opioid withdrawal associated with NAS.

The Possibility of Early Discharge for Newborns Being Monitored for Neonatal Abstinence Syndrome Based on Modified Finnegan Score Distributions.

We tested the hypothesis that Modified Finnegan Neonatal Scoring System (MFNSS) scores can guide early discharge at 72 hours for newborns at risk for neonatal abstinence syndrome (NAS). A retrospective cohort study with a primary outcome of early discharge of newborns at risk for NAS using mean MFNSS scores recorded before pharmacologic treatment was performed. Quantile regression was used to develop percentile curves of mean MFNSS scores. A total of 202 term newborns at risk for NAS with 5066 mean MFNSS scores recorded before pharmacologic treatment were studied. Sixty-eight of 121 (56%) newborns not treated at 72 hours had mean MFNSS scores <50th percentile and only 1 was ultimately treated (1.5%, 95% confidence interval: 0% to 8%). No newborns with mean MFNSS scores <25th percentile at 72 hours were treated. Newborns at risk for NAS with mean MFNSS scores <50th percentile can be safely discharged by 72 hours if families can assure close outpatient follow-up.

Heightened sympathetic arousal is demonstrated by skin conductance responsivity to auditory stimuli in a small cohort of neonates with opiate withdrawal.

To determine the effects of auditory stimulus on skin conductance (SC) in infants with severe neonatal abstinence syndrome (NAS) that required morphine treatment (MT) compared with NAS infants that did not require morphine treatment (non-MT). We prospectively enrolled opiate-exposed term infants without polysubstance exposure. Skin conductance responses to an auditory stimulus (ringing a bell for 3s) near the time of discharge were obtained. Skin conductance was measured before, during, and after the stimulus. Non-parametric tests were used to determine between group and within phase differences. Infants were off MT at the time of SC measurement in response to an auditory stimulus. In a 2-group comparison of MT vs. non-MT infants, there was significantly higher SC responsivity to an auditory stimulus (p <0.05) in the MT group as compared with the non-MT group near discharge. The mean +SE peak morphine dose was 0.85+0.20mg/kg/day in the MT group. The mean Length of Stay (LOS) was 32 vs. 7 (p <0.05) days respectively, for the MT vs. the non-MT group. Our preliminary data suggest that in infants with severe NAS symptoms, higher sympathetic arousal in response to an auditory stimulus persists at discharge, underscoring the need for ongoing evaluation and specialized care at home.

Biomarkers for Bronchopulmonary Dysplasia in the Preterm Infant.

Bronchopulmonary dysplasia (BPD) is a chronic inflammatory lung disease of very-low-birth-weight (VLBW) preterm infants, associated with arrested lung development and a need for supplemental oxygen. Over the past few decades, the incidence of BPD has significantly raised as a result of improved survival of VLBW infants requiring mechanical ventilation. While early disease detection is critical to prevent chronic lung remodeling and complications later in life, BPD is often difficult to diagnose and prevent due to the lack of good biomarkers for identification of infants at risk, and overlapping symptoms with other diseases, such as pulmonary hypertension (PH). Due to the current lack of effective treatment available for BPD and PH, research is currently focused on primary prevention strategies, and identification of biomarkers for early diagnosis, that could also represent potential therapeutic targets. In addition, novel histopathological, biochemical, and molecular factors have been identified in the lung tissue and in biological fluids of BPD and PH patients that could associate with the disease phenotype. In this review, we provide an overview of biomarkers for pediatric BPD and PH that have been identified in clinical studies using various biological fluids. We also present a brief summary of the information available on current strategies and guidelines to prevent and diagnose BPD and PH, as well as their pathophysiology, risk factors, and experimental therapies currently available.

Skin conductance at baseline and postheel lance reflects sympathetic activation in neonatal opiate withdrawal.

AIM: Skin conductance (SC) provides an objective measure of autonomic system regulation through sympathetic-mediated filling of sweat glands. This study aimed to test the utility of SC to detect sympathetic activation in neonatal abstinence syndrome (NAS). METHODS: Fourteen term (mean, SE: 38.8 ± 0.35 weeks gestational age) neonates with chronic prenatal opiate exposure were enrolled. SC (peaks/seconds and mean of peaks) was measured at baseline, during heel lance/squeeze (HLS) and recovery from HLS at 24-48 (mean 38) hours of life prior to treatment for NAS. Blinded coders with established reliability assessed neonates using the Modified Finnegan Neonatal Scoring System (MFNSS). Nonparametric tests were used to determine group differences, phase differences from baseline to HLS and HLS to recovery, and associations between MFNSS and SC measures. RESULTS: Neonates that would later require morphine treatment for NAS (n = 6) had higher baseline SC mean of peaks than those that did not require treatment (n = 8) (p < 0.05). Moreover, there were unique phase differences between groups and SC positively correlated with MFNSS (p < 0.05). CONCLUSION: SC provides early identification of NAS severity. However, a larger sample is needed to determine sensitivity and specificity of SC for early identification of NAS and treatment effectiveness.