Ethical and Legal Issues Surrounding Genetic Testing in the NICU.

Clinicians practicing in a modern NICU are noticing an increase in the proportion of patients who undergo genetic testing as well as changes in the types of genetic testing patients receive. These trends are not surprising given the increasing recognition of the genetic causes of neonatal illness and recent advances in genetic technology. Yet, the expansion of genetic testing in the NICU also raises a number of ethical questions. In this article, we will review the ethical issues raised by genetic testing, with a focus on the practical implications for neonatologists. First, we outline the complexities of measuring benefit, or utility, for neonatal genetic testing. Next, we discuss potential harms such as inequity, unexpected findings, disability biases, and legal risks. Finally, we conclude with a discussion of ethical issues related to consent for genetic testing. Throughout this article, we highlight solutions to challenges toward the ultimate goal of minimizing harms and maximizing the substantial potential benefits of genetic medicine in the NICU.

Race and Ethnicity of Infants Enrolled in Neonatal Clinical Trials: A Systematic Review.

Importance: Representativeness of populations within neonatal clinical trials is crucial to moving the field forward. Although racial and ethnic disparities in research inclusion are well documented in other fields, they are poorly described within neonatology. Objective: To describe the race and ethnicity of infants included in a sample of recent US neonatal clinical trials and the variability in this reporting. Evidence Review: A systematic search of US neonatal clinical trials entered into Cochrane CENTRAL 2017 to 2021 was conducted. Two individuals performed inclusion determination, data extraction, and quality assessment independently with discrepancies adjudicated by consensus. Findings: Of 120 studies with 14 479 participants that met the inclusion criteria, 75 (62.5%) included any participant race or ethnicity data. In the studies that reported race and ethnicity, the median (IQR) percentage of participants of each background were 0% (0%-1%) Asian, 26% (9%-42%) Black, 3% (0%-12%) Hispanic, 0% (0%-0%) Indigenous (eg, Alaska Native, American Indian, and Native Hawaiian), 0% (0%-0%) multiple races, 57% (30%-68%) White, and 7% (1%-21%) other race or ethnicity. Asian, Black, Hispanic, and Indigenous participants were underrepresented, while White participants were overrepresented compared with a reference sample of the US clinical neonatal intensive care unit (NICU) population from the Vermont Oxford Network. Many participants were labeled as other race or ethnicity without adequate description. There was substantial variability in terms and methods of reporting race and ethnicity data. Geographic representation was heavily skewed toward the Northeast, with nearly one-quarter of states unrepresented. Conclusions and Relevance: These findings suggest that neonatal research may perpetuate inequities by underrepresenting Asian, Black, Hispanic, and Indigenous neonates in clinical trials. Studies varied in documentation of race and ethnicity, and there was regional variation in the sites included. Based on these findings, funders and clinical trialists are advised to consider a 3-point targeted approach to address these issues: prioritize identifying ways to increase diversity in neonatal clinical trial participation, agree on a standardized method to report race and ethnicity among neonatal clinical trial participants, and prioritize the inclusion of participants from all regions of the US in neonatal clinical trials.

Clinician perception of care at the end of life in a quaternary neonatal intensive care unit.

Introduction: Care for neonates at the end of life (EOL) is often challenging for families and medical teams alike, performed suboptimally, and requires an experienced and compassionate clinician. Much literature exists on adult and pediatric EOL care, but limited studies examine the neonatal process. Methods: We aimed to describe clinicians' experiences around EOL care in a single quaternary neonatal intensive care unit as we implemented a standard guideline using the Pediatric Intensive Care Unit-Quality of Dying and Death 20 tool. Results: Surveys were completed by 205 multidisciplinary clinicians over three time periods and included 18 infants at EOL. While most responses were high, a meaningful minority were below goal (<8 on 0-10 scale) for troubling symptom management, conflict between parents and staff, family access to resources, and parent preparation of symptoms. Comparison between Epochs revealed improvement in one symptom management and four communication categories. Satisfaction scores related to education around EOL were better in later Epochs. Neonatal Pain, Agitation, and Sedation Scale scores were low, with few outliers. Discussion: These findings can guide those aiming to improve processes around neonatal EOL by identifying areas with the greatest challenges (e.g., conflict management) and areas that need further study (e.g., pain management around death).

Congenital pleuropulmonary blastoma in a newborn with a variant of uncertain significance in DICER1 evaluated by RNA-sequencing.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest form of PPB occurring from birth to approximately two years of age, is often mistaken for a congenital pulmonary airway malformation, as the two entities can be difficult to distinguish on imaging and pathology. Diagnosis of PPB should prompt workup for DICER1 syndrome, an autosomal dominant tumor predisposition syndrome. We report a newborn with a congenital PPB presenting with tachypnea and hypoxia, who was found to have variant of uncertain clinical significance (VUS) in DICER1. CASE PRESENTATION: A term female infant developed respiratory distress shortly after birth. Initial imaging was concerning for a congenital pulmonary airway malformation versus congenital diaphragmatic hernia, and she was transferred to a quaternary neonatal intensive care unit for management and workup. Chest CT angiography demonstrated a macrocytic multicystic lesion within the right lower lobe without systemic arterial supply. The pediatric surgery team was consulted, and the neonate underwent right lower lobectomy. Pathology revealed a type I PPB. Oncology and genetics consultants recommended observation without chemotherapy and single gene sequencing of DICER1, which identified a germline VUS in DICER1 predicted to alter splicing. RNA-sequencing from blood demonstrated that the variant resulted in an in-frame deletion of 29 amino acids in a majority of transcripts from the affected allele. Due to the patient's young age at presentation and high clinical suspicion for DICER1 syndrome, tumor surveillance was initiated. Renal and pelvic ultrasonography were unremarkable. CONCLUSION: We present the case of a term neonate with respiratory distress and cystic lung mass, found to have a type I PPB with a germline VUS in DICER1 that likely increased her risk of DICER1-related tumors. Nearly 70% of patients with PPB demonstrate germline mutations in DICER1. Review of RNA sequencing data demonstrates the difficulty in classifying splice variants such as this. Penetrance is low, and many patients with pathogenic DICER1 variants do not develop a malignancy. Best practice surgical and oncologic recommendations include an individualized approach and tumor board discussion. This case highlights the importance of a multidisciplinary team approach and the utility of international registries for patients with rare diagnoses.

Case report of congenital methemoglobinemia: an uncommon cause of neonatal cyanosis.

BACKGROUND: Methemoglobinemia can be an acquired or congenital condition. The acquired form occurs from exposure to oxidative agents. Congenital methemoglobinemia is a rare and potentially life-threatening cause of cyanosis in newborns that can be caused by either cytochrome B5 reductase or hemoglobin variants known as Hemoglobin M. CASE PRESENTATION: A term male infant developed cyanosis and hypoxia shortly after birth after an uncomplicated pregnancy, with oxygen saturations persistently 70-80% despite 1.0 FiO2 and respiratory support of CPAP+ 6 cm H2O. Pre- and post-ductal saturations were equal and remained below 85%. Initial radiographic and echography imaging was normal. Capillary blood gas values were reassuring with normal pH and an elevated pO2. Investigations to rule out hemolysis and end-organ dysfunction were within acceptable range. Given the absence of clear cardiac or pulmonary etiology of persistent cyanosis, hematologic causes such as methemoglobinemia were explored. No family history was available at the time of transfer to our institution. Unconjugated hyperbilirubinemia > 5 mg/dL (442 µmol/L) interfered with laboratory equipment measurement, making accurate methemoglobin levels unattainable despite multiple attempts. Initial treatment with methylene blue or ascorbic acid was considered. However, upon arrival of the presumed biological father, a thorough history revealed an extensive paternal family history of neonatal cyanosis due to a rare mutation resulting in a hemoglobin M variant. Given this new information, hematology recommended supportive care as well as further testing to confirm the diagnosis of congenital methemoglobinopathy. Whole genome sequencing revealed a likely pathogenic variation in hemoglobin. The neonate was discharged home at 2 weeks of age on full oral feeds with 0.25 L/min nasal cannula as respiratory support, with close outpatient follow-up. By 5 weeks of age, he was weaned off respiratory support. CONCLUSION: Congenital methemoglobinemia should be considered in the differential diagnosis for newborns with persistent hypoxemia despite normal imaging and laboratory values. Accurate quantification of methemoglobin concentrations is challenging in neonates due to the presence of other substances that absorb light at similar wavelengths, including HbF, bilirubin, and lipids.