Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.

Importance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test. Design, Setting, and Participants: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021. Exposure: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform. Main Outcomes and Measures: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care). Results: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis. Conclusions and Relevance: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.

Failure to thrive, oral intake, and inpatient status prior to gastrostomy tube placement in the first year of life is associated with persistent use 1-year later.

BACKGROUND: Gastrostomy tube (GT) placement is a common procedure in infants (≤1-year-old). There is variation in patient selection and a paucity of studies examining which patients require long term enteral access. The objective of this study was to assess demographic and clinical factors associated with persistent GT use (PGU) at 1-year after placement. METHODS: We performed a single-institution retrospective review of patients ≤1-year-old who underwent GT placement from January 31, 2014, and January 31, 2020, using institutional NSQIP-P data supplemented with chart review. Multivariable logistic regression analysis was performed to identify factors associated with PGU. Clinical predictors were selected a priori, and a p-value less than 0.05 was used to detect a significant association. RESULTS: 140 patients were included, and 118 had a 1-year follow-up. At 1-year following GT placement, 38 patients had weaned from their GT (32.2%). Failure to thrive (FTT), and inpatient admission prior to surgery are associated with increased odds of PGU at 1-year after surgery, OR: 5.19 and 6.02, respectively. There is an inverse association between the percentage of feeds taken by mouth at the time of surgery and the odds of PGU at 1-year (OR: 0.03). CONCLUSION: Patients who have FTT (documented prior to surgery) or an inpatient admission prior to GT had a higher odds of PGU at 1-year post-op. Additionally, the amount taken by mouth at the time of GT placement was inversely related to PGU. These factors are important in determining the need for a surgical gastrostomy tube. LEVEL OF EVIDENCE: II.

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study.

Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. Design, Setting, and Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. Main Outcomes and Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. Conclusions and Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.

Neuroblastoma in a Neonate: A Case Report.

Neuroblastoma represents approximately 6 to 10 percent of childhood cancers, yet is one of the most common solid tumors observed in neonates; approximately 700 cases are reported in the United States each year. Neuroblastoma occurs secondary to oncogene mutations that cause abnormal proliferation of neural crest cells and tumor formation anywhere along the spinal cord. Visible manifestations include a blueberry rash and subcutaneous skin nodules. Common histologic findings include multifocal, small, round, blue cell tumors. Cytogenetics testing differentiates aggressive versus nonaggressive forms of neuroblastoma. Treatment ranges from supportive care to surgery and chemotherapy; targeted molecular therapies and immunotherapy offer opportunity to individualize treatment. Morbidity and mortality are contingent upon age at diagnosis and genetic abnormalities. Neonatal clinicians must establish and maintain active knowledge of the current science pertaining to this neoplasm to assist in early identification and timely initiation of medical management. This article presents a case report and comprehensive discussion of the state of the science on metastatic familial (congenital) neuroblastoma.

The problems of moderate preterm infants.

Moderate preterm infants are the largest group of preterm infants but are an understudied population. Care practices are adapted from studies of full term infants or extremely preterm infants. Studies are needed to tailor treatments for this vulnerable population. The NRN began investigation in this population with a registry of characteristics, and neonatal outcomes of these infants. This work compares outcomes of MPR with those of full term infants reported in the literature.

Neonatal Resuscitation Training: Implications of Course Construct and Discipline Compartmentalization on Role Confusion and Role Ambiguity.

BACKGROUND: The Neonatal Resuscitation Program's (NRP's) Sixth Edition introduced simulation-based training (SBT) into neonatal life support training. SBT offers neonatal emergency response teams a safe, secure environment to rehearse coordinated neonatal resuscitations. Teamwork and communication training can reduce tension and anxiety during neonatal medical emergencies. PURPOSE: To discuss the implications of variability in number and type of simulation scenario, number and type of learners who comprise a course, and their influence upon scope of practice, role confusion, and role ambiguity. METHODS: Relevant articles from MEDLINE, CINAHL, EMBASE, Google Scholar, the World Health Organization, the American Heart Association, and NRP were included in this integrative review of the literature. FINDINGS/RESULTS: Purposeful synergy of optimal SBT course construct with teamwork and communication can resist discipline compartmentalization, role confusion, and role ambiguity. Five key themes were identified and coined the "5 Rights" of NRP SBT. These "5 Rights" can guide healthcare institutions with planning, implementation, and evaluation of NRP SBT courses. IMPLICATIONS FOR PRACTICE: NRP SBT can facilitate optimal team function and reduce errors when teams of learners and varied scenarios are woven into the course construct. The simulated environment must be realistic and fully equipped to encourage knowledge transfer and attainment of the NRP's key behavioral outcomes. IMPLICATIONS FOR RESEARCH: Investigation of teamwork and communication training with NRP SBT, course construct, discipline compartmentalization, and behavioral and clinical outcomes is indicated. Investigation of outcomes of SBT using a team-teaching model, combining basic and advanced practice NRP instructors, is indicated.

Have Changing Palivizumab Administration Policies Led to More Respiratory Morbidity in Infants Born at 32-35 Weeks?

OBJECTIVES: To determine differences in the incidence of respiratory morbidity during the first year of life among infants born 32(0/7)-34(6/7) weeks' gestational age (GA) before and after the administration policy for palivizumab, as written by the American Academy of Pediatrics, was updated in 2009. STUDY DESIGN: Secondary analysis of the dataset collected for the Gastrointestinal Risk Factors for Wheezing in Premature Infants study, which enrolled preterm infants without bronchopulmonary dysplasia and followed them by parental questionnaires at 3, 6, 9, and 12 months adjusted age for prematurity. Participants were included if they were enrolled in Gastrointestinal Risk Factors for Wheezing in Premature Infants, born 32(0/7)-34(6/7) weeks' GA, and completed the 12-month questionnaire. We compared rates of recurrent wheezing, respiratory medication use, and health care use before (Epoch 1) and after (Epoch 2) the 2009 administration policy change. RESULTS: A total of 165 infants met inclusion criteria. There was a significant increase in recurrent wheezing in Epoch 2 (46.2%) vs Epoch 1 (28.8%) (OR 2.22 [95% CI 1.08-4.53], P = .03). There was a nonsignificant increase in visits to the emergency department in Epoch 2 (27.4%) vs Epoch 1 (15.3%) (OR 2.12 [95% CI 0.91-4.96], P = .08). There were no differences in hospital admissions or respiratory medication use. CONCLUSIONS: Infants born 32(0/7)-34(6/7) weeks' GA treated after the American Academy of Pediatrics administration policy change in 2009 had a greater incidence of recurrent wheezing than those treated according to the previous policy. It will be important to track rates of recurrent wheezing after the 2014 administration policy, because it may be an important factor in future cost-effectiveness analyses.

Quality initiatives related to moderately preterm, late preterm, and early term births.

Most premature infants born in the United States each year are classified as either moderately preterm (MPT) or late preterm (LPT) infants. Unnecessary variation in care and lack of evidence-based practices may contribute to the morbidities of prematurity. Quality-improvement (QI) initiatives designed for neonates have primarily focused on extremely low-gestational-age newborns. However, the lessons learned in this group of infants could be applied to decreasing unnecessary variation among MPT and LPT infants. Practice variation in the timing of nonindicated preterm deliveries, the use of progesterone, respiratory care practices, feeding management, and discharge planning are particularly in need of QI.

Comparative effectiveness of surfactant preparations in premature infants.

OBJECTIVE: To compare effectiveness of 3 surfactant preparations (beractant, calfactant, and poractant alfa) in premature infants for preventing 3 outcomes: (1) air leak syndromes; (2) death; and (3) bronchopulmonary dysplasia (BPD) or death (composite outcome). STUDY DESIGN: We conducted a comparative effectiveness study of premature infants admitted to 322 neonatal intensive care units in the US from 2005-2010 who were treated with beractant, calfactant, or poractant alfa. We compared the incidence of air leak syndromes, death, and BPD or death, adjusting for gestational age (GA), antenatal steroids, discharge year, and small for GA status. RESULTS: A total of 51282 infants received surfactant; 40% received beractant, 30% calfactant, and 30% poractant alfa. Median birth weight was 1435 g (IQR 966-2065); median GA was 30 weeks (27-33). On adjusted analysis, we observed a similar risk of air leak syndromes (calfactant vs beractant OR = 1.17 [95% CI: 0.95, 1.43]; calfactant vs poractant OR = 1.23 [0.98, 1.56]; beractant vs poractant OR = 1.06 [0.87, 1.29]), death (calfactant vs beractant OR = 1.14 [0.93, 1.39]; calfactant vs poractant OR = 0.98 [0.78, 1.23]; beractant vs poractant OR = 0.86 [0.72, 1.04]), and BPD or death (calfactant vs beractant OR = 1.08 [0.93, 1.26]; calfactant vs poractant OR = 1.19 [1.00, 1.41]; beractant vs poractant OR = 1.10 [0.96, 1.27]). CONCLUSIONS: Beractant, calfactant, and poractant alfa demonstrated similar effectiveness in prevention of air leak syndromes, death, and BPD or death in premature infants when adjusted for site. Previously described differences in mortality between surfactants likely do not represent true differences in effectiveness but may relate to site variation in outcomes.

Predictors of bronchopulmonary dysplasia.

Although significant advances in respiratory care have been made in neonatal medicine, bronchopulmonary dysplasia (BPD) remains the most common serious pulmonary morbidity in premature infants. The development of BPD is the result of the complex interactions between multiple perinatal and postnatal factors. Early identification of infants at the most risk of developing BPD through the use of estimators and models may allow a targeted approach at reducing BPD in the future.