The Effect of Size and Asymmetry at Birth on Brain Injury and Neurodevelopmental Outcomes in Congenital Heart Disease

Poor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.

Impact of the Coronavirus Pandemic on High-Risk Infant Follow-Up (HRIF) Programs: A Survey of Academic Programs

Objective: The impact of the COVID-19 pandemic on the functioning and services of academic high-risk infant follow-up (HRIF) clinics throughout North America. Study Design: Prospective 25-question questionnaire survey through REDCAP links that was sent over 10 weeks, to 105 US and 10 Canadian programs. Finally, 59 of 105 US programs and 5 of 10 Canadian responses were analyzed using SAS version 9.4. Results: In the US, 67% of programs reported closures between 1–5 months, whereas in Canada 80% of programs closed for 1–3 months. In the US 86% of programs provided telemedicine visits and only 42.5% provided multidisciplinary HRIF telemedicine visits. We enumerated innovative approaches specifically for the conduct of Telemedicine visits, the need for the standardization of various tests and services in a telemedicine setting, and to emphasize the urgent need for more government funding to improve follow-up and developmental services to this fragile group of newborns.

Development of Healthcare Service Design Concepts for NICU Parental Education

The objective of this study was to develop healthcare service design concepts through an empirical study utilizing design thinking to improve the quality of caregiver education provided in the neonatal intensive care unit (NICU). This study adopted the Double Diamond Process of service design comprising the discover, define, and development stages. We identified 7 issues, organized into 10 healthcare service design concepts associated with NICU education: improving the design of educational material, improving materials for high-risk infant guidance, a practicum kit, a parent proficiency checklist, a systematic parent education manual, predictable guidelines for tests and treatment plans, waiting time that provides comfort, message cards that convey feelings, a reservation system for visits, and a post-discharge information sharing platform. The service concepts’ effectiveness was verified through evaluations by healthcare experts. The results represent customers’ perspectives and experiences regarding parental education. The application of the healthcare service design method could be further developed in future studies. The 10 service concepts derived from this study can be applied and evaluated as specific NICU educational programs.

Rural Residence and Factors Associated with Attendance at the Second High-Risk Infant Follow-up Clinic Visit for Very Low Birth Weight Infants in California

Objective This study was aimed to determine factors associated with attendance at the second high-risk infant follow-up (HRIF) visit (V2) by 20 months of corrected age after a successful first visit (V1), and the impact of rural residence on attendance rates in a statewide population of very low birth weight (VLBW; <1,500 g) infants. Study Design Data linked from the California Perinatal Quality of Care Collaborative (CPQCC) Neonatal Intensive Care Unit (NICU) database and CPQCC-California Children's Services (CCS) HRIF database. Multivariable logistic regression evaluated independent associations of sociodemographic, maternal, family, neonatal clinical, and individual HRIF program differences (factors) with successful V2 in VLBW infants born in 2010 to 2012. Results Of 7,295 eligible VLBW infants, 75% (5,475) attended V2. Sociodemographic factors independently associated with nonattendance included maternal race of Black (adjusted odds ratio [aOR] = 0.61; 95% confidence interval [CI]: 0.5–0.75), public insurance (aOR = 0.79; 95% CI: 0.69–0.91), and rural residence (aOR = 0.74; 95% CI: 0.61–0.9). Factors identified at V1that were associated with V2 attendance included attending V1 within the recommended window (aOR = 2.34; 95% CI: 1.99–2.75) and early intervention enrollment (aOR = 1.39; 95% CI: 1.12–1.61). Neonatal factors associated with attendance included birth weight ≤750 g (aOR = 1.83; 95% CI: 1.48–2.5). There were significant program differences with risk-adjusted rates ranging from 43.7 to 99.7%. Conclusion Sociodemographic disparities and HRIF program factors are associated with decreased attendance at V2 among VLBW infants. These findings highlight opportunities for quality and process improvement interventions starting in the NICU and continuing through transition to home and community to assure participation in HRIF. Key Points

Resolving driver events in MLL-r negative high-risk infant ALL.

10030 Background: Infant acute lymphoblastic leukemia (ALL) is the only subtype of childhood ALL whose outcome has not improved over the past two decades. The most important prognosticator is the presence of rearrangements in the Mixed Lineage Leukemia gene (MLL-r), however, many patients present with high-risk clinical features but without MLL-r. We recently identified two cases of infant ALL with high-risk clinical features resembling MLL-r, but were negative for MLL-r by conventional diagnostics. RNA sequencing revealed a partial tandem duplication in MLL (MLL-PTD). We thus aimed to determine if MLL-PTD, other MLL abnormalities, or other genetic or transcriptomic features were driving this subset of high-risk infant ALL without MLL-r. Methods: We obtained 19 banked patient samples from the Children’s Oncology Group (COG) infant ALL trial (AALL0631) from MLL wildtype patients as determined by FISH and cytogenetics. Utilizing deep RNA-sequencing, we manually inspected the MLL gene for MLL-PTD, while also performing automated fusion detection and gene expression profiling in search of defining features of these tumors. Results: 3 additional MLL-PTDs were identified, all in patients with infant T-cell ALL, whereas both index cases were in patients with infant B-cell ALL. Gene expression profiling analysis revealed that all five MLL-PTD infants clustered together. Eight infants (7 with B-cell ALL) were found to have Ph-like expression. Five of these 8 infants were also found to have an IKZF1/JAK2 expression profile; one of these five had a PAX5-JAK2 fusion detected. Two infants (including the one noted above) had novel PAX5 fusions, known drivers of B-cell leukemia. Additional detected fusions included TCF3-PBX1 and TCF4-ZNF384. Conclusions: MLL-PTDs were found in both B- and T-cell infant ALL. Though Ph-like ALL has been described in adolescents and young adults, we found a substantial frequency of Ph-like expression among MLL-WT infants. Further characterization of these infants is ongoing. If replicated in other infant cohorts, these two findings may help explain the poor prognosis of MLL-WT ALL when compared to children with standard risk ALL, and offer the possibility of targeted therapy for select infants.

PATH-24. MOLECULAR CLASSIFICATION OF HIGH RISK INFANT EMBRYONAL BRAIN TUMORS ENROLLED IN THE ACNS0334 TRIAL: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP

Young children with embryonal brain tumors including medulloblastoma (MB), supratentorial primitive neuro-ectodermal tumor, or pineoblastoma have historically been considered high-risk patients with poor outcomes despite the use of intensive radiation-sparing treatment. In the ACNS0334 phase III trial, 91 consented children &lt;36 months old with the above diagnoses were randomized to intensive induction chemotherapy with or without methotrexate followed by consolidation with stem cell rescue. Here we present the results of a centralized integrated molecular analysis including global methylation profiling (65/91), and whole exome sequencing of tumor (46/91) and germline (35/91) DNA. Unsupervised clustering analyses of methylation profiles using multiple orthogonal methods against a reference dataset of 1200 pediatric brain tumors, revealed known and new molecular entities. For tumors diagnosed as MB on central pathology review, 7.3% (3/41) had a non-MB molecular diagnosis (2 embryonal tumor with multiple rosettes/ETMR, 1 group MYC pineoblastoma), with the remainder as MB Group SHH (11/41), Group3 (25/41), and Group4 (2/41). Among histologic non-MBs, 3/24 (12.5%) were molecular entities not intended for trial inclusion (1 each for ATRT, pleomorphic xanthoastrocytoma, and high-grade glioma). ETMR, historically considered a rare entity, was molecularly identified in a significant proportion (14/65; 21.5%) of samples. Among MB-SHH, we detected deleterious PTCH1 mutations in 6/9 tumors but none among 5 germline samples tested; a germline SUFU frameshift mutation with tumor LOH was also observed in MB-SHH. Correlation of these and other molecular features to the parallel clinical analysis will yield important markers of risk stratification and predictors of treatment response.