A Multicenter Descriptive Study of 176 Neonatal-Onset Urea Cycle Disorder Patients Hospitalized in Level IV Neonatal Intensive Care Units
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
The neonatal presentation of urea cycle disorders (UCDs) is nonspecific and often one of extremis. These disorders are collectively rare and even less common when stratified by individual named disorders. Sizeable investigations of UCDs are uncommon; most studies detail single case reports or small case series with a focus on general presentation, survival rates, ongoing pharmacologic interventions, and long-term neurodevelopmental outcomes. Comprehensive reports of the neonatal intensive care unit (NICU) course, including presentation, interventions, and outcomes, remains unpublished. Early recognition of these conditions is crucial as newborn screening for UCDs is currently limited, but good treatment options exist that can improve survival and neurodevelopmental outcomes if initiated early. A multicenter study was performed of patients cared for in 29 Level IV NICUs to characterize the neonatal presentation of UCDs, identify comorbidities, and describe interventions and hospital outcomes.
Methods:
This retrospective multicenter descriptive study utilized the Children’s Hospitals Neonatal Database from 2010-2023 to assess presentation, interventions, and short-term outcomes for a cohort of neonatal-onset UCD patients. Data were analyzed collectively and stratified by named diagnoses. The cohort data was summarized using count and percentages for categorical variables, and median with interquartile range for continuous variables. The difference between specific named diagnosis in terms of demographic and other patient-level characteristics was tested using Chi-Square, Fisher’s Exact and Kruskal-Wallis Test as appropriate. All analyses were performed using SAS Enterprise Guide v8.3 (SAS, Cary, NC). Results were considered statistically significant when p<0.05.
Results:
There were 176 neonates with named UCDs in the cohort: carbamoyl phosphate synthetase 1 (CPS1) deficiency (n=9), ornithine transcarbamylase (OTC) deficiency (n=72), argininosuccinate synthetase (ASS) deficiency (n=59), and argininosuccinate lyase (ASL) deficiency (n=36). A minority of patients (75; 42.6%), were discharged home from a birth hospital prior to NICU admission, with a median age at NICU admission of 5 [3,7] days. Respiratory failure was noted in 60 (34.1%) neonates at the time of NICU admission necessitating intubation and mechanical ventilation. Most neonates with a UCD had a central line during admission (128; 72.7%), with OTC deficiency patients having had the greatest need (67; 93.1%; p<0.001). The duration of needing a central line was greatest for patients with CPS1 deficiency (23 [20,45] days; p=0.032) followed by OTC deficiency (11 [4,30] days). A minority of neonates underwent dialysis during admission (30; 17%), with hemodialysis most common. The greatest need for hemodialysis was seen in neonates with OTC deficiency (18; 25%) and CPS1 deficiency (4; 44.4%; p=0.002). The most common organ systems to experience complications during NICU admission were neurologic (71; 40.3%), hematologic (51; 29.0%), and respiratory (44; 25.0%), with significantly higher rates of these complications in the OTC deficiency patients: neurologic (39; 54.2%; p=0.012), hematologic (31; 43.1%; p=0.003), respiratory (26; 36.1%; p=0.029). Overall, 21 (11.9%) patients experienced in-hospital mortality and neonates with OTC deficiency (16; 22.2%; p<0.001) were at greatest risk for death during the NICU admission. At discharge, 75 of 143 (52.4%) neonates were consuming at least some human milk and 67 (46.9%) were discharged home with a feeding tube.
Conclusion:
Neonatal-onset UCDs are associated with significant morbidity and mortality, but heterogeneity exists among the specific named UCDs. Location of urea cycle enzymatic deficit affects outcomes, with proximal UCDs, and specifically OTC deficiency, requiring more interventions than distal UCDs and experiencing the highest mortality risk. Neurologic, hematologic, and respiratory complications are pervasive in the neonatal presentation of UCDs and require prompt attention while addressing the primary mechanism of disease.
The neonatal presentation of urea cycle disorders (UCDs) is nonspecific and often one of extremis. These disorders are collectively rare and even less common when stratified by individual named disorders. Sizeable investigations of UCDs are uncommon; most studies detail single case reports or small case series with a focus on general presentation, survival rates, ongoing pharmacologic interventions, and long-term neurodevelopmental outcomes. Comprehensive reports of the neonatal intensive care unit (NICU) course, including presentation, interventions, and outcomes, remains unpublished. Early recognition of these conditions is crucial as newborn screening for UCDs is currently limited, but good treatment options exist that can improve survival and neurodevelopmental outcomes if initiated early. A multicenter study was performed of patients cared for in 29 Level IV NICUs to characterize the neonatal presentation of UCDs, identify comorbidities, and describe interventions and hospital outcomes.
Methods:
This retrospective multicenter descriptive study utilized the Children’s Hospitals Neonatal Database from 2010-2023 to assess presentation, interventions, and short-term outcomes for a cohort of neonatal-onset UCD patients. Data were analyzed collectively and stratified by named diagnoses. The cohort data was summarized using count and percentages for categorical variables, and median with interquartile range for continuous variables. The difference between specific named diagnosis in terms of demographic and other patient-level characteristics was tested using Chi-Square, Fisher’s Exact and Kruskal-Wallis Test as appropriate. All analyses were performed using SAS Enterprise Guide v8.3 (SAS, Cary, NC). Results were considered statistically significant when p<0.05.
Results:
There were 176 neonates with named UCDs in the cohort: carbamoyl phosphate synthetase 1 (CPS1) deficiency (n=9), ornithine transcarbamylase (OTC) deficiency (n=72), argininosuccinate synthetase (ASS) deficiency (n=59), and argininosuccinate lyase (ASL) deficiency (n=36). A minority of patients (75; 42.6%), were discharged home from a birth hospital prior to NICU admission, with a median age at NICU admission of 5 [3,7] days. Respiratory failure was noted in 60 (34.1%) neonates at the time of NICU admission necessitating intubation and mechanical ventilation. Most neonates with a UCD had a central line during admission (128; 72.7%), with OTC deficiency patients having had the greatest need (67; 93.1%; p<0.001). The duration of needing a central line was greatest for patients with CPS1 deficiency (23 [20,45] days; p=0.032) followed by OTC deficiency (11 [4,30] days). A minority of neonates underwent dialysis during admission (30; 17%), with hemodialysis most common. The greatest need for hemodialysis was seen in neonates with OTC deficiency (18; 25%) and CPS1 deficiency (4; 44.4%; p=0.002). The most common organ systems to experience complications during NICU admission were neurologic (71; 40.3%), hematologic (51; 29.0%), and respiratory (44; 25.0%), with significantly higher rates of these complications in the OTC deficiency patients: neurologic (39; 54.2%; p=0.012), hematologic (31; 43.1%; p=0.003), respiratory (26; 36.1%; p=0.029). Overall, 21 (11.9%) patients experienced in-hospital mortality and neonates with OTC deficiency (16; 22.2%; p<0.001) were at greatest risk for death during the NICU admission. At discharge, 75 of 143 (52.4%) neonates were consuming at least some human milk and 67 (46.9%) were discharged home with a feeding tube.
Conclusion:
Neonatal-onset UCDs are associated with significant morbidity and mortality, but heterogeneity exists among the specific named UCDs. Location of urea cycle enzymatic deficit affects outcomes, with proximal UCDs, and specifically OTC deficiency, requiring more interventions than distal UCDs and experiencing the highest mortality risk. Neurologic, hematologic, and respiratory complications are pervasive in the neonatal presentation of UCDs and require prompt attention while addressing the primary mechanism of disease.