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Meta-Analysis
. 2025 Nov;48(6):e70090.
doi: 10.1002/jimd.70090.

Impact of Newborn Screening on Survival and Developmental Outcome in Classic Isovaleric Aciduria: A Meta-Analysis

Anna T Reischl-Hajiabadi  1 , Sven F Garbade  1 , Florian Gleich  1 , Elena Schnabel-Besson  1 , Roland Posset  1 , Matthias Zielonka  1 , Georg F Hoffmann  1 , Stefan Kölker  1 , Ulrike Mütze  1
Affiliations
Meta-Analysis

Impact of Newborn Screening on Survival and Developmental Outcome in Classic Isovaleric Aciduria: A Meta-Analysis

Anna T Reischl-Hajiabadi et al. J Inherit Metab Dis. 2025 Nov.

Abstract

Classic isovaleric aciduria (cIVA) is a rare inherited metabolic disorder characterized by recurrent life-threatening metabolic decompensations and neurocognitive impairment in untreated patients. This meta-analysis aims to assess the impact of early diagnosis by newborn screening (NBS) on mortality and neurocognitive outcome. A systematic literature search for articles published until 2022 was conducted following PRISMA protocol guidelines. We investigated effects on clinical outcomes and survival, analyzing outcome parameters using meta-analytical measures and estimating effect sizes with a random-effects model. Overall, 20 studies were included, reporting on 240 individuals with cIVA. Individuals identified by NBS presented with a lower frequency of neurological symptoms (13.0% vs. 44.9%; p = 0.0040) and developmental delay (6.1% vs. 51.2%; p < 0.0001), and had a lower mortality rate (1.1% vs. 10.9%; p = 0.0320). The quality of healthcare systems did not have a measurable impact on neurocognitive outcome and mortality. Despite the beneficial effect of NBS on clinical outcome and mortality, it could not reliably prevent the manifestation of neonatal decompensation in all individuals with cIVA identified by NBS. Early diagnosis through NBS is essential for the timely initiation of therapy and for improving outcomes and survival rates in individuals with cIVA.

Keywords: core outcome set; isovaleric acidemia; mortality; neonatal screening; systematic review.

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Conflict of interest statement

S.K. and G.F.H. received research grants from the Dietmar Hopp Foundation, St. Leon‐Rot, Germany (grant numbers 23011221, 1DH2011117). R.P. received consultancy fees from Immedica Pharma AB. The other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
PRISMA flow diagram demonstrating the flow of information of the meta‐analysis. Finally, a total of 20 studies were included in the analyses. Nine studies included data on individuals with cIVA identified by NBS (cIVA‐NBS) and 17 studies included data on individuals diagnosed after onset of symptoms (cIVA‐Sympt).
FIGURE 2
FIGURE 2
Mortality rate for classic IVA. Identification by NBS (cIVA‐NBS) versus diagnosis after onset of symptoms (cIVA‐Sympt). The Random effects model measures the mean weighted effect size (indicated by diamonds) and CI (confidence interval). Each square size reflects the study weight. Patients identified by NBS show a significant lower mortality rate (cIVA‐NBS: 1.1%; 95% CI 0–0.06; cIVA‐Sympt: 10.9%; 95% CI 0.03–0.19; [χ 2(1) = 4.6, p = 0.0320; Q(25) = 53.56, p = 0.0008; I 2 = 53.3%]).
FIGURE 3
FIGURE 3
Occurrence of neurological symptoms until last follow‐up in classic IVA. Identification by NBS (cIVA‐NBS) versus diagnosis after onset of symptoms (cIVA‐Sympt). The Random effects model measures the mean weighted effect size (indicated by diamonds) and CI (confidence interval). Each square size reflects the study weight. Patients identified by NBS show less often neurological symptoms (cIVA‐NBS: 13.0%; 95% CI 0–0.27; cIVA‐Sympt group 44.9%; 95% CI 0.28–0.62; [χ 2(1) = 8.3, p = 0.0040; Q(17) = 56.78, p < 0.0001; I 2 = 70.1%]).
FIGURE 4
FIGURE 4
Occurrence of developmental delay until last follow‐up in classic IVA. Identification by NBS (cIVA‐NBS) versus diagnosis after onset of symptoms (cIVA‐Sympt). The Random effects model measures the mean weighted effect size (indicated by diamonds) and CI (confidence interval). Each square size reflects the study weight. Patients identified by NBS show a significantly lower proportion of developmental delay (cIVA‐NBS: 6.1%; 95% CI 0–0.19; cIVA‐Sympt: 51.2%; 95% CI 0.36–0.67; [χ 2(1) = 18.2, p < 0.0001; Q(19) 80.27, p < 0.0001; I 2 = 76.3%]).
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