CYP2C9*2 is Associated with Indomethacin Treatment Failure for Patent Ductus Arteriosus

Abstract

Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34–10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

Mouse models of patent ductus arteriosus (PDA) and their relevance for human PDA

“…In addition, genetic variants in the CYP2C9 enzyme are associated with increased risk of indomethacin treatment failure in preterm neonates. 130 SNPs, generally defined as occurring in >1% of the population, and rare variants occurring in <1% of the population certainly contribute to syndromic disorders, although distinctions between these are contentious and vary between populations. 131 The involvement of SNPs and variants in PDA is a rapidly evolving field of research.…”

Patent Ductus Arteriosus of the Preterm Infant

“…12 Still, only 10% of PDA cases are associated with chromosomal abnormalities. 13 Therefore, single-nucleotide polymorphisms associated with nonsyndromic PDA may be more informative regarding genetic regulation of the more common sporadic cases of PDA 14,15 (Table 1).…”

The Impact of Pharmacogenetics on Pharmacokinetics and Pharmacodynamics in Neonates and Infants: A Systematic Review

“… 21 Besides other factors (GA, surfactant use), the presence of CYP2C9*2 (adjusted OR, 3.74) was associated with indomethacin treatment failure (defined by the need for surgical ligation, 35% of cases) in a 3-center cohort study on 144 preterm (GA 22–32 weeks) cases. 21 This paper confirmed a previously published case-control (52 non-responders versus 96 responders, <32 weeks) analysis. Besides GA, these authors identified an association between CYP2C9 rs2153628 (increased odds of response 1.92) or rs1799853, and DA response.…”