Morphine biotransformation genes and neonatal clinical factors predicted behaviour problems in very preterm children at 18 months

BACKGROUND: Behaviour problems are prevalent among children born very preterm (≤ 32 weeks gestation), and have been associated with morphine exposure. Morphine accumulation in the brain is determined by genetic variations related to morphine biotransformation. The objective of the study was to investigate whether morphine-biotransformation genotypes contribute to individual differences in long-term effects of morphine on behaviour at 18 months corrected age (CA). METHODS: 198 children born very preterm (24–32 weeks gestation) were followed from birth and seen at 18 months CA. Relationships between child behavior (Internalizing, Externalizing on the Child Behavior Checklist), morphine exposure, neonatal clinical variables, and morphine biotransformation gene variants in ABCB1, UGT1A9, UGT 2B7*2, ABCC2, ABCC3, SLCO1B1, CYP3A4, COMT were examined. FINDINGS: Neonatal clinical predictors and genotypes accounted for 39% of the overall variance in behaviour. In children with the minor allele of UGT1A9 rs17863783 (marker of UGT1A6*4, UDP-glucuronosyltransferase), greater morphine exposure (p = ·0011) was associated with more Internalizing behaviour. More Externalizing behaviour was predicted by greater morphine exposure in children with the COMT rs4680 Met/Met genotype (p = ·0006). INTERPRETATION: Genetic variations that affect relative accumulation of morphine in the brain, together with neonatal clinical factors, are differentially related to anxiety and depressive symptoms (internalizing) and to acting out (externalizing) behaviours at 18 months CA in children born very preterm. FUND: NIH/NICHD HD039783 (REG); CIHR MOP86489 (REG), MOP68898 (SPM), MOP79262 (SPM, REG).