Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study.
A large number of women receive codeine for obstetric pain while breastfeeding. Following a case of fatal opioid poisoning in a breastfed neonate whose codeine prescribed mother was a CYP2D6 ultrarapid metabolizer (UM), we examined characteristics of mothers and infants with or without signs of central nervous system (CNS) depression following codeine exposure while breastfeeding in a case-control study. Mothers of symptomatic infants (n = 17) consumed a mean 59% higher codeine dose than mothers of asymptomatic infants (n = 55) (1.62 (0.79) mg/kg/day vs. 1.02 (0.54) mg/kg/day; P = 0.004). There was 71% concordance between maternal and neonatal CNS depression. Two mothers whose infants exhibited severe neonatal toxicity were CYP2D6 UMs and of the UGT2B7*2/*2 genotype. There may be a dose-response relationship between maternal codeine use and neonatal toxicity, and strong concordance between maternal-infant CNS depressive symptoms. Breastfed infants of mothers who are CYP2D6 UMs combined with the UGT2B7*2/*2 are at increased risk of potentially life-threatening CNS depression.
Madadi
P
P
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
Ross
C J D
CJ
Hayden
M R
MR
Carleton
B C
BC
Gaedigk
A
A
Leeder
J S
JS
Koren
G
G
D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D001049:Apnea / Q000139:chemically induced; D001942:Breast Feeding / Q000009:adverse effects*; D016022:Case-Control Studies; D003061:Codeine / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008895:Milk, Human / Q000737:chemistry*; D009293:Opioid-Related Disorders / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy; D010597:Pharmacogenetics
D000701:Analgesics, Opioid; D019389:Cytochrome P-450 CYP2D6; D003061:Codeine