Pharmacogenetics of Fatal Morphine Poisoning in a

Pharmacogenetics of Fatal Morphine Poisoning in a Breastfed Neonate of a
Codeine Using Mother
Gideon Koren, James Cairns, David Chitayat, Andrea Gaedigk,
Steven J. Leeder
Motherisk Program, Hospital for Sick Children, Toronto (G. Koren,
FRCPC); Ontario Coroner Office (J. Cairns MD); Prenatal Diagnosis
Program, Mount Sinai Hospital, Toronto (D. Chitayat, FRCPC), Children’s
Mercy Hospital, Kansas City (A. Gaedigk PhD, S. J. Leeder, PhD)
Correspondence to:
Dr. Gideon Koren
[email protected]
A full term healthy male infant, delivered vaginally, who was breastfed by a codeine-using
mother, exhibited intermittent periods of difficulty in breastfeeding and lethargy starting on
Day 7. On Day 12 he exhibited grey skin and decreased milk intake. Subsequently, he was
found dead on Day 13. Postmortem analysis showed no anatomical anomalies and blood
morphine concentration (the active metabolite of codeine) of 70 ng/mL by gas
chromatography-mass spectrometry (GC-MS). Neonates breastfed by mothers receiving
codeine-typically have morphine serum concentrations of 0-2.2 ng/mL(1).
The mother was prescribed Tylenol 3 (codeine 30 mg and acetaminophen 500 mg) after birth
for episiotomy pain (initially 2 tab. 6 hourly and half that dose from Day 2 due to somnolence
and constipation). She continued Tylenol 3 for two weeks. Due to poor neonatal feeding, she
stored milk on Day 9 which was measured for morphine by specific ELISA and GC-MS at 87
ng/mL. Typical milk levels after repeated maternal codeine range from 1.9 to 20.5 ng/mL at
doses of 60 mg q6H. Genotype analysis was conducted for cytochrome P450 2D6 (CYP2D6),
the enzyme catalyzing the O-demethylation of codeine to morphine(2). The mother was
heterozygous for a CYP2D6*2A allele with CYP2D6*2x2 gene duplication, classified as an
ultra-rapid metabolizer. This genotype leads to enhanced formation of morphine from codeine,
consistent with the somnolence and constipation experienced by her(3). The maternal
grandfather, the father and infant possessed two functional CYP2D6 alleles (CYP2D6*1/*2
genotypes, classified as extensive metabolizers. The maternal grandmother was an ultra-rapid
metabolizer (Figure ).
The clinical and laboratory picture in this case is consistent with opioid toxicity leading to
neonatal death. Most of the analgesic and CNS depressing effects of codeine are secondary to
its metabolism to morphine by CYP2D62. The high milk level of morphine corroborates the
clinical picture in the infant. Milk was available only at half of the initial codeine dose;
conceivably peak milk concentration of morphine was higher.
Codeine is a commonly used analgesic after labor for pain associated with episiotomy and
caesarian section. The American Academy of Pediatrics lists codeine as compatible with
breastfeeding, despite lack of sufficient published data to support this recommendation(4).
Because the vast majority of pregnant women initiate breast feeding, the safety of codeine
during breastfeeding must be established.
This case reveals that polymorphism in CYP2D6 may be life threatening for some breastfed
babies. Given that a CYP2D6 ultra-rapid metabolizer genotype occurs in 1% in Caucasians and
up to 30% in some parts of Asia and Africa(5), this polymorphism is clinically important.
Several strategies can be considered to prevent life threatening neonatal toxicity (Table):
1) Avoiding breastfeeding in cases of maternal use of codeine. While this approach can
prevent neonatal toxicity, it would prevent the benefits of breastfeeding from thousands of
2) Genotyping all postpartum women who are planned to receive codeine.
This strategy would identify CYP2D6 ultra-metabolizers who are at risk of neonatal poisoning.
Presently this test is not available in most clinical facilities.
3) Careful follow up of all women on codeine, and testing mother-child pairs when the mother
is experiencing symptoms consistent with opioid toxicity.
4) Following up closely all breastfed infants of codeine-using mothers and test morphine levels
whenever there are adverse events consistent with opioid toxicity. Morphine measurement is
not routine in most facilities. In any suspicious case, naoloxone may reverse and thus
corroborate opioid toxicity. Whatever clinical approach is taken, codeine cannot be considered
as a safe drug for all infants during breastfeeding. To the best of our knowledge, this is the
first record of a breastfed baby succumbing to toxicity through breastmilk.
1) Meny RG, Naumburg EG, Alger LS, Brill-Miller H, Brown S: Codeine and the
breastfed neonate. J Hum Lact 1993; 9: 237-40.
2) Meyer UA. Pharmacogenetics of adverse drug reactions. Lancet 2000; 356: 1667-71.
3) Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J: Codeine
intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004; 351:
4) Committee on Drugs. American Academy of Pediatrics. The transfer of drugs and other
chemicals into human milk. Pediatrics 2001; 108: 776-89.
5) Cascarbi I. Pharmacogenetics of cytochrome P4502D6: genetic background and
clinical implication. Eur J Clin Invest 2003; 33 (Suppl 2); 17-22.
Supported by Genome BC, the Ivey Chair in Molecular Toxicology, University of Western
Ontario, and the Canadian Institutes for Health Research.
Pedigree of the family’s CYP2D6 genotype.
Table : Clinical Strategies to Manage Breastfeeding While on Codeine
Avoid codeine when
Avoid high dose codeine
(240 mg/d) for more than a
few days
Avoiding potential neonatal
Minimizing potential
neonatal toxicity
Avoid breastfeeding when
on codeine
Informing and monitoring
mother and baby for signs
of opioid toxicity
Avoiding potential neonatal
Intervening early and
preventing serious toxicity;
ability to give antidote
Predicting mothers at risk of Expensive, not presently
producing excess of
Genotyping mother for 2D6
Potential uncontrolled
maternal pain
*Suboptimal maternal pain
*May still be too high a
dose for ultra rapid
Losing the benefits of
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