- Email: [email protected]
Codeine and breastfeeding – Authors' reply
Correspondence
Authors’ reply
Reuters
The printed journal includes an image merely for illustration
626
Nicholas Bateman and colleagues’ comments seem to stem from fundamental flaws in their understanding of perinatal toxicology, and their lack of recognition that a baby is not a small adult when it comes to morphine toxicology. Our original submission to The Lancet that included all details was shortened to one page at the editors’ request. Bateman and colleagues suggest that the infant’s milk intake was too low to result in morphine poisoning; however, this baby regained his birthweight by day 10, indicating appropriate milk intake to that point. Bateman and colleagues reason that a mother and infant would be expected to have the same clinical features, but they seem to ignore the fact that neonates are much more sensitive than adults to the ventilatory depressant effects of morphine.1 The single measure of morphine in milk after maternal codeine use was sevenfold higher than previously described, and was probably much higher before the mother halved her dose. The attempt by Bateman and colleagues to extrapolate morphine dose on the basis of a single measure in milk is inappropriate. Bateman and colleagues acknowledge the complexities of codeine metabolism, yet they compare serum morphine in the reported baby to a previous case in which a mother received morphine rather than codeine. The two cases are different in age, in maternal mode of drug administration, and probably in genotype. In the previous case, the mother stopped morphine on postnatal day 7, and resumed it later. Thus, that infant was not exposed to morphine continually, exhibiting low levels. Bateman and colleagues’ second concern about the source of paracetamol in the infant’s blood ignore dramatic post-mortem fluctuations in paracetamol concentrations in different blood collection sites in the same individual.2 By contrast,
morphine does not seem to exhibit post-mortem redistribution in human beings.3 Paracetamol was undetectable in gut content; if codeine-paracetamol had been given to the baby orally, paracetamol concentrations in the gut should have been excessively high. There have been previous reports of codeine risk during breastfeeding. In one,4 four premature infants exhibited neonatal apnoea 4–6 days after administration of 60 mg codeine to breastfeeding mothers, which is similar to our case, and corresponds to a build-up of neonatal morphine concentrations. When breastfeeding was withheld and codeine discontinued, apnoea resolved within 24–48 h. In another report,5 ten out of 12 full-term infants who had unexplained apnoea, bradycardia, or cyanosis were exposed to opioids through breastmilk, six specifically to codeine. With support from Genome BC, we are now studying mother–baby pairs exposed to codeine during breastfeeding. We have identified an additional case of serious neonatal toxicity with active gene duplication that could have been fatal unless the mother discontinued breastfeeding.6 Our study corroborates a 20% risk of CNS depression and clear doseresponse characteristics. By use of the Naranjo probability scale for adverse drug reactions, this neonatal syndrome scores in the “definite” range. Bateman and colleagues seem to disregard the obvious: neonatal opioid death in a breastfed infant of a CYP2D6 ultrarapid metaboliser mother, with a documented high concentration of morphine in milk. We deeply hope that practising physicians pay more attention to the neonate as a vulnerable target of drug toxicity, realising that codeine can be dangerous for some babies. We declare that we have no conflict of interest.
Parvaz Madadi, David Chitayat, *Gideon Koren [email protected]
Motherisk Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada (PM, GK); University of Western Ontario, London, Ontario, Canada (GK); and Prenatal Diagnosis Program, Mount Sinai Hospital, Toronto, Ontario, Canada (DC) 1
2
3
4
5
6
Bragg P, Zwass MS, Lau, M, Fisher DM. Opioid pharmacodynamics in neonatal dogs: differences between morphine and fentanyl. J Appl Physiol 1995; 79: 1519–24. Yonemitsu K, Pounder DJ. Postmortem toxicokinetics of co-proxamol. Int J Legal Med 1992; 104: 347–53. Gerostamoulos J, Drummer OH. Postmortem redistribution of morphine and its metabolites. J Forensic Sci 2000; 45: 843–45. Davis JM, Bhutain VK. Neonatal apnea and maternal codeine use. Develop Pharm 1985; 170A: 359. Naumburg EG, Meny RG. Unexplained neonatal apnea, bradycardia, cyanosis: An association with opioids in breast milk. Clin Res 1987; 35: 79A. Madadi P, Ross CJD, Carlton BC, et al. Pharmacogenetics of codeine toxicity during breastfeeding. Presented at the Cold Spring Harbor Laboratory/Wellcome Trust Meeting on Pharmacogenetics; Hinxton, UK; Oct 17–20, 2007.
Lack of publication bias related to results from trastuzumab study As principal investigator (EAP) and lead statistician (VJS) for the N9831 adjuvant trastuzumab study, we appreciate the opportunity to respond to Scott Metcalfe and colleagues’ Comment (May 17, p 1646).1 We developed the statistical design and analysis plan for N9831, and have done every aspect of this study in full collaboration with colleagues in the North American Breast Intergroup and with the approvals of the National Cancer Institute (NCI) and the Food and Drug Administration (FDA). We are acutely aware of the importance of our N9831 trial in terms of being the only phase III randomised trial to assess chemotherapy (group A) versus either sequential (group B) or concurrent (group C) incorporation of trastuzumab. On Jan 26, 2004, the leadership of the two studies N9831 and B-31 submitted a proposal to the FDA for the integrated data analysis of B-31 www.thelancet.com Vol 372 August 23, 2008
Authors’ reply
Reuters
The printed journal includes an image merely for illustration
626
Nicholas Bateman and colleagues’ comments seem to stem from fundamental flaws in their understanding of perinatal toxicology, and their lack of recognition that a baby is not a small adult when it comes to morphine toxicology. Our original submission to The Lancet that included all details was shortened to one page at the editors’ request. Bateman and colleagues suggest that the infant’s milk intake was too low to result in morphine poisoning; however, this baby regained his birthweight by day 10, indicating appropriate milk intake to that point. Bateman and colleagues reason that a mother and infant would be expected to have the same clinical features, but they seem to ignore the fact that neonates are much more sensitive than adults to the ventilatory depressant effects of morphine.1 The single measure of morphine in milk after maternal codeine use was sevenfold higher than previously described, and was probably much higher before the mother halved her dose. The attempt by Bateman and colleagues to extrapolate morphine dose on the basis of a single measure in milk is inappropriate. Bateman and colleagues acknowledge the complexities of codeine metabolism, yet they compare serum morphine in the reported baby to a previous case in which a mother received morphine rather than codeine. The two cases are different in age, in maternal mode of drug administration, and probably in genotype. In the previous case, the mother stopped morphine on postnatal day 7, and resumed it later. Thus, that infant was not exposed to morphine continually, exhibiting low levels. Bateman and colleagues’ second concern about the source of paracetamol in the infant’s blood ignore dramatic post-mortem fluctuations in paracetamol concentrations in different blood collection sites in the same individual.2 By contrast,
morphine does not seem to exhibit post-mortem redistribution in human beings.3 Paracetamol was undetectable in gut content; if codeine-paracetamol had been given to the baby orally, paracetamol concentrations in the gut should have been excessively high. There have been previous reports of codeine risk during breastfeeding. In one,4 four premature infants exhibited neonatal apnoea 4–6 days after administration of 60 mg codeine to breastfeeding mothers, which is similar to our case, and corresponds to a build-up of neonatal morphine concentrations. When breastfeeding was withheld and codeine discontinued, apnoea resolved within 24–48 h. In another report,5 ten out of 12 full-term infants who had unexplained apnoea, bradycardia, or cyanosis were exposed to opioids through breastmilk, six specifically to codeine. With support from Genome BC, we are now studying mother–baby pairs exposed to codeine during breastfeeding. We have identified an additional case of serious neonatal toxicity with active gene duplication that could have been fatal unless the mother discontinued breastfeeding.6 Our study corroborates a 20% risk of CNS depression and clear doseresponse characteristics. By use of the Naranjo probability scale for adverse drug reactions, this neonatal syndrome scores in the “definite” range. Bateman and colleagues seem to disregard the obvious: neonatal opioid death in a breastfed infant of a CYP2D6 ultrarapid metaboliser mother, with a documented high concentration of morphine in milk. We deeply hope that practising physicians pay more attention to the neonate as a vulnerable target of drug toxicity, realising that codeine can be dangerous for some babies. We declare that we have no conflict of interest.
Parvaz Madadi, David Chitayat, *Gideon Koren [email protected]
Motherisk Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada (PM, GK); University of Western Ontario, London, Ontario, Canada (GK); and Prenatal Diagnosis Program, Mount Sinai Hospital, Toronto, Ontario, Canada (DC) 1
2
3
4
5
6
Bragg P, Zwass MS, Lau, M, Fisher DM. Opioid pharmacodynamics in neonatal dogs: differences between morphine and fentanyl. J Appl Physiol 1995; 79: 1519–24. Yonemitsu K, Pounder DJ. Postmortem toxicokinetics of co-proxamol. Int J Legal Med 1992; 104: 347–53. Gerostamoulos J, Drummer OH. Postmortem redistribution of morphine and its metabolites. J Forensic Sci 2000; 45: 843–45. Davis JM, Bhutain VK. Neonatal apnea and maternal codeine use. Develop Pharm 1985; 170A: 359. Naumburg EG, Meny RG. Unexplained neonatal apnea, bradycardia, cyanosis: An association with opioids in breast milk. Clin Res 1987; 35: 79A. Madadi P, Ross CJD, Carlton BC, et al. Pharmacogenetics of codeine toxicity during breastfeeding. Presented at the Cold Spring Harbor Laboratory/Wellcome Trust Meeting on Pharmacogenetics; Hinxton, UK; Oct 17–20, 2007.
Lack of publication bias related to results from trastuzumab study As principal investigator (EAP) and lead statistician (VJS) for the N9831 adjuvant trastuzumab study, we appreciate the opportunity to respond to Scott Metcalfe and colleagues’ Comment (May 17, p 1646).1 We developed the statistical design and analysis plan for N9831, and have done every aspect of this study in full collaboration with colleagues in the North American Breast Intergroup and with the approvals of the National Cancer Institute (NCI) and the Food and Drug Administration (FDA). We are acutely aware of the importance of our N9831 trial in terms of being the only phase III randomised trial to assess chemotherapy (group A) versus either sequential (group B) or concurrent (group C) incorporation of trastuzumab. On Jan 26, 2004, the leadership of the two studies N9831 and B-31 submitted a proposal to the FDA for the integrated data analysis of B-31 www.thelancet.com Vol 372 August 23, 2008