1-877-439-2744 Motherisk Helpline
1-800-436-8477 Morning Sickness
1-877-327-4636 Alcohol and Substance
1-866-937-7678 Exercise in Pregnancy
1-888-246-5840 HIV and HIV Treatment
416-813-6780 Motherisk Helpline
Pregnancy & Breastfeeding Resources
- Read more in our News Archive
Current Studies at Motherisk
The Safety of Diclectin in Breastfeeding
Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
Diclegis Surveillance Program Study
Diclectin Surveillance Program Study
Study seeks women between 4 and 12 weeks in their pregnancy with morning sickness (NVP)
Pregnancy in Women with Multiple Sclerosis
Alcohol Use during Pregnancy
Autoimmune Diseases in Pregnancy Project
Safety of codeine during breastfeeding
Parvaz Madadi, Gideon Koren, MD, FRCPC, James Cairns, MD, David Chitayat, MD, Andrea Gaedigk, PHD, J. Steven Leeder, PHARMD, PHD, Ronni Teitelbaum, MSC, Tatyana Karaskov, MD, Katarina Aleksa, PHD
Recently a newborn died from morphine poisoning when his mother used codeine while breastfeeding. Many patients receive codeine for postlabour pain. Is it safe to prescribe codeine for nursing mothers?
When a mother is an ultrarapid metabolizer of cytochrome P450 2D6, she produces much more morphine when taking codeine than most people do. In this situation, newborns might be exposed to toxic levels of morphine when breastfeeding. Options to reduce this risk include discontinuing codeine after 2 to 3 days of use and being aware of symptoms of potential opioid toxicity in both mothers and newborns.
Un nouveau-né est récemment décédé d’un empoisonnement à la morphine parce que sa mère avait pris de la codéine pendant qu’elle allaitait. De nombreuses patientes reçoivent de la codéine pour les douleurs après le travail. Est-il sécuritaire de prescrire de la codéine aux mères qui allaitent?
Si la mère métabolise ultra rapidement le cytochrome P450 2D6, elle produit beaucoup plus de morphine lorsqu’elle prend de la codéine que la plupart des autres personnes. Dans une telle situation, un nouveau-né pourrait être exposé à des taux toxiques de morphine quand il est allaité. Pour réduire le risque, on peut, entre autres, cesser l’utilisation de la codéine après 2 ou 3 jours, et demeurer vigilant face aux éventuels symptômes d’une intoxication aux opioïdes chez la mère et le nourrisson.
Codeine is commonly used in the postpartum period for pain associated with episiotomy and cesarian section. As most mothers initiate breastfeeding, the safety of codeine and its pharmacologically active metabolite, morphine, among breastfed infants is of primary concern. The American Academy of Pediatrics and major authoritative texts list codeine as compatible with breastfeeding,1,2 despite insufficient published data to support this recommendation. To illustrate the need for further assessment of codeine and morphine transfer into breast milk, we describe a recently published case of a full-term, breastfed infant who died in a manner consistent with morphine overdose.3 Pharmacogenetic assessment of maternal drug biotransformation was consistent with enhanced formation of the pharmacologically active opioid, morphine. To the best of our knowledge, this is the first record of a breastfed baby succumbing to toxicity through breast milk.
A newborn male infant, born after an unremarkable pregnancy and delivery (birth weight 3.88 kg, 90th percentile), developed difficulty breastfeeding and increasing lethargy at 7 days of age. At 11 days of age, he was taken to a pediatrician owing to concerns about his skin colour and decreased milk intake. The pediatrician noted that the infant had gained his birth weight. Subsequently, on day 13, an ambulance team found the baby cyanotic and without vital signs. Resuscitation, which was initiated at home and continued in the hospital’s emergency department, was unsuccessful. Full postmortem analysis failed to identify an anatomic cause of death.
Hepatic steatosis was investigated for medium-chain acyl-CoA dehydrogenase deficiency, which was ruled out. Other fatty acid oxidative disorders, organic acidemias, congenital adrenal hyperplasia, hypothyroidism, and galactosemia were also ruled out. Postmortem toxicologic testing using gas chromatography–mass spectrometry revealed a blood concentration of morphine at 70 ng/mL and acetaminophen at 5.9 µg/mL. Neonates receiving morphine for analgesia have been reported to have serum concentrations of morphine at 10 to 12 ng/mL.4
Review of the medical records revealed that in the immediate postpartum period the mother was prescribed Tylenol® 3 (codeine 30 mg and acetaminophen 500 mg). Initially she took 2 tablets twice daily, but she halved the dose on postpartum day 2 owing to somnolence and constipation. Following the development of poor neonatal feeding, the mother expressed milk and stored it in a freezer. Analysis of the milk for morphine using a specific enzyme-linked immunosorbent assay method for morphine revealed a concentration of 87 ng/mL. At this level, the cross-reactivity of the assay with codeine in our laboratory is less than 4%. The morphine measurement was further confirmed by gas chromatography–mass spectrometry.
To address the potential contribution of pharmacogenetic factors to maternal response and neonatal outcome following codeine administration, genotype analysis was conducted for cytochrome P450 2D6 (CYP 2D6), the enzyme catalyzing the O-demethylation of codeine to morphine,4 and for uridine diphosphate–dependent glucuronosyltransferase 2B7 (UGT 2B7), the enzyme catalyzing the formation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).5
The mother was found to be compound heterozygous for a CYP 2D6*2A allele and a CYP 2D6*2x2 gene duplication. In essence, the mother had 3 functional CYP 2D6 genes and would be classified as an ultrarapid metabolizer. The phenotypic consequence of this genotype is enhanced formation of morphine from codeine, consistent with the symptoms of somnolence and constipation that she experienced with the initial doses of Tylenol® 3. Both the father and the infant possessed 2 functional CYP 2D6 alleles (CYP 2D6*1/*2 genotypes). Both the mother and the infant were homozygous for the UGT 2B7*2 (-161TT, 802TT) allele, which has been associated with increased M6G:morphine compared with the UGT 2B7*1 allele (-161C, 802C).6,7 Morphine-6-glucuronide is a highly active metabolite of morphine.
The clinical and toxicologic pictures in this case are consistent with opioid toxicity leading to neonatal death. Codeine itself has only mild opioid properties, while most of its analgesia and central nervous system–depressant effects are secondary to its biotransformation to morphine, a reaction catalyzed by CYP 2D6.5 While most people are extensive metabolizers of codeine to morphine, CYP 2D6 gene duplication results in an ultrarapid metabolizer phenotype (in an estimated 1% of people in Finland and Denmark, 10% of people in Greece and Portugal, and 29% of people in Ethiopia) and, thus, the potential for substantially increased production of morphine from codeine.8 In adults, this has been shown to result in serious opioid toxicity even with small doses of codeine,6 an observation consistent with the symptoms of opiate excess experienced by the mother in this case. Furthermore, the high levels of morphine in the breast milk in this case (86 ng/mL) corroborate the clinical picture observed in the infant. Breastfed infants of mothers prescribed 60 mg of codeine for postnatal pain achieved maximum plasma morphine concentrations of only 2.2 ng/mL.7 In our case, a milk sample was available only for a period when the mother halved her dose. Hence, assuming linear kinetics, it is likely that peak levels of morphine in the milk were approximately 100 ng/mL.
The predominant routes of morphine elimination include biotransformation to M3G and M6G. The production of the active metabolite M6G is almost exclusively catalyzed by UGT 2B7.9 Sawyer et al10 reported increased M6G:morphine in individuals homozygous for the single nucleotide polymorphisms constituting the UGT 2B7*2 allele. Since the mother’s genotype was UGT 2B7*2/*2, it is possible that the infant might have also been exposed to higher than anticipated concentrations of the pharmacologically active M6G metabolite, and not just of morphine itself.
There are several previous reports of somnolence11 and neonatal apnea12 in babies exposed to codeine through breast milk, suggesting that varying degrees of opioid toxicity are more prevalent than commonly assumed. Codeine is widely perceived to be compatible with breastfeeding, owing to previously measured low levels of morphine in milk.1,2 Our case reveals that polymorphism in CYP 2D6 and possibly UGT 2B7 can be life threatening for some breastfed babies. Given that a CYP 2D6 ultrarapid metabolizer genotype occurs at a frequency of 1% to 29%, genetic combination would be expected to occur quite commonly among breastfeeding mothers.
As demonstrated by this case, the common practice of prescribing codeine in the postpartum period cannot be regarded as safe for all breastfed infants. Therefore, we propose several clinical approaches that can be considered to prevent life-threatening neonatal toxicity, each with its benefits and disadvantages (see box). Whatever clinical approach is taken, codeine cannot be considered safe during breastfeeding.
Strategies to prevent neonatal morphine toxicity
1. Avoid prescribing codeine and use nonsteroidal anti-inflammatory drugs. This approach might not be possible in cases of severe pain.
2. Prescribe codeine-containing products for 2 to 3 days only, so neonatal accumulation of morphine is prevented.
3. Genotype all postpartum women about to receive codeine. This approach will identify CYP 2D6 and UGT 2B7 genotypes associated with the potential for increased formation of pharmacologically active codeine metabolites, morphine and possibly M6G, and, thus, individuals who are at risk of neonatal toxicity. Currently these tests are not available in most clinical facilities.
4. Carefully follow up all women taking codeine; test both mother and child when mothers are experiencing opioid toxicity.
5. Closely follow up all breastfed infants of codeine-using mothers; test morphine levels whenever there are adverse events consistent with opioid toxicity. In any case where you suspect opioid toxicity, a naloxone test might reverse, and thus corroborate, that toxicity.
- Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993;43(371):245-8. Abstract/FREE Full Text
- Mazzotta P, Stewart D, Atanackovic G, Koren G, Magee LA. Psychosocial morbidity among women with nausea and vomiting of pregnancy: prevalence and association with anti-emetic therapy. J Psychosom Obstet Gynaecol 2000;21(3):129-36. CrossRef | Medline | Google Scholar
- Chou FH, Lin LL, Cooney AT, Walker LO, Riggs MW. Psychosocial factors related to nausea, vomiting, and fatigue in early pregnancy. J Nurs Scholarsh 2003;35(2):119-25. CrossRef | Medline | Google Scholar
- Swallow BL, Lindow SW, Masson EA, Hay DM. Psychological health in early pregnancy: relationship with nausea and vomiting. J Obstet Gynaecol 2004;24(1):28-32. CrossRef | Medline | Google Scholar
- Mazzotta P, Stewart DE, Koren G, Magee LA. Factors associated with elective termination of pregnancy among Canadian and American women with nausea and vomiting of pregnancy. J Psychosom Obstet Gynaecol 2001;22(1):7-12. CrossRef | Medline | Google Scholar
- Atanackovic G, Navioz Y, Moretti ME, Koren G. The safety of higher than standard dose of doxylamine-pyridoxine (Diclectin) for nausea and vomiting of pregnancy. J Clin Pharmacol 2001;41(8):842-5. Medline | Google Scholar
- Shrim A, Boskovic R, Maltepe C, Navioz Y, Garcia Bournissen F, Koren G. Pregnancy outcome following use of large doses of vitamin B6 in the first trimester. J Obstet Gynaecol 2006;26(8):749-51. Medline | Google Scholar
- Duchesnay. Product center-Diclectin [website]. Laval, QC: Duchesnay; 2006. Available from: http://www.duchesnay.com/product_diclectin.html. Accessed 2007 October 23.
- Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG 2004;111(9):940-3. CrossRef | Medline | Google Scholar
- Asker C, Norstedt Wikner B, Kallen B. Use of antiemetic drugs during pregnancy in Sweden. Eur J Clin Pharmacol 2005;61(12):899-906. Epub 2005 November 18. CrossRef | Medline | Google Scholar
- Berkovitch M, Mazzota P, Greenberg R, Elbirt D, Addis A, Schuler-Faccini L, et al. Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study. Am J Perinatol 2002;19(6):311-6. CrossRef | Medline | Google Scholar
- Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2003;(4):CD000145.
- Portnoi G, Chng LA, Karimi-Tabesh L, Koren G, Tan MP, Einarson A. Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy. Am J Obstet Gynecol 2003;189(5):1374-7. CrossRef | Medline | Google Scholar
- Thaver D, Saeed MA, Bhutta ZA. Pyridoxine (vitamin B6) supplementation in pregnancy. Cochrane Database Syst Rev 2006;(2):CD000179.
- Nordeng H, Havnen GC. Use of herbal drugs in pregnancy: a survey among 400 Norwegian women. Pharmacoepidemiol Drug Saf 2004;13(6):371-80. CrossRef | Medline | Google Scholar
- Borrelli F, Capasso R, Aviello G, Pittler MH, Izzo AA. Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol 2005;105(4):849-56. CrossRef | Medline | Google Scholar
- Mills E, Duguoa JJ, Perri D, Koren G. Herbal medicines in pregnancy and lactation: an evidence-based approach. New York, NY: Taylor & Francis; 2006.
- Heazell A, Thorneycroft J, Walton V, Etherington I. Acupressure for the in-patient treatment of nausea and vomiting in early pregnancy: a randomized control trial. Am J Obstet Gynecol 2006;194(3):815-20. Medline | Google Scholar
- Garbis H, Elefant E, Diav-Citrin O, Mastroiacovo P, Schaefer C, Vial T, et al. Pregnancy outcome after exposure to ranitidine and other H2-blockers. A collaborative study of the European Network of Teratology Information Services. Reprod Toxicol 2005;19(4):453-8. CrossRef | Medline | Google Scholar
- Diav-Citrin O, Arnon J, Shechtman S, Schaefer C, van Tonningen MR, Clementi M, et al. The safety of proton pump inhibitors in pregnancy: a multi-centre prospective controlled study. Aliment Pharmacol Ther 2005;21(3):269-75. CrossRef | Medline | Google Scholar
- Penney DS. Helicobacter pylori and severe nausea and vomiting during pregnancy. J Midwifery Womens Health 2005;50(5):418-22. CrossRef | Medline | Google Scholar
- Golberg D, Szilagyi A, Graves L. Hyperemesis gravidarum and Helicobacter pylori infection: a systematic review. Obstet Gynecol 2007;110(3):695-703. CrossRef | Medline | Google Scholar
- Levichek Z, Atanackovic G, Oepkes D, Maltepe C, Einarson A, Magee L, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002;48:267-8, 277. Abstract/Free Full Text