Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).
The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).
Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).
Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.
In most cases, this remains true. But considering the common practice of prescribing codeine for pain after childbirth with episiotomy or by cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.
A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain.
Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.
In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.
Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.
Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.
Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.