JUNE 15, 2007


Codeine linked to breastfeeding danger

Warnings and class action suit follow Toronto neonate's poisoning death

Asian and African babies are at greater risk of rapidly metabolizing codeine

A class action suit over the death of an apparently healthy Toronto newborn, who died last year from opiate toxicity from breast milk, has renewed the debate over prescribing Tylenol 3 to breastfeeding mothers. After the baby's death, doctors at Toronto's Hospital for Sick Children issued a warning that codeine given for postnatal pain can produce deadly concentrations of morphine in breast milk.

Tariq Jamieson was delivered vaginally at full term and healthy weight — everything appeared normal. His mother Rani suffered some lingering pain from an episiotomy so she was prescribed two tablets of Tylenol 3 twice daily — a common pain treatment for mothers who have just given birth. Doctors halved that dose after two days due to constipation and somnolence.

Tariq developed increasing lethargy from the seven-day mark, and at 11 days was brought to a pediatrician due to concerns about his skin colour and poor feeding. He had, however, regained his birth weight. But two days later the family called an ambulance. Responders found the infant cyanotic and lacking vital signs. Attempts at resuscitation failed.

On post mortem, the child was found to have a blood concentration of acetaminophen at 5.9 µg/mL and morphine at 70 ng/mL. That morphine concentration is about six times higher than would normally be considered safe in a neonate.

Tylenol 3 contains 500mg of acetaminophen and 30mg of codeine. Codeine is metabolized to morphine in the body, but not all patients metabolize it at the same rate. Ms Jamieson was genotyped and found to carry three CYP 2D6 genes, which create the enzyme catalyzing the O-demethylation of codeine to morphine. This essentially made her an ultra-rapid metabolizer of codeine to morphine, leading to an unexpectedly fast build-up of the opiate in her breast milk.

This is the first reported case ever of a child dying from opioid poisoning due to a breastfeeding mother's use of codeine, and it was a fairly exceptional case. Not only did Ms Jamieson have three CYP 2D6 genes, but her husband and baby both had two, making all of them "extensive metabolizers."

But it is not so exceptional as to be safely ignored. The ultrarapid metabolizer genotype occurs in about 1% of Caucasians, but runs as high as 30% in some African and Asian populations. For every baby whose life is threatened, many others may suffer morbidity, depressed breathing, lethargy or poor feeding. Even two CYP 2D6 genes can lead to unexpectedly high concentrations of morphine in breastmilk.

The child's mother, not surprisingly, has said that codeine "should not be used by nursing mothers under any circumstance." But the experts at the Hospital for Sick Children's Motherisk program, who still have to deal with maternal pain somehow, are not quite ready to go that far. Instead they suggest sensible approaches to minimize the risk.

There are five strategies available, they suggest. One is simply to avoid using codeine in breastfeeding mothers. But this may leave the mother with uncontrolled pain. Another option is to give the codeine but avoid breastfeeding. No neonatologist, however, is going to recommend stopping breastfeeding at this crucial early stage if it can possibly be avoided.

A middle road is to give codeine, but limit concentrations by not giving a high dosage (240 mg/day codeine) for more than a few days. But the Motherisk team worries that this may not control pain adequately, and could still lead to toxic levels of morphine in the milk of ultrarapid metabolizers.

The ideal solution would be to genotype all mothers then limit codeine only in the cases of fast metabolizers — those with two or three 2D6 genes. Unfortunately this would be very expensive, and few centres currently have the facilities to do it.

That leaves old-fashioned clinical judgement. The mother should be informed of the potential for opioid toxicity, then she and the infant should be monitored closely for danger signs. If symptoms appear, administering naxolone, morphine's antidote, will generally solve the problem and, in doing so, confirm it.

In the longer run, the question of codeine's safety in breastfeeding mothers will have to be revisited. The American Academy of Pediatrics guidelines on the transfer of drugs into human milk, published in Pediatrics in September 2001, list codeine as a "maternal medication usually compatible with breastfeeding" and report no evidence of symptoms in infants or effect on lactation. It now appears as though that conclusion will have to be revisited, as the Motherisk researchers openly attack the guidelines for overlooking the risk of codeine in breastfeeding "despite lack of sufficient published data to support this recommendation." Motherisk is now recruiting patients for its own study on the subject.



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