Is codeine safe for post-partum pain?
In re-examining 2005 tragedy, doctors find new information that raises questions, doubts
For more than a decade, health agencies around the world have cautioned against prescribing codeine to nursing mothers for pain relief following childbirth, warning that dangerous levels of morphine, a byproduct of the drug, can pass through breast milk.
Anew paper by two pharmacologists at Sunnybrook hospital casts doubt over the evidence underpinning this clinical guideline. That evidence stems largely from an influential Toronto case report in which researchers at the time blamed the 2005 death of a 13-day-old baby on morphine-laced breast milk, sparking widespread concern about codeine and breastfeeding.
The peer-reviewed paper, which has been accepted for publication in the scientific journal Clinical Pharmacology and Therapeutics, disputes the findings in that case.
It is the latest attempt to correct flaws in the vast body of published work by disgraced former Motherisk director Dr. Gideon Koren, who was the lead author of the Toronto case report. The new paper also raises questions for the office of the chief coroner of Ontario, which relied on Koren’s expertise in its investigation of the boy’s death.
Dr. David Juurlink, the head of clinical pharmacology and toxicology at Sunnybrook and the University of Toronto, and co-author Dr. Jonathan Zipursky, re-examined the case. Citing information from the coroner’s report that was not included in the case reports co-authored by Koren, they found the explanation that the baby died from opioid toxicity due to breastfeeding is “implausible,” and push back against the likelihood of this phenomenon in general. The fact missing from previous publications was the codeine level in the boy’s blood.
Dr. Ronald Cohn, CEO of Toronto’s Hospital for Sick Children, which housed Motherisk for more than 30 years, and Dr. David Naylor, former dean of medicine at U of T, where Koren held cross-appointments, are among a group of academics now calling for the Lancet, which first published the Toronto case report, to retract it.
The baby’s mother rejects the new paper, which she says “just presents the baseless speculations of the authors,” and should be withdrawn from the scientific record. In an email, Rani Jamieson said Juurlink and Zipursky “are very clearly insinuating that (her son) Tariq had been given his fatal overdose through another channel,” but that they omit “any information that would cause people to doubt their claims.”
“If someone presents a more serious analysis I will definitely look at it,” Jamieson said, “but, so far, I haven’t seen any genuine questions about his case.”
Jamieson launched a lawsuit in 2007 against the makers of Tylenol 3, Johnson & Johnson and Janssen-Ortho Inc. She said she is still pursuing her claim.
Janssen said in a statement: “We sympathize with the Jamieson family loss 15 years ago. The safety and well-being of patients who use our medicines is our highest priority.”
Juurlink and Zipurksy stand by their findings. They say their paper is not an endorsement of the use of codeine while breastfeeding and does not offer an alternative explanation for how the baby ingested the drug that apparently killed him.
“The goal of our paper was to correct the scientific record by laying out in detail the flaws in Koren’s reasoning,” Juurlink said in an email. “We are not the first to publicly question Koren’s original interpretation of this case.”
None of the experts contacted for this story said they support the use of codeine in breastfeeding because of the unpredictable way it converts to morphine. However, Juurlink and Zipursky say they worry the warning about codeine may have led doctors to prescribe stronger, more addictive opioids in its place.
A Sick Kids spokesperson said CEO Cohn is contacting Health Canada, which “is best suited to determine how these new findings may affect the current clinical recommendations.”
Ontario’s chief coroner Dr. Dirk Huyer, who was not in the role at the time of the boy’s death, said he could not comment on whether he will act on the findings in the new paper, citing provisions in the provincial coroners act that prohibit him from discussing death investigations.
“We took Juurlink’s information,”
Huyer said in an interview. “We listened to him in great detail and appreciated his perspective and considered that carefully.”
Juurlink said he first brought his doubts about the original interpretation to the coroner’s office before Huyer took over in 2013.
In 2015, Juurlink said he met with Huyer, who told him that, “faced with differing expert opinions, a decision had been made to retain the original interpretation of the case,” Juurlink said.
He said he told Huyer that he wanted to publish a “critical reappraisal of the case, explaining why the prevailing interpretation was flawed,” but that Huyer “made it clear that any such publication would have to be limited to information already in the public domain.”
Juurlink said Huyer changed his position in early 2019, after Sick Kids announced a wholesale review of Koren’s published work, amid a Star investigation that identified possible problems with more than 400 of Koren’s papers. (Naylor, who was interim CEO of Sick Kids at the time, joined Juurlink in asking Huyer to allow him to publish additional details from the file.)
Huyer said that, from his perspective, “there was no hesitation about publication,” and that he “does not recall that particular part of the meeting” with Juurlink in 2015.
“He’s seen the file. He’s published the codeine (level) under my watch. So I don’t know what specifically he’s referring to,” Huyer said.
Koren retired from Sick Kids in 2015 amid a scandal involving Motherisk’s hair-testing lab that tore apart families and prompted two government-commissioned inquiries.
In 2005, when Jamieson’s son died, Koren was a prominent pediatric pharmacologist and toxicologist. The Motherisk program was regarded as the world’s foremost source of drug-safety advice for pregnant women and their doctors.
Jim Cairns was Ontario’s deputy chief coroner at the time. He told the Star he enlisted Koren’s expertise after receiving the baby’s toxicology report. The report showed a very high level of morphine in his blood.
Jamieson had been prescribed a combination of acetaminophen and codeine — marketed as Tylenol 3 — for pain relief after the birth. The active metabolite in codeine is morphine, which is released when the drug is broken down by the body.
According to the case report Koren and Cairns co-authored in the Lancet in 2006, tests showed the baby’s mother carried multiple copies of the gene that converts codeine to morphine, making her an “ultra-rapid metabolizer” of codeine. This resulted in dangerous levels of morphine in her breast milk, Koren and his co-authors concluded. (Morphine was also detected in a sample of breastmilk the mother had pumped and frozen, the authors also noted.)
The paper recommended that nursing mothers avoid codeine as a first line of treatment for pain relief because it “cannot be considered a safe drug for all infants during breastfeeding.” Health Canada, the U.S. Food and Drug Administration and the European Medicines Agency subsequently issued warnings about this risk.
The case report also drew skepticism. In 2008, in a letter published in the Lancet, Dr. Nicholas Bateman, a clinical pharmacologist based in Scotland, disputed the conclusions.
The degree to which different drugs pass to breast milk varies. Using research on the topic that Koren published in 1990 as a baseline, Bateman said the amount of codeine the mother consumed would have put the baby’s blood morphine concentration “well within” the range that is associated with safe, effective therapy.
Bateman also argued the level of acetaminophen found in the baby’s blood was “far too high to be derived from breastmilk.”
In their paper, Juurlink and Zipursky build on Bateman’s criticisms using evidence from the baby’s original toxicology report that has not been mentioned in previous accounts: the level of codeine in the baby’s blood.
According to Juurlink and Zipursky, the baby’s blood codeine level was “roughly 50 times higher than peak concentration seen in neonates of mothers taking codeine while breastfeeding.”
This can’t be explained by the mother’s genetics, they write, and suggests the codeine was metabolized to morphine by the baby, as opposed to the mother, which led to the high level of morphine found in his system after he died.
They say it would take “a highly improbable combination of factors” for opioids from breastfeeding to lead to an overdose in a baby. This includes severely impaired kidney function, which would prevent the drug from being flushed out before dangerous levels can build up. (The baby’s pediatrician noted that he had five wet diapers the day before he died, which suggests this was not a factor in the Toronto case, they assert after their review of the coroner files.)
The authors combed the scientific literature for other cases of babies who suffered suspected opioid overdoses from breastfeeding, and found none were conclusive, despite the proliferation of these drugs in the past 20 years. Besides the Toronto case, only one report described a breastfed baby who died while the mother was taking opioids. In that case, they note, the baby also suffered head injuries, and the original report authors “were openly skeptical about the possibility of breast milk as the sole source of oxycodone.”
Koren, who returned to Israel after leaving Sick Kids, did not respond to multiple requests for comment for this story. He is listed as a full professor at Ariel University’s medical school in the West Bank, and recently launched a new journal, called Motherisk International.
Cairns retired from the coroner’s office in 2008. He declined to comment on why the baby’s codeine level was not included in the Lancet report, which he co-authored, as well as reports on the case he co-authored with Koren a few months later in Canadian Pharmacists Journal and in 2007 in Canadian Family Physician.
“At the time that we investigated that death, we believed that the conclusion we reached was correct,” he said. “That was based on the science as we knew it then, and whether this new stuff is correct or not, I have no clue. I genuinely believed at the time that we were accurate.”
Three of Koren’s other co-authors who responded to questions for this story said they were unaware of the baby’s codeine level at the time of publication, and that it should have been included.
Rani Jamieson told the Star she “never had any reasons to doubt the results of all the scientific and forensic investigations that were done” in her son’s case.
Jamieson, who had three children after Tariq died, dismissed the analysis in the new paper as “shoddy” and “academically dishonest.” She said the authors misrepresented some of the studies they cite, and disputes that Tariq’s blood codeine level upends the original finding in the case.
Although Tariq’s precise blood codeine concentration was not previously published in the scientific literature, Jamieson said that the fact that he had high codeine levels was “never hidden,” noting it was mentioned in a commentary on the case published in the Lancet in 2008. (That paper referenced the lawsuit she filed against the pharmaceutical companies.)
“I feel very strongly, as I have since Tariq’s death, that more information needs to be put out worldwide on the lack of actual testing done by drug companies on the potentially devastating effects of taking prescription drugs during pregnancy and breastfeeding,” she said. “I don’t want any other families to suffer the same kind of tragedy that we experienced, and I don’t see how this new paper addresses that concern at all.”
Juurlink acknowledged the questions the new paper tackles are “sensitive,” and that he and Zipursky sought feedback “from experts in pediatrics, pharmacology, toxicology, drugs and lactation, pharmacogenetics, and forensic pathology before submitting it for publication.”
In May, Juurlink and Zipursky sent a letter to the editor of The Lancet, asking for the 2006 case report to be retracted, as well as to the editors of the two other journals that subsequently published the case report.
Other signatories include Dr. Milton Tenenbein, a University of Manitoba professor of pediatrics and child health, Texas Tech University professor Thomas Hale, who runs the InfantRisk Center, and Bateman, who first disputed the findings in The Lancet in 2008, as well as Cohn and Naylor.
“This is not a matter of earlier conclusions being overturned by later scientific advancements,” they wrote. “For more than a decade now Koren either knew or ought to have known that his original interpretation of the case was flawed yet he took no corrective action.”
In an email, a spokesperson for the Lancet said the journal is “aware of the concerns that have been recently raised” about the 2006 case report coauthored by Koren and is reviewing the report it received from Juurlink and his colleagues.
The editors of Canadian Family Physician and Canadian Pharmacists Journal told the Star they are reviewing the new paper.
Sick Kids’ internal review of Koren’s papers is ongoing. A hospital spokesperson said a preliminary review of nearly 1,000 articles has identified “some studies that required specific indepth reviews from conflict-of-interest, research ethics, scientific or other perspectives,” but declined to provide further details.
“At the time that we investigated that death, we believed that the conclusion we reached was correct.”
JIM CAIRNS FORMER ONTARIO DEPUTY CHIEF CORONER
The Star’s 2018 investigation into 400 publications authored or co-authored by Dr. Gideon Koren was conducted in partnership with Ryerson University School of Journalism students Stefanie Phillips, Emerald Bensadoun, Kate Skelly and Alanna Rizza.