Opioids kill by suppressing the drive to breathe. They bind to receptors in the brain stem, altering the neurons that maintain patterns of respiration. Carbon dioxide builds up in the bloodstream, hypoxia sets in, and circulation falters. Brain damage follows, then death.
The coroner’s office asked one of Canada’s leading pediatricians and toxicologists, Gideon (Gidi) Koren, to examine Tariq’s file. For the past two decades, Koren had been running a program at the Hospital for Sick Children called Motherisk, which provided guidance for pregnant women and new mothers about drugs and breast-feeding. He was widely considered to be among the most capable research scientists in the field. Koren met with Rani’s physician and quickly ruled out foul play. “There was no evidence of psychiatric issues,” he later wrote. Instead, Koren interpreted the toxicology report as a scientific revelation: if mothers with a certain genetic predisposition took even a mild dose of codeine, the amount of morphine that ended up in their breast milk could kill their children.
A dose of codeine brings relief from pain only when the liver metabolizes a fraction of it into morphine. But the exact proportion that is converted into morphine can vary. Most people have two copies of the gene that carries out the conversion. Koren invited Rani to be tested, and discovered that she had three.
The concentration of morphine in Tariq’s blood was measured at seventy nanograms per millilitre. “If you have levels above twenty, you stop breathing,” Koren later said. Six months after Tariq’s death, Koren obtained a sample of Rani’s breast milk, which she had kept in her freezer. His lab measured its morphine concentration at eighty-seven nanograms per millilitre. Koren was stunned. “The level was several fold higher than ever described in the literature,” he noted. “This was the first time in history that a baby was reported dying from breast milk.”
Koren had long studied the transmission of opioids into breast milk. But he had never identified a mortal risk. Now, along with a few colleagues—including the deputy chief coroner of Ontario, James Cairns—he published his findings in The Lancet, one of the world’s top medical journals. Some women, like Rani, have a genetic predisposition to convert codeine into morphine faster and in higher quantities than the rest of the general population. Therefore, the authors concluded, “codeine cannot be considered as a safe drug for all infants during breastfeeding.”
The implications were terrifying. Millions of women—up to forty per cent of breast-feeding mothers in North America, according to Koren and his colleagues—might be prescribed codeine for postpartum pain, and yet almost none were being tested to see if they, like Rani, had more than the usual number of codeine-metabolizing genes. The risk was unevenly distributed across the population, according to ethnic background. Mothers from Finland have a one in a hundred chance of being so-called ultra-rapid metabolizers, according to Koren’s paper. But in Ethiopia the odds can rise to almost one in three.
“What an amazing nest.”
Cartoon by Amy Hwang
Few academic-journal articles have had so abrupt an effect on the daily practice of medicine. Prior to its publication, the American Academy of Pediatrics had listed codeine as generally compatible with breast-feeding. “After we published it in Lancet, the F.D.A.—the Food and Drug Administration—said, ‘This is enough for us to change labelling,’ ” Koren said. Canadian and European health regulators soon followed suit. Doctors started prescribing other opioids for postpartum pain, such as hydromorphone and oxycodone, whose metabolic pathways are more predictable and less subject to genetic variations.
The Jamiesons’ identities were not revealed in Koren’s article. But they went public on April 30, 2007—exactly two years after Tariq’s death—filing a class-action lawsuit against Johnson & Johnson and a subsidiary, the manufacturer of Tylenol-3, on behalf of “all persons in Canada” who had ingested the products of the drug through breast milk. “This terrible tragedy should never have occurred, and I am determined to see that this does not happen to other children,” Rani said. “What can they give me? Can they give me my son back? I want other people not to have their children die or be damaged.”
The Jamiesons went on to have three more children—all boys, who grew up in the shadow of the brother they never met. “You’re consumed with a certain sadness that’s always there,” Rani told a reporter, seven years after Tariq’s death. Two decades later, she still finds April the most difficult month: “It’s always there.”
Koren continued to sound the alarm about codeine for years. “He was always on a plane somewhere, and always had a million spinning plates—meetings, talks, conferences,” David Juurlink, a Canadian clinical toxicologist and a colleague of Koren’s at the Hospital for Sick Children, told me. Koren published more papers about the Jamieson case, and his Motherisk program provided data for studies of patients who had been prescribed codeine for postpartum pain. His ability to distill complex scientific processes into clear public-health messaging made him a regular commentator in the press. “It’s quite common not to know why a baby dies,” Koren said, in an interview for Canadian television. “I am quite sure that quite a few of those were codeine in breast milk. But no one checked. You don’t check, you do not find.”
Juurlink first met Koren in the late nineties, when he was a resident in clinical pharmacology. Koren, who had been practicing medicine in Canada since 1982, was leading rounds. “When you were with Gidi, you really felt like you were in the presence of someone who wasn’t just an expert—in the truest sense of the word—but was also a kind, good-natured, thoughtful, and intellectually agile man,” Juurlink recalled. “He was very avuncular. It was really one of the highlights of my training, learning from him.” Koren was revered by colleagues, and he had almost six hundred publications in scientific journals.