Canadian women with severe morning sickness are being prescribed a powerful anti-nausea drug suspected of causing deformities in some babies, a Toronto Star investigation has found.

The drug, ondansetron, is approved by Health Canada to treat nausea and vomiting in chemotherapy and surgery patients. It is not approved to treat pregnant women, but some doctors prescribe it “off label” without hard proof it is safe for expectant mothers.

So little is known about how ondansetron affects pregnant women that the drug manufacturer says such use is “not recommended” for these vulnerable patients.

At least 20 Canadian women treated with ondansetron for vomiting in pregnancy experienced serious suspected side-effects, including two infant deaths and multiple cases of newborns with heart defects and kidney malformations, according to a Star analysis of 2012 records.

Curiously, information about these unapproved treatments is not publicly available from Health Canada.

The Star discovered this crucial information after analyzing a massive trove of data found in the U.S. Food and Drug Administration’s public side-effect report database.

This database holds thousands of publicly available records of side-effects suffered by Canadian patients. (Read more about what they reveal in tomorrow’s Star).

Ondansetron is just one of several powerful drugs being prescribed to Canadians for unapproved uses.

The controversial and common practice is known as an “off-label” use of a drug. Off label means a drug is used for a condition or age group for which it hasn’t been approved.

There is no law or regulation stopping doctors from prescribing drugs off label. And, the Star has found, they are doing so with little oversight.

There are innovative off-label uses of drugs that have helped patients, but many off-label prescriptions are written with no solid scientific proof that the drug will be safe or effective.

In 2012, a Senate committee told Health Canada officials it was concerned about whether the regulator was monitoring the effect of off-label prescriptions on vulnerable Canadians, especially pregnant women.

Yet Health Canada, which was criticized by the auditor general in 2011 for poor drug safety monitoring, says it has not reviewed these reported birth defects. The regulator has issued no warnings to prescribers or the public about pregnant women taking ondansetron for morning sickness.

Four of the Canadian babies featured in the FDA side-effect reports reviewed by the Star were born weighing as little as four-and-a-half pounds. In six cases, a suspected side-effect of ondansetron was listed as “fetal growth restriction.”

The Star looked at Canadian side-effect reports filed in the FDA database between 2010 and 2013. Each report is the opinion of the doctor, pharmacist or patient that a particular drug has caused a reaction. Patients’ names are taken out of the reports to protect their privacy.

All the ondansetron cases are from 2012. They include:

A baby born with a “musculoskeletal anomaly.”

A doctor reported that ondansetron was the suspected cause of a baby’s mouth deformity, jaundice, heart murmur and two heart defects, including “atrial septal defect,” otherwise known as a hole in the heart.

Because most women experience nausea and vomiting during the first trimester, they would be taking the drug at the same time the fetus is most vulnerable to developing malformations and deformities.

Roughly 10 to 15 per cent of pregnant women receive drugs to treat morning sickness, according to a recent U.S. study.

In the Canadian cases found in the FDA database, doctors prescribed ondansetron to treat “hyperemesis gravidarum,” an extreme form of morning sickness marked by relentless vomiting causing significant weight loss and dehydration. Left untreated, the condition puts both the mother and fetus at risk.

GlaxoSmithKline makes a brand-name version called Zofran and several other companies manufacture generics.

The Star contacted the companies mentioned in the side-effect reports.

Glaxo said “the safety of ondansetron for use in human pregnancy has not been established. . . . (The company) monitors and reports all adverse event reports . . . and works closely with regulatory authorities in Canada to include relevant safety information for physicians and patients within our product labels.”

Generic maker Mylan Inc. refused to comment. India-based Ranbaxy Pharmaceuticals also declined to comment.

Last year, Ranbaxy USA pleaded guilty and paid a $130-million criminal fine, admitting it distributed adulterated drugs and made fraudulent statements to the FDA. Ondansetron was not one of the drugs named in the indictment, though Amir Attaran, a University of Ottawa law professor who has studied drug regulations, says Health Canada should not trust any products from the company.

On its website, Health Canada says Ranbaxy’s version of ondansetron is approved for sale.

The controversial use of ondansetron in pregnant women has been the subject of several studies in the last decade, with conflicting results and scientists from Toronto to Denmark saying more research is needed.

A 2011 study suggested the drug doubles the chance of babies being born with cleft palate.

Concerns about ondansetron’s safety were briefly placated after a study regarding the risk of adverse outcomes was published in the Feb. 28, 2013, issue of the prestigious New England Journal of Medicine.

The researchers tracked more than 600,000 Danish births using national birth and prescription registries, and found the drug was not associated with a significant increased risk of spontaneous abortion, stillbirth or defect.

But the same day the study was presented at a drug safety conference in Montreal, another group of Danish doctors introduced contradictory findingsbased on the same national registries.

Those researchers, looking at nearly 900,000 births, detected a two-fold increase in heart defects in babies whose mothers received ondansetron. They have since expanded the study to include more births and arrived at the same conclusion; they recently submitted their results to an academic journal, the lead researcher told the Star.

Medical practice guidelines, including those approved by the Society of Obstetricians and Gynaecologists of Canada, urge caution, saying ondansetron should be used only after exhausting other medications that have been tested in pregnant women and are approved to treat morning sickness.

Meanwhile, confusion spreads among pregnant women.

On online message boards, some mothers readily recommend the drug to others, raving about how it quelled their nausea.

At the Hospital for Sick Children in Toronto, the Motherisk program, a leading source of information and advice for expectant mothers, gets several calls a week from women asking about their ondansetron prescriptions. In 2012, staff fielded 194 such calls.

Motherisk call takers and counsellors track these patients and their babies’ health but have little hard information about the drug to share with anxious mothers.

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“Here is a drug not meant for pregnancy, given in pregnancy, with no data. So how do you know it’s safe for a baby? It’s an extrapolation that doctors do,” says Motherisk director Dr. Gideon Koren. “They think it’s the last chance for your patient. They think that there’s an edge for that drug compared to other drugs.”

For Christina Salvatori, ondansetron was the only drug that relieved her hyperemesis gravidarum. In late 2012, about four weeks into her pregnancy, she was crippled with violent vomiting.

Her symptoms were so severe she lost about 20 per cent of her body weight over the next two months. Salvatori spent 10 weeks of her pregnancy in hospital, six of them hooked up to a tube pumping 2,000 calories and nutrients into her each day.

“As all mothers, I wanted a drug-free pregnancy,” she said from her home in British Columbia. “When you’re in that state — you can’t sleep, you can’t eat, you can’t drink, you just physically can’t do anything — you know it’s not sustainable for your body or the baby. You have to take something.”

During an early hospitalization, doctors tried a battery of anti-nausea medications. Nothing worked until ondansetron.

Her husband researched the drug. The couple grew troubled about conflicting findings on its safety. She continued taking ondansetron right up to the day she gave birth to a healthy girl.

Ten months later, Salvatori said she would take ondansetron again. It was the only thing that got her through the pregnancy, she said.

But she said doctors and women should be cautious of using a drug with so much uncertainty surrounding its off-label use. She thinks Health Canada should track women like her. “If someone has to go on these medications, follow it and see what the effects are — monitor it.”

It is a drug regulator’s job to watch for signals that a drug may be harming the public.

Health Canada and other drug regulators began collecting side-effect reports in the 1960s in the wake of the thalidomide tragedy. The sedative, prescribed to treat the symptoms of morning sickness, caused thousands of serious birth malformations across the world.

Side-effect reports detailing cases of sick, vulnerable women taking a powerful drug and giving birth to babies with defects are a “signal that should be looked into,” Koren said.

Ondansetron is already on Health Canada’s radar: it has issued alerts concerning an increased risk of heart arrhythmias and possibly fatal reactions for patients on the drug for approved treatments.

The regulator, however, says there is no reason to probe the reported birth deformities.

“Currently, no emerging safety issues requiring further assessment related to ondansetron use in pregnant women have been identified,” a spokesperson said in a statement.

The Star found that Health Canada has not shared recent reports of birth defects showing women were given ondansetron to treat morning sickness. When pressed, Health Canada released some of this information to the Star, but has not released the information to the public.

“All the information should be provided by Health Canada in this database for the benefit of all the physicians who treat pregnant women,” said Mercedes Benegbi, executive director of Thalidomide Victims Association of Canada. “The only way to prevent a tragedy is the sharing of information.”

Doctors can learn of potential off-label uses of drugs from a range of sources, including published medical research and by word-of-mouth from other doctors.

It is illegal for drug companies to promote off-label uses to doctors.

In 2012, the U.S. Department of Justice reached a $3-billion settlement with GlaxoSmithKline after the government alleged the company promoted the off-label uses of several drugs, including Zofran, the company’s brand-name version of ondansetron.

Court documents alleged the company gave doctors kickbacks to prescribe the drug for morning sickness and disseminated false information about Zofran’s safety and effectiveness.

The company told the Star that as part of the settlement it admitted no wrongdoing “in connection with physician prescribing of Zofran in the U.S.”

North of the border, where Glaxo says its sales reps do not promote off-label uses of ondansetron or other products, Health Canada has never investigated or even asked the company about its ondansetron sales practices.

Jesse McLean can be reached at jmclean@thestar.ca or 416-869-4147.