Last December, the Supreme Court of British Columbia set a bold precedent: it green-lit the first class action suit in Canada alleging that an antidepressant taken by a woman during pregnancy caused a birth defect in her child. Faith Gibson of Surrey, B.C., named “representative plaintiff,” had been prescribed Paxil, a selective serotonin reuptake inhibitor (SSRI), in December 2002. Her daughter, Meah Bartram, was born in September 2005 with a hole in her heart. The defect was repaired months later, but Meah remains a “sickly” child, prone to infection. Two weeks after her birth, Health Canada and Paxil’s manufacturer, GlaxoSmithKline Inc. (GSK), issued an advisory stating that paroxetine (Paxil’s generic name) taken in the first trimester may pose “an increased risk” of cardiovascular defects.
Gibson’s lawyers allege GSK knew or should have known about the risks and that it failed to apprise Gibson or her physicians. Gibson had asked her doctor if she should go off the drug during pregnancy; she was told it was “100 per cent safe.” More than two dozen women have applied to be screened for class membership since December, says Vancouver lawyer David Rosenberg, who is representing Gibson.
GSK has appealed the decision to register the case as a class action; it contends it acted appropriately in its clinical trials, as well as in the safety monitoring and marketing of Paxil, updating pregnancy information as data became available, spokeswoman Michelle Smolenaars Hunter told Maclean’s.
Legal wrangling over Bartram vs. GlaxoSmithKline is destined to play out for years. But already the case has put a spotlight on a controversial yet surprisingly little discussed subject: the rising use of SSRIs during pregnancy. This is despite the fact that animal studies dating to the early ’80s linked SSRIs with increased risk of birth defects, and that SSRIs—which are believed to ease depression by blocking the reabsorption of the neurotransmitter serotonin in the brain—are not approved for use in pregnancy, except where “the potential benefit outweighs the potential risk,” to quote one Canadian label warning.
More than 2,500 lawsuits linking birth defects to use of SSRIs, a category that includes Zoloft and Prozac, have been launched in the U.S. (the only one to reach verdict at trial, Kilker vs. GSK, in 2009, ruled for the plaintiff). Many cases are settled out of court (in 2010, Bloomberg News reported GSK agreed to pay more than $1 billion to resolve more than 800 birth defect cases). Regulators have also issued further warnings. One, from the U.S. Food and Drug Administration in 2005 downgraded Paxil from a C rating (“potential benefits may warrant use of the drug in pregnant women despite potential risks”) to D (“positive evidence of human fetal risk”).
Yet, despite rising cautions regarding risks, SSRIs have become the top-prescribed drugs in pregnancy, surpassing those for diabetes or nausea, says Anick Bérard, director of the medications and pregnancy unit at Ste-Justine University Hospital and a professor at the pharmacy faculty of the Université de Montréal. And their use is on the rise. Bérard estimates 12 to 15 per cent of expectant women take SSRIs, even though short- and long-term risks aren’t known; for ethical reasons, pregnant women are not allowed to participate in the randomized, controlled clinical trials that would reveal such risks. But Bérard points to significant epidemiological, or population, studies that outline the relationship between SSRI use and a small but decided risk of miscarriage and stillbirth, persistent pulmonary hypertension and heart defects in newborns, as well as neonatal withdrawal syndrome. Data from animal and human studies also raise serious concerns that exposure to SSRIs during pregnancy damages the developing brain and may cause neurodevelopmental abnormalities, including autism.
Complicating matters is the fact that research in the field is wildly conflicting and riven with conflicts of interest. A 2006 Journal of the American Medical Association (JAMA)study, for instance, found that women who stopped taking SSRIs when pregnant were far more likely to relapse into depression; the report stoked controversy when it was revealed all of the 13 authors had failed to disclose drug-company funding. The same data can sometimes even yield divergent conclusions. Take two studies based on 1.6 million infants born in five Nordic countries between 1996 and 2007: one, in the British Medical Journal in 2012, concluded that potentially fatal persistent pulmonary hypertension in newborns more than doubled with mothers’ SSRI use in late pregnancy. But a 2013 JAMA study reported SSRIs pose no infant mortality risk.
The spectre of pregnant women being prescribed drugs that alter brain chemistry—and come with serious side effects, including suicide risk—might seem incongruous in a culture in which expectant women are told to avoid soft cheeses, alcohol, even Aspirin. What has paved the way, however, is research sounding alarms about the even greater risks posed by clinical depression during pregnancy. And at the forefront of that research is the world’s largest and most trusted source on the safety of drugs, toxins and chemicals on pregnancy and lactation: the Motherisk program at Toronto’s world-renowned Hospital for Sick Children—and the unit’s high-profile director, Gideon Koren.
Since its founding in 1985, Motherisk has consulted with more than 250,000 women in its clinic and on phone lines, and answered their questions about the safety of drugs, chemicals and toxins in pregnancy. It also conducts its own research, which includes tracking pregnant women, though it doesn’t stage randomized drug safety trials. Over the years, Motherisk has produced 92 papers on depression. It has consistently asserted that depression during pregnancy poses greater risks to mother and unborn child than SSRIs. Untreated depression, it warns, can lead to habits—alcohol and drug abuse, smoking, poor nutrition—that compromise fetal development. It also links stress hormones, or cortisol, with premature birth, lower birth weight, gestational hypertension and pre-eclampsia.
The centre has vocally dismissed regulator warnings about SSRIs, including Health Canada’s 2005 Paxil advisory, which Motherisk claimed was “based on small non-peer review, unpublished studies.” It also noted that no association with a higher risk of congenital malformations has been shown for SSRIs as a class. A 2010 Motherisk report found no increased risk of neonatal heart defects with maternal paroxetine use; in reports published in 2011 and 2012 they ascribed the higher number of cardiac malformations seen in unborn children of depressed women who took SSRIs to “ascertainment bias”—the fact anxious and depressed women are more likely to have the scans that identify them. Motherisk reassured women in 2005 that “beyond the first trimester, a drug cannot cause cardiac malformation,” and a 2006 Motherisk report notes many cardiac malformations “resolve spontaneously.”
SSRI risks in pregnancy are “small” next to those posed by clinical depression, Motherisk reports conclude repeatedly. A 2012 study states that for women diagnosed with the condition, “the benefits of [SSRI] therapy far outweigh the potential minimal risks.” It wants to see all pregnant women screened for depression, even those without symptoms or a history. The message is clear: by taking SSRIs during pregnancy, a depressed woman can protect both herself and her unborn child.
And it’s heard by a huge audience. Motherisk is the first port of call for doctors and patients alike; it influences clinical practice at home and abroad. When the duchess of Cambridge was hospitalized for severe nausea, Koren was the media go-to. Motherisk’s research is also used by pharmaceutical companies to defend birth defect cases, says Sean Tracey, the Houston lawyer who prevailed in Kilker vs. GSK.
Yet a rising chorus of researchers is questioning Motherisk’s stance on SSRI use in pregnancy. One of the most vocal is psychiatrist and psychopharmacologist David Healy, director of the North Wales department of psychological medicine at Cardiff University. Healy, who prescribes SSRIs selectively, says there’s no good data suggesting untreated depression is more dangerous to mother and child than SSRIs.
And the damage done by SSRI use, he says, may actually be worse than the numbers suggest. Studies have also linked SSRI use in pregnancy to higher “voluntary terminations,” or abortions, he says, prompted in part by birth defects detected in prenatal scanning. Clinical depression in pregnancy is a serious concern, Healy told Maclean’s. “But effective treatments exist that are less risky for the fetus.” In his 2012 book Pharmageddon, Healy identifies rising SSRI use in pregnancy as the most ominous portend of the grip Big Pharma now exerts over medicine.
When Heidi Murkoff published the first edition of What to Expect When You’re Expecting?in 1984, 2½ pages were devoted to postnatal depression. The book’s current and fourth edition allots more than seven pages to depression—from pre-pregnancy, through the newly coined “antepartum” to postnatal—plus two pages to antidepressants. The intervening three decades have seen a 180-degree turn from the gauzy view that pregnancy’s flood of happy hormones protects women from depression, to warnings that pregnancy itself is a trigger. By the time Murkoff’s book was made into a very bad film in 2012, the stressed-out, combustible pregnant woman was a stock character. “Well, I’m calling it!” a woman in the movie rants, “Pregnancy sucks! Making another human being is really hard! I have no control over my body or my emotions!” That view is now so engrained that when Yahoo! CEO Marissa Mayer reported she had “a really easy, healthy pregnancy” last year, she was accused of lying.
Pregnancy’s emergence as a new frontier for female depression can be seen as a continuation of a broader cultural theme dating to “hysteria” in antiquity: the notion that female reproductive function predisposes one to irrationality and anxiety. According to a 2011 Centers for Disease Control (CDC) study, 10 per cent of women between 18 and 39 are on antidepressants, with women far more likely than men to be prescribed them. Anti-anxiety and antidepressant medications are now even emerging as the 21st century’s “mother’s little helper,” the nickname Valium was given in the ’60s. Last month, an ABC News story titled “Moms on Xanax: women say antidepressants, anti-anxiety meds make them better moms,” quoted an upcoming study in the medical journal Pediatricsthat suggests as many as one in five new mothers suffers from “heightened anxiety” in the weeks and months after childbirth. One woman, Melissa Sanchez, told Good Morning Americashe was prescribed the SSRI Celexa after she “psychically collapsed” after her son’s birth. She reported she “has no doubt that her anti-anxiety drug made her a better mother.”
No one disputes that depression during or after pregnancy is real, but the presumption that all pregnant women may be at risk reflects a real shift. Drug companies have successfully capitalized on this theme by aggressively targeting women of child-bearing years. Evidence presented at U.S. birth defect trials reveals the extent of this marketing, which includes planting “ghostwritten” studies (reports generated by drug companies who pay prominent researchers to put their names on them and then publish them in respected medical journals—an unethical but common practice). In 2000, GSK launched a “Mother knows best” campaign to market Paxil; it planned to make it “the drug of choice for women.”
The strategy appears to have worked. Filings in the Canadian Paxil class action show nearly six million Paxil prescriptions were written between 1993 and 2009 to Canadian women of child-bearing age. Being prescribed an SSRI can put women on a treadmill, says Barbara Mintzes, an assistant professor in the department of pharmacology and therapeutics at the University of British Columbia who has studied the pharmaceutical industry’s effect on public health for 20 years: “Many who become pregnant are told to stay on the drugs, even if they don’t have depression symptoms, out of fear of a recurrence.” Healy cites another concern: “Women often aren’t told about addiction risks or the difficulty of withdrawal, which creates problems if they become pregnant.”
Hayley Wine, a 41-year-old Toronto mother of three who has taken antidepressants since she was diagnosed with clinical depression at age 16, reports a sea change in attitudes over the past decade. When she was pregnant with her first child in 2004, she stopped taking medication for fear of fetal harm. She did the same for her second pregnancy, but became depressed, so her doctor told her to go back on. She consulted with Motherisk and was told risks arising from depression were greater. She didn’t stop taking the drugs for her third pregnancy, which had complications, she says. She’s now been told her baby will experience neonatal withdrawal when she stops nursing. “So many moms I speak to now don’t go off their meds,” she says, noting some were prescribed SSRIs by GPs to treat migraines.
That’s not surprising. A 2005 study, “The marketization of depression: The prescribing of SSRI antidepressants to women,” by Janet Currie for the group Women and Health Protection, notes nearly four-fifths of prescriptions for antidepressants are written by GPs; the CDC reports that less than one-third of people on antidepressants see a mental health professional, which means most are prescribed without a clinical depression diagnosis by a specialist. Healy is not alone in noting SSRIs are based on an unproven hypothesis that has become medical orthodoxy: that depressed people have lower serotonin levels. “It creates the perception that leaving depression untreated is like leaving tuberculosis untreated,” he says.
On Motherisk.org,depression is listed with tuberculosis, asthma and epilepsy, and is described as a “chronic condition,” and warns that “puberty marks the beginning of the increased risk for depression in women.” All women visiting the centre are asked to fill out the Edinburgh postnatal depression scale, which gauges their mood over the previous seven days. Motherisk doesn’t diagnose depression, but puts screening results in a woman’s file for her doctor. That women going through a huge, hormonally driven life change would answer in the affirmative to some of the test’s 10 questions—“I have been anxious or worried for no good reason,” and, “Things have been getting on top of me”—isn’t surprising. A score of 10 or more, which would be easy to reach, indicates “possible depression.”
Screening for depression generally—not only in pregnancy—is a controversial topic. A 2011 Canadian Medical Association Journalanalysis called general screening “a resource-intensive endeavour, [which] does not yet show evidence of benefit and would have unintended negative effects for some patients.” In the 2009 Journal of Affective Disorders study, “Are we over-pathologizing motherhood?” Stephen Matthey, a psychologist then at the University of Sydney, assessed the Edinburgh scale to conclude, “around 50 per cent of women scoring high are not in fact depressed.” Many of the diagnostic criteria for depression—weight loss, sleep problems, fatigue—can as easily be attributed to new parenthood, Matthey writes.
They may also be a product of socioeconomic pressures. Assuming that maternal depression is what poses risk to the fetus is blinkered, says Françoise Baylis, the Canada Research chair in bioethics and philosophy at Dalhousie University: “Does [maternal] depression lead to these harms or does it have more to do with other factors such as poverty and lack of social support?” she asks.
Given most women don’t see a psychiatrist after screening, and that Motherisk carries so much weight with doctors, critics feel there is a real chance of women going on drugs with not much more than a single questionnaire.
Mintzes also expresses concern that widespread screening “will normalize the idea that pregnancy is a high-risk experience for the psychiatric condition of depression, which it’s not.” It’s “a recipe for finding false positives,” she says, which could lump women with no or mild depression with those with major depression: “Given research indicating SSRIs are no more effective than placebos for mild depression, this could put unborn children at needless risk.”
Bérard questions the value of screening without providing treatment services: “Screening to do what?” she asks. “To give pregnant women antidepressants?” She too is leery of Motherisk’s claim that untreated depression is more harmful to an unborn child than an SSRI. It isn’t supported by any evidence she has seen, outside of Motherisk’s, she says—“And I look at the literature day in, day out.”
One criticism that observers like Mintzes make is that Motherisk receives some funding from drug companies, though exactly how much is hard to discern. Industry funds fuel much medical research, but Motherisk’s role counselling pregnant women raises heightened concerns about potential bias.
That concern doesn’t just apply to questions about SSRIs. Women wanting information on morning sickness, for instance, can call a toll-free Motherisk “morning sickness helpline”—which is “partly sponsored by” Duchesnay, a Blainville, Que., company that makes Diclectin, the only prescription drug in Canada for nausea and vomiting in pregnancy. Diclectin is a generic version of Bendectin, a drug removed voluntarily from the U.S. market in 1983 by Merrell Dow after it was subject to hundreds of birth defect lawsuits, none successful. The controversy surrounding the drug isn’t mentioned on Motherisk’s website. Motherisk.org also recruits advertising, calling itself “a prime online venue for corporate sponsors”; it sells “sponsor tiles” with space for a company’s name, location and a “value-neutral description of products” for $1,500 a month.
Alan Cassels, a drug policy expert affiliated with the University of Victoria, has questioned the objectivity of Motherisk’s research, writing that it is “obviously drug tainted.” And Mintzes says any organization providing advice to pregnant women and their health care providers should be completely independent of the manufacturers of the products they are discussing. “Pregnancy is a time women require more protection, not less,” she says. She would like Motherisk to refer to SSRI risks cited in other studies and to also list Health Canada warnings, so women can judge for themselves: “Its message is consistently one of dismissing potential harm of SSRIs and a fairly unnuanced approach to depression treatment in pregnancy,” she says.
A schism has grown between the scientific research community’s view of Motherisk’s SSRI research and the public’s faith in it, Bérard says: “Motherisk is losing ground in terms of credibility and impact. But in the lay public area, the reason why they’re still out there—they’re very vocal and high-profile. They make good news—and nobody bothers to check anything.”
Sitting in his eighth-floor office, surrounded by teddy bears used in Sick Kids’ “Bear Theatre” Christmas fundraiser, Gideon Koren appears an affable, grandfatherly advocate for maternal and childhood health. “Life begins before birth,” he says. The well-connected MD wields considerable influence. Koren lectures internationally, sits on myriad boards—among them scientific journals and drug companies—and is a prolific researcher known for forging alliances between industry and the hospital. “ ‘Gidi’ is Sick Kids’s clinical-trial rainmaker,” a former colleague says. His CV, which tops 150 pages, is laden with honours and awards. In practice for four decades—three of them at Sick Kids, 28 years running Motherisk—Koren has also generated controversy. People may remember him as the doctor who wrote anonymous poison-pen letters about his former research partner Nancy Olivieri in the infamous Apotex scandal of the late ’90s.
Koren speaks with the genial paternal authority of someone who runs a maternal-research authority with a staff of 71. Depression screening in pregnancy is vital, he says: “Many women don’t even know they’re depressed.” Over-diagnosis simply “means the test is working.” Ideally, a woman who scores high will then see a psychiatrist, though that doesn’t always happen, Koren admits.
Inappropriate prescribing is a worry, he says: “There’s an immense drive to tell consumers that drugs solve everything.” But he’s more concerned about SSRI risks being exaggerated. His 2012 report, “Depression in pregnancy: time to stop terrifying pregnant women,” blasts researchers who “continue to terrify women who are at serious life-threatening risk if not treated pharmacologically.” Koren waves off his critics: “There is a lot of quackery going on,” he says. “Most of these epidemiologists have not seen a pregnant woman in their lives—except for themselves in the mirror. Everything we do, we have a control group who are healthy, who don’t take the product. They don’t have access to these women.”
Koren scolds Health Canada for its 2005 Paxil advisory: “The government never talked to any psychiatrists, not to us, not to any experts. They just took what Glaxo told them, including telling women to stop taking the drug in the third trimester. I don’t have words to tell you how irresponsible that is,” he says, referring to the nasty side effects that can accompany sudden SSRI withdrawal.
GSK acted responsibly, he says: “They ran to the government the minute they thought they saw something. They were the first to think that Paxil had more cardiac malformations.” He brushes off criticism that the unit’s research is biased by pharmaceutical funding. No SSRI research is funded by the drug’s manufacturers, he says, although Eli Lilly has provided research grants and Apotex, which produces paroxetine, has funded a Motherisk study of fetal alcohol syndrome. “I wish they would give us money,” he jokes. “Eli Lilly refused to give us money,” he says of Motherisk’s attempt to get funding for a study involving its drug Prozac. Companies are wary of conflicts of interest, he continues: “Glaxo refused to give us money. They don’t want to be seen as if they support that research because it will mean that they want you to take that medication.” Koren rejects the criticism that Motherisk research is “drug tainted,” pointing to its studies that showed serious fetal risks associated with corticosteroids and lithium.
Yet industry money can influence outcomes, as exposed by the scandal arising from hematologist Nancy Olivieri going public with what she believed to be serious side effects in deferiprone, a drug to treat a childhood blood disorder she was researching with Koren. He sent out vicious, anonymous letters to discredit Olivieri, then denied doing so until presented with DNA evidence. A later investigation revealed behaviour unimaginable from the editor of Textbook of Ethics in Pediatric Research: Koren also put his name on reports drafted and co-authored by Apotex-funded researchers that used Olivieri’s data but didn’t mention risks she’d identified; he gave incorrect and false testimony against Olivieri. He also failed to disclose a $250,000 “miscellaneous” grant from Apotex that continued to rely on his research to defend its drug with regulators and in court actions.
Sick Kids initially sided with Koren and Apotex, and removed Olivieri as head of the research program; she was later reinstated. Koren was reprimanded by the University of Toronto, the hospital, and the Ontario College of Physicians and Surgeons, which termed his behaviour “childish, vindictive and dishonest.” He was slapped with a six-month suspension (four with pay) and fines, resigned from two positions and lost another administrative position as well as a research chair, though he kept his Motherisk post.
Today, Koren bristles at any suggestion of personal conflicts of interest. “I’ll sue you if you say I’m involved with drug companies,” he says. He later clarifies that he works with the industry, and his Motherisk biography notes that he is a paid consultant to Duchesnay. A Sick Kids 2002 research disclosure shows Koren received $240,000 from Duchesnay between 1994 and 2002. Drug companies don’t market to pregnant women, Koren says: “All of them tell women not to take medication—unless the benefit is beyond the risk.” Now that knotty risk-benefit equation is about to be tested by Bartram vs. GlaxoSmithKline and a spate of new U.S. lawsuits against other manufacturers. Maybe they’ll bring us closer to understanding what exactly is at risk here—and just who benefits. Pregnant women need to know, and they’re not alone.