Michelle David never pictured herself as a nurse. She was squeamish about needles and couldn’t stand the sight of blood. When she learned, in 2005, that she was pregnant with a second child, she was a dancer for the NBA’s Philadelphia 76ers. She loved the job and hoped to return to it. But by the time her son, Lyam, turned one, David had left her dancing career behind and enrolled in nursing school. As a new student, she was already familiar with some of the medical procedures being taught — such as how to insert a nasogastric feeding tube: She’d learned them to care for Lyam.
At six weeks, Lyam was barely eating. One night, his breathing became severely labored. David rushed him to Philadelphia’s St. Christopher’s Hospital for Children, where doctors told her he was going into cardiac arrest. He’d been born with holes in his heart and would need two open-heart surgeries immediately. Before the first could be scheduled, Lyam started vomiting blood, and his organs began to shut down. Unable to breathe on his own, he was placed on a ventilator for four months. When he was finally stable, he underwent both of the surgeries in less than a month.
“After the second, it was bad, because he had drainage tubes,” David, 31, told me. “It was just — he looked so bad. I wasn’t prepared for that.” David had been matter-of-fact, even upbeat, as she’d described her son’s medical history, but she now was overcome by emotion. “I’m sorry,” she said, covering her face with her hand. Tears rolled down her cheeks. “It just really stinks that he’s going to have to go through it again.” David was referring to the open-heart surgery that Lyam will need within the next three years to fix yet another anomaly — all of which were caused by the boy’s in utero exposure to the selective serotonin reuptake inhibitor (SSRI) Paxil, a Philadelphia jury ruled in October 2009.
David’s doctor had prescribed Paxil for the mild anxiety she suffered after the death of a close friend. When she became pregnant a year later, she asked both him and her ob-gyn about the drug. Neither doctor was concerned, which isn’t surprising: Paxil was one of the most-prescribed antidepressants at the time, and a number of psychiatrists were delivering nationwide talks for their fellow physicians endorsing the safety and efficacy of the drug during pregnancy.
But in December 2005, two months after Lyam was born, the FDA asked Paxil’s manufacturer, GlaxoSmithKline, to change the drug’s pregnancy-use classification from Category C (“animal reproduction studies have shown an adverse effect on the fetus, and the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks”) to Category D (“positive evidence of human fetal risk”). The move came following the early results of two studies showing that women who took paroxetine (Paxil’s generic name) during the first trimester were one and a half to two times more likely to have a baby with a heart defect — in most cases, atrial or ventricular septal defects like Lyam’s. The FDA issued a public health advisory to doctors and clinics about Paxil and the danger of congenital heart defects.
The jury that ruled in David’s favor also found that GlaxoSmithKline had “negligently failed to warn” her doctor about the increased risk of such problems and awarded David $2.5 million in compensation. It was the first and only SSRI case to ever reach verdict, though Glaxo has since settled more than $1 billion worth of claims out of court. David’s attorney, Sean Tracey, says that there are many more cases pending against Paxil and other SSRI makers — this summer alone, 19 suits were filed against Zoloft — or awaiting settlement.
Tracey first learned about Paxil-related birth defects in 2006, when another lawyer walked into his office with a client named Lisa Collins, whose son, Chase, was born with part of his heart missing. Like David, Collins did not suffer from major depression or anxiety; she was prescribed Paxil for occasional claustrophobia. When Collins became pregnant, her family doctor assured her that it was “perfectly safe” to continue taking the drug. But just two weeks after he was delivered, Chase needed open-heart surgery. The strokes he suffered after the procedure left him with brain damage. GlaxoSmithKline reached a confidential settlement with Collins in 2008.
Despite cases like Lyam’s and Chase’s, the debate about the use of SSRIs during pregnancy is far from over. And the number of pregnant women taking SSRIs is as high as it’s ever been.
Given the number of things women are told to avoid during pregnancy — alcohol, aspirin, unpasteurized cheese, and sushi, to name just a few — it may seem surprising that antidepressants aren’t verboten too. But in recent years, doctors have become as concerned about the impact of depression on the mother and child as they are about the harm SSRIs might do to the fetus. An estimated 3 percent of pregnant women suffer from major depression, giving them a lifetime suicide risk 20 times higher than average. “The women I see say, ‘Nothing gets me excited. I don’t want to go out of the house, I can’t get my stuff done at work, my boss has noticed,’ ” offers Kara Driscoll, MD, a psychiatrist at Northwestern Memorial Hospital in Chicago who specializes in treating depressed expectant mothers. “You can have a severe episode of depression without being suicidal. It’s just the symptoms are really quite profound.” (Those symptoms include lethargy, an inability to focus, feeling hopeless or guilt-ridden, eating or sleeping too much or not enough, and crying often.)
Perhaps most worrisome, the heaviest predictor of postpartum depression, which afflicts an estimated 13 percent of new mothers, is depression during pregnancy. (And expectant mothers with a history of major depression who go off their meds during pregnancy are five times more likely to relapse, according to a 2006 study in The Journal of the American Medical Association.) Postpartum depression can leave women unable to care for their babies or form an adequate emotional attachment with them, causing lags in language, behavior, and intellectual development. A tiny fraction of cases manifest in a dangerous illness called postpartum psychosis, marked by auditory hallucinations, alienation from others, and urges to harm oneself or one’s baby.
Against that backdrop, Driscoll believes that all pregnant women should be screened for depression, as is the practice at Northwestern. “Twice during pregnancy, our OBs administer a screening scale. So no matter what — whether you’re talking about symptoms of depression or not — they’re going to go ahead and ask you about them. Because we’ve found women have symptoms who haven’t been assessed, who are not being treated.”
Gideon Koren, MD, a Canadian toxicologist and pediatrician who runs Toronto’s Motherisk, the world’s largest research and counseling center for expectant mothers, is, if anything, a stronger advocate for screening. An avuncular figure with gold-rimmed glasses and white hair, he boasts that Motherisk’s “research influences much of the counseling in the United States.” His counselors use a standard 10-question survey (called the Edinburgh Postnatal Depression Scale) with any expectant mother who calls or walks into the office. “A lot of women don’t feel good, and they don’t know it’s because of depression,” he says. “The condition is seriously underdiagnosed.”
When a woman scores a 13 or higher, she’s referred to a psychiatrist and will likely be encouraged to start a regimen of antidepressants. “If a woman scores between 10 and 13,” Koren says, “you still have to tell the physician that she’s borderline and she should be followed up. She’s almost there.”
1. I have been able to laugh and see the funny side of things
As much as I always could
Not quite so much now
Definitely not so much now
Not at all
2. I have looked forward with enjoyment to things
As much as I ever did
Rather less than I used to
Definitely less than I used to
Hardly at all
3. I have been anxious or worried for no good reason
No, not at all
Hardly ever
Yes, sometimes
Yes, very often
4. Things have been getting on top of me
Yes, most of the time I haven’t been able to cope at all
Yes, sometimes I haven‘t been coping as well as usual
No, most of the time I have coped quite well
No, I have been coping as well as ever
5. I have felt sad or miserable
Yes, most of the time
Yes, quite often
Not very often
No, not at all
Those are my answers to several questions from the Edinburgh Postnatal Depression Scale test, based on how I felt during the first trimester of my pregnancy. The baby was unplanned, and suddenly I was stressed about how I was going to support her and get myself into an apartment more appropriate for a child — not to mention that for the first three months I was vomiting nonstop. Given the situation, it’s probably foreseeable that I’d score as high as a 10, which, by Koren’s standards, would have resulted in a letter to my doctor and possibly a prescription for an antidepressant. That’s despite the fact that I’ve never been diagnosed with a mood disorder, and by the time I entered my second trimester, my more troubling answers would have changed for the better. “The thing about screening is, the more you screen, the more you find,” said Barbara Mintzes, PhD, an expert on pharmaceutical policy at the University of British Columbia. “So it’s not necessarily a good recommendation to screen healthy people, because you can end up in a situation where you have a lot of false positives.”
According to a 2008 study in the American Journal of Obstetrics & Gynecology, more than 6 percent of all pregnant women take SSRIs, a fourfold increase since 1996. While the medical community is virtually unanimous in the belief that women with major depression should take medication during pregnancy, the real, hotter issue — the one that Michelle David says applies to her case — is whether more moderately depressed or anxious women should do the same. It’s not a small matter: A 2009 Psychiatric Services study found that nearly four fifths of antidepressant prescriptions aren’t written by psychiatrists; another report, published last year in Health Affairs, found that nearly three quarters of these prescriptions are written without a psychiatric diagnosis, and, its authors point out, patients who get mental-health care from “general medical settings tend to have much less severe psychiatric problems.”
The first point of debate is what harms the fetus more: midlevel depression and anxiety, or the SSRIs prescribed to treat them. Talk to a handful of pregnant women these days and you’ll hear echoes of this concern: “I’m so stressed out all the time — am I hurting my baby?” Much of the medical research that tries to answer the question has focused on which factor — SSRIs or depression/anxiety — has a stronger relationship with low birth weight and premature birth. That’s because very small and early babies disproportionately suffer devastating conditions such as cerebral palsy and blindness, while even less dramatic weight and gestational deficits have been linked to more subtle neurological and developmental impairments. And the truth is, when you sift through the data, it’s something like a draw: Both SSRIs and depression are implicated with modest upticks in prematurity and low birth weight, although often only among poor women. (For depression, the physiological mechanism for fetal harm is theorized to be undue exposure to stress hormones like cortisol or compromises in immune function; for SSRIs, it’s the influence of extra serotonin on the developing brain.) “People have a hard time accepting that sometimes science is in the process of figuring things out, and I think, frankly, that’s where we’re at,” says Columbia University psychiatry professor Catherine Monk, PhD.
The second issue is whether SSRIs cause, in rare instances, serious heart disorders like Lyam’s. No one is arguing that depression is the culprit for heart-wall defects, but some doctors say antidepressants aren’t the reason for them either. Over the years a number of studies have not found a higher incidence of septal heart defects in SSRI takers, but some of the most recent research has turned up noteworthy increases. A 2008 report in the British Journal of Clinical Pharmacology found “major cardiovascular anomalies” were about five times higher among the infants of Prozac takers and three times higher among the babies of Paxil takers. A 2009 study in the British Medical Journal concluded that children whose mothers took Zoloft were more than three times as likely to be born missing pieces of their heart walls.
Another worry, because of its severity, is something called Persistent Pulmonary Hypertension of the Newborn (PPHN) — a condition in which oxygen can’t be absorbed into the bloodstream, which afflicted the infants of mothers who took SSRIs (any SSRI) after their twentieth week at a six-times-higher rate in a 2006 New England Journal of Medicine report. (Because the numbers of serious birth defects are quite small overall, even something like a sixfold expansion in PPHN means the disease would occur in six to 12 babies per 1,000, rather than roughly one out of 1,000; the more devastating heart defects are even less common.) Finally, SSRIs have been implicated in “neonatal abstinence syndrome,” a several-week-long drug withdrawal that may include tremors, excessive crying, fever, rapid breathing, vomiting, problems feeding and sleeping, and even seizures.
Perhaps only because it’s been studied more than the other SSRIs, Paxil’s story — the research on its possible fetal effects and its winding journey through the regulatory system — provides a compelling case for why it’s hard to confidently weigh the risks and benefits of taking antidepressants during pregnancy. It took 12 years for the drug to go from Category B (“animal reproduction studies have failed to demonstrate a risk to the fetus”) to Category C to Category D. “Every doctor I’ve deposed says, ‘Well, it wasn’t Category D when I prescribed it,’ ” says Karen Barth Menzies, an attorney who’s sued Glaxo on behalf of pregnant women. “They get very defensive.”
Indeed, David’s family physician testified that Glaxo drug reps used Paxil’s Category C rating as a selling point for prescribing the drug to women in their childbearing years. For its part, Glaxo insisted throughout much of the trial that it had never marketed Paxil for use by expectant mothers, though three people independently told me they’d seen a video the company has shown to MDs in which a woman named Mary Beth talks with her doctor about how helpful Paxil was during her pregnancy. Her newborn was completely healthy, she says, adding that she plans to have another child and will take Paxil during that pregnancy, too.
Because pregnant women are excluded from clinical trials of new drugs for ethical reasons, the FDA relies on drug companies to conduct animal studies for information about fetal risks. Some of the first research to assess Paxil’s impact on rat pups was conducted in the late 1970s. Investigators divided pregnant rodents into four groups: Three received varying doses of Paxil, the fourth nothing. Sixty-six percent of the pups born to the rats on the lowest dose of Paxil died within four days, and that percentage increased as the dosage did. Only 12 percent of pups born to the unexposed mothers expired. In an internal memo obtained by lawyer Tracey, John Baldwin, an employee of Beecham (which later became Glaxo) who reviewed the studies, stated that it “supports the possibility of embryo lethality.” Suzanne Parisian, MD, a former FDA medical officer, testified at Lyam’s trial that Glaxo never did follow-up studies, nor did it alert the FDA about Baldwin’s statements. “They should have,” she said. “But better yet would have been to address it [with further research].”
This was not the only document that suggested Glaxo was aware of potential problems with Paxil: Tracey uncovered a company review from 1998 that found “an alarmingly high number” of reports of birth defects linked to the drug, and a report showed Glaxo officials were “almost certain” that Paxil caused the birth defects that prompted one woman to abort her fetus. (Internal e-mails that I obtained reveal that Glaxo has tried to hide other negative information about Paxil, canceling a long-term panic disorder study in 2000 because it showed that people who quit the drug suffered withdrawal. “Yes, Virginia, there is a God,” wrote a medical writer who’d been assigned to describe the research results. “[Glaxo]* cancelled our project 1059 (long-term panic disorder study). Reason: the side effect data analysis was terribly unfavorable to our favorite antidepressant. And we hate when that happens!” Asked for comment, Glaxo did not respond.
In a switch pharmaceutical companies have lobbied for, the letter categories will soon be dropped. Instead of seeing, for example, a Category D on Paxil’s label, doctors will find a long summary of the medical literature. Critics of the new system fear that physicians will be overwhelmed by the mountain of detail and simply won’t read the new statements, but FDA official Lisa Mathis, MD, (who has since left the FDA) defends the change as a means to “increase the judicious use of medication.”
Among those arguing that SSRIs are relatively harmless to unborn children — and depression quite pernicious — are a fair number of doctors who are paid by pharmaceutical companies to act as consultants, conduct clinical trials, and serve on speakers’ bureaus. Drug companies refer to the physicians they tap for such roles as “thought leaders” or “key opinion leaders” (KOLs), and the management of the discourse around a drug is important enough to the industry that just under a third of their marketing budgets are spent on so-called KOLs, according to a 2004 study of the 15 largest pharmaceutical makers.
Such ties between drug companies and physicians, which have attracted increasing suspicion and criticism in recent years, also complicate the risk-benefit analysis of taking an SSRI during pregnancy. JAMA, for instance, was forced to print a correction to the study that found a higher depression-relapse rate among women who stopped taking antidepressants during pregnancy versus those who didn’t after discovering that seven of its 13 authors, including lead author Lee S. Cohen, had failed to disclose that they were funded in some capacity by the pharmaceutical industry (including Glaxo and other makers of SSRIs) — in this case, there were more than 60 unreported conflicts.
When I called the main expert witness for Glaxo in Lyam’s case, Anthony Scialli, MD, to ask him how he saw his connections to the drug industries, he quickly replied, “Well, I don’t have any connections to the drug industries. I only prescribe generic drugs, which are not promoted, and I don’t meet with drug reps and I don’t read drug advertising and I don’t go to pharmaceutical-company-sponsored programs. So I suppose I could be influenced, but it would be kind of hard. They’d probably have to put a billboard up outside my apartment.”
Scialli runs a popular online database called Reprotox that health-care providers can consult to see if a particular substance is harmful to the fetus. Reprotox’s take on the impact of SSRIs is unalarmist: While the SSRIs Paxil, Zoloft, and Prozac are associated with “mild, transient” cases of neonatal syndrome, none affect fetal brain development — “unlike maternal depression,” the site warns. Congenital heart defects have been linked to Paxil and Prozac, Reprotox continues, but inconsistently. (“Over the years,” Scialli testified at Lyam’s trial, “I have presented to people the evidence that has been available, and it has been changing somewhat over the years, but the evidence has always been inconsistent, and so over the years I have been able to tell people that the best evidence shows that Paxil does not cause birth defects.”)
“I do consulting for drug companies on the effects of drugs during pregnancy,” he continued on the phone when I pressed him about conflicts of interest in medicine. “The drug company is coming to me asking that question; they’re not coming to me saying, ‘Would you whitewash our drug?’ ” A former KOL, Scialli is a consultant for dozens of pharmaceutical makers (“No idea,” he said, when asked how many exactly). When I asked him specifically about SSRIs, he told me he couldn’t talk about it: “Because I’m involved in litigation with SSRIs.”
Thomas Sadler, PhD, an adjunct professor at the University of Utah, is far less sanguine about drug industry clout. In fact, he left the Teratology Society, the field’s professional organization, over the issue. A former editor of the society’s journal, which front-line doctors can consult for guidance about so-called teratogenic agents (everything from certain prescription drugs to environmental toxins like mercury), Sadler said drug companies were relentless in their efforts to “inundate the journal with negative findings” — that is, to publish studies showing that their products caused no adverse impacts on pregnancy. “A fellow scientist used to say, ‘How can a society who goes to bed with the people who make the teratogens actually do teratology?’ ” he recalled.
At one meeting in 1998 to determine the direction of the Teratology Society, Sadler remembers, a major “action point” was for the organization to rid itself of pharmaceutical-industry connections and become strictly research oriented. “The leaders [at the time] were people who had closer ties to the drug companies,” he continued. “And they didn’t want that.” The leaders prevailed, he said.
Sadler became interested in antidepressants in the late ’80s through a fellow developmental biologist, Jean Lauder, PhD, who’d been studying Prozac and the role of serotonin on neurological development. “Lo and behold, we started seeing some abnormalities in our [mouse] embryos,” Sadler said. “No one had ever published or talked about that fact, so it kind of caught [Eli] Lilly by surprise.” Sadler, with Lauder, was the first to present findings at a Teratology Society meeting indicating that SSRIs might cause birth defects.
Sadler acknowledges that the absolute risk of birth defects is small, but he says it’s a “hard thing,” because “at some point it starts to add up. And then you think about 100,000 kids in a state being born and 1,000 of them having a heart birth defect, and then you introduce SSRIs into the mix and you’ve got 1,500. And this happens every year, so that in 10 years there are an additional 5,000 kids with heart defects that should not have them. When does it get to mean something?” Sadler is referring to both lethal and nonlethal heart birth defects, but he has a point: Even if the risk is tiny for any one individual, for a population it can add up, especially as more women take the medication.
So what is an expectant mother to do? Again, there’s really no question that women with major depression should seriously consider staying on their meds, or starting them if need be. Pharmacological fixes for milder cases are the rub, and a woman’s choice ultimately depends on whose argument she decides to credit. Koren says that depression is a bear of an illness that threatens mother and child, even when it’s not classified as major. “[The mother’s] quality of life is very low. She may not be thinking of taking her life, but she may be very anxious.” Too much has been made of the risks of SSRIs, he insists. “There’s a lot of quackery in this field. It’s a national sport to scare pregnant women.”
Even the Israeli researcher who coauthored the study showing a three- and fivefold higher risk of heart defects among the babies of women who took Paxil and Prozac seemed to downplay the dangers to children exposed to SSRIs. “Many heart anomalies can now be treated,” he said after the study was released.
On the other side, Adam C. Urato, MD, a maternal-fetal specialist at Tufts Medical Center in Boston, rails against the ease with which SSRI prescriptions are handed out to expectant mothers. “The conventional wisdom has been that depression is like diabetes and depressed pregnant women need to stay on their antidepressants just like pregnant diabetics need to take their insulin,” he wrote in CommonHealth. “And this counseling gets repeated on a daily basis in doctors’ offices around the globe and in news reports on this topic. The problem is that it just isn’t true.”
A particular irony for those opposed to the proliferation of antidepressant use during pregnancy: The scientific data seem to demonstrate that SSRIs work to quell major depression but they’re no better than a placebo in mild to moderate cases.
Lyam is now six years old. He loves the scar from the drainage tube that he has on his chest because, as he told David, the three slits make him “look like a shark.” Last winter, David texted me to say that Lyam was back in the hospital for a week because his aorta had started to collapse and his surgeon had to insert a stent. Doctors have warned her that after Lyam’s upcoming open-heart surgery, he may lose the ability to identify letters and colors, because the total bypass it requires slows the brain. At his cardiologist’s office, David saw the panicked expression on her son’s face as his doctor spoke of surgery. “As a mom, even if your kid just bumps their leg…” David said, trailing off as she started to cry again. “I’d be terrified if I had to have open-heart surgery.”
Lyam may need to have a fourth surgery around the time he turns 18, but his doctor thinks it will be his last. He will need to see a cardiologist regularly for the rest of his life, and he won’t be able to play soccer and contact sports, but otherwise he should live a normal life.
David still has mild anxiety, but she now relies on meditation to cope with it. She wishes she’d been told about the risks of SSRIs and believes that stronger warnings are imperative. “In terms of a risk versus benefit, I don’t think [Paxil] was effective,” she told me. “I had a lot more anxiety after my son was born.”
This article was reported in partnership with The Investigative Fund at The Nation Institute, now known as Type Investigations.