Why pregnant women deserve drug trials

It’s easy to gloss over health care disparities until they start really affecting you or your loved ones. When I became pregnant this summer, I discovered the dearth of information available about drug safety during pregnancy. (I wrote a little about it in this Slate article published in July.) Women who rely on medication get pregnant—for instance, one in eight pregnant women takes antidepressants, which could pose serious risks, as I’ve discussed elsewhere—and pregnant women develop complications that require medicine. Yet the only drugs that have been approved by the FDA for use during pregnancy are for gestation- or birth-related problems, not for conditions like depression, hypertension or infection. And if you ask two obstetricians for their opinions about a drug’s safety, they’ll sometimes give you two different answers, as I discovered when I looked into taking Sudafed for a nasty cold I had this fall.

Certainly, it seems unethical to expose a fetus to a potentially dangerous drug in a clinical trial—after all, it cannot consent. But isn’t it worse to expose a fetus to a drug without any safety data at all, and outside the structured trial setting, where there is no patient monitoring? Yes, clinical trials in pregnant women could be dangerous. But not having them is even more so, given that pregnant women have to take drugs anyway—and without any knowledge of how they might affect them or their unborn children. Remember the sedative thalidomide, which caused pregnant women to give birth to babies with missing limbs in the 1950s, and DES, a drug prescribed to prevent miscarriages that increased the risk that female babies would develop rare vaginal cancers? Might we have avoided these disasters, or at least lessened their magnitude, if thalidomide and DES had been tested in controlled clinical trials in pregnant women first?

Thankfully, we haven’t had any major disasters like these in decades, but the government still makes drug recommendations based on little data. Take flu shots: The CDC has been telling pregnant women to get seasonal flu shots since the 1960s, but the first randomized, prospective trial testing the vaccine on pregnant women and their babies was not completed until 2008—and it was comprised of just 340 subjects in Bangladesh. (Luckily, the trial suggests that flu shots are safe, although it only tracked the health of the babies for 24 weeks after birth.) For decades, then, the FDA’s recommendations and assurances about flu shots were not based on clinical trial evidence, but retrospective data, which is often flawed. “The agency said, ‘there’s so much risk, we won’t put you in a trial—but as soon as it’s approved in a different population, we’ll give it to you,’” explains Francoise Baylis, a bioethicist at the Dalhousie University in Canada. (Not that the FDA is entirely to blame—drug companies certainly have little interest in testing their compounds in pregnant women, a small population that could pose them serious liability risks.)

I struggled over the decision to get a flu shot myself. For one thing, last year in an article in the Atlantic, veteran science journalists Shannon Brownlee and Jeanne Lenzer raised questions over whether the vaccine actually works. And although pregnant women who catch the flu in the first half of their pregnancy are at an increased risk of giving birth to children who develop schizophrenia, given the timing of my pregnancy, I was at low risk for getting the flu then anyway—and I know from conversations with Caltech biologist Paul Patterson that there is a possibility that the vaccine itself confers this same increased risk. (For more about the link between prenatal infections, vaccines and mental illness, check out this feature I wrote in Scientific American MIND in 2008.) On the other hand, I also know that it could be dangerous to get sick in my third trimester, when I will be at an increased risk for serious respiratory problems. In the end, I decided to get the flu shot once I reached the halfway point in my pregnancy, when I felt the potential schizophrenia risk was minimal, and the shot could still (possibly) protect me towards the end of my pregnancy. Still, my decision was a gamble based on a lot of incomplete information.

It’s not just flu shots, though: pregnant women are taking more medicines than ever now, as they’re having babies later in life—when they tend to be on more drugs—and medical breakthroughs have made some pregnancies possible for the very first time. “We have people with cystic fibrosis who never in decades past would survive long enough to consider pregnancy, who are now living well into middle age and beyond,” says Ruth Faden, executive director of the Johns Hopkins Berman Institute of Bioethics. These women typically need to take medications throughout their pregnancy, yet no one knows their effects.

So what’s the solution? There isn’t a perfect one, but Baylis and Faden argue that there should be trials designed to test drugs in pregnant women who are going to be taking them no matter what. That way, structures are at least in place to collect data and look for adverse events. As for new experimental drugs, Baylis recommends incorporating pregnant women into later-stage trials, once the drugs have been shown to be safe and effective for other adults. “Instead of thinking of research as a risky activity,” she says, “we need to think of the continued off-label use of drugs [during pregnancy] as the risky activity.”

Citations:

Zaman, K., Roy, E., Arifeen, S., Rahman, M., Raqib, R., Wilson, E., Omer, S., Shahid, N., Breiman, R., & Steinhoff, M. (2008). Effectiveness of Maternal Influenza Immunization in Mothers and Infants New England Journal of Medicine, 359 (15), 1555-1564 DOI: 10.1056/NEJMoa0708630

Brown, A. (2005). Prenatal Infection as a Risk Factor for Schizophrenia Schizophrenia Bulletin, 32 (2), 200-202 DOI: 10.1093/schbul/sbj052

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36 Responses to Why pregnant women deserve drug trials

  1. Very interesting and provocative post. The same is true for trials in children, of course, and drug companies now have a financial incentive to conduct trials in kids. The question is whether or not the right trials — and well-designed trials–will be conducted.

  2. Gaythia says:

    While I agree with the author above that “Certainly, it seems unethical to expose a fetus to a potentially dangerous drug in a clinical trial” I do not agree that the alternative is: “But isn’t it worse to expose a fetus to a drug without any safety data at all, and outside the structured trial setting, where there is no patient monitoring?” I do not believe that this accurately reflects what has been happening.
    I believe that one of the points that should be made in a post such as this one is that it is vitally important that women and their partners seek professional help in evaluating their medical, nutritional and other health risks well BEFORE conception takes place. This would, in my opinion, entail updating any needed vaccines, if possible. While my own pregnancy experiences are not recent, I am positive that good obstetricians will still work closely with personal physicians, internists and specialists in dealing with any areas of concern, including medication use. Additionally, I’d like to see a link supporting the statement: “It’s not just flu shots, though: pregnant women are taking more medicines than ever now, as they’re having babies later in life—when they tend to be on more drugs”. Is that actually true? Aren’t patients and medical professionals more aware of drug interactions now than they were previously?
    By following the link to Francoise Baylis above, and then: Novel Tech Ethics -> Women’s health ->Research and Pregnant women; I came to several links to papers including this one: http://www.nejm.org/doi/full/10.1056/NEJMp1003462 which I believe gives a clear outline of seemingly well thought out protocols for the monitoring and evaluation of medication use in pregnancy. Based on what I read in the websites linked to above I personally do not believe that any of the medical professionals named here would agree with the statement that: “Might we have avoided these disasters, or at least lessened their magnitude, if thalidomide and DES had been tested in controlled clinical trials in pregnant women first?” The medical professionals advocating the testing of medication in pregnant women do seem to be very concerned about current levels of off label drug use in women, and the lack of comprehensive monitoring of medication use that is currently taking place. As the author of this post does describe in the final paragraph above these professionals are advocating carefully controlled testing, in which procedures and protocols (including pretesting in less vulnerable groups) would be in place. After all, I am sure that neither you nor I would want to be tested during pregnancy for the next thalidomide, and certainly ethical physicians and pharmaceutical professionals would not want to be responsible for dispensing them.
    The accurate and comprehensible communication of science to the public is quite important. As with the previous post, you have selected some interesting topics for discussion, but I’d like to see more care taken regarding some of the phrasing!

  3. Thanks, Gaythia, for your thoughtful comment. I completely agree that it’s crucial for women to discuss their medical histories and potential concerns with health care providers before they conceive. I made sure to update my vaccinations before I got pregnant, for instance. But many women are still going to face the very difficult decision of whether or not to stay on a drug (like an antidepressant) during pregnancy, and even a doctor’s most careful monitoring won’t be able to ensure that a medication is having no effect on the baby’s long-term health. For that, I think we need drug trials that track a fetus’s health not only during pregnancy, but also long after.

    You asked after my claim that pregnant women are taking lots of drugs these days. Two statistics I have recently found: one, from the NEJM paper you linked to, claims that 64 percent of American pregnant women are given prescriptions for one or more medications (not including vitamins). And this paper notes that half of all pregnant women from 1996 to 2000 received drugs from categories C, D, or X.

    As for thalidomide and DES, you’re right: no woman would want to participate in a trial for a drug that turned out to cause serious birth defects or cancer. But by not testing them, thousands of people were hurt. How can we know that the next new antipsychotic drug or diabetes drug won’t also cause serious problems, unless it is tested? I’m not suggesting that we round up a group of unsuspecting pregnant women and force drugs down their throats. As I explain in my post (and as the NEJM paper you linked to points out), one possible solution is to monitor women who are going to be taking drugs no matter what. Perhaps there should have been a small population of women who, instead of just being prescribed thalidomide, were given the drug in the context of a trial so that their birth outcomes could have been carefully monitored. These women would have taken the drug anyway—but in a trial, the risks could have been identified much more quickly, with the end result that many fewer families would have been affected.

  4. Thanks for your comment, Shannon—I’m a big fan of your work. I completely agree that it’s crucial to have the right kinds of trials. I don’t think there’s a consensus on trial design yet, but I know a lot of smart people are working on it, so here’s hoping that things will change soon.

  5. Gaythia says:

    It seems to me that both papers you cite give statistics for the high rate of use of prescription drugs over some period of time by pregnant women, but neither documents any increase relative to any previous time. And, in fact your point could have been just as effectively made without the “more medications now than ever” part.

    With regards to thalidomide, in this country, I believe that we ought to all honor the work of Dr. Frances Oldham Kelsey, the FDA pharmacologist who blocked (over great opposition) the release of thalidomide in this country for the treatment of pregnant women for morning sickness until some previous indications of neurological effects could be better documented. This led to the Kefauver Harris Amendment of 1962 which I believe marked the first time that drug manufactures were required to demonstrate that drugs were safe and effective.

    See: http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html

  6. Gaythia, the idea that more pregnant women take medications now came from my interview with Ruth Faden, executive director of the Johns Hopkins Berman Institute of Bioethics, who explained to me that “as more and more women are older when they become pregnant, many women go into their pregnancies with a chronic disease already on medication.” So the implication is that since pregnant women are older now then there used to be, there is a trend towards higher prescription drug use. I can’t find a study that compares current use versus use in the past, but I did find this 1991 study that reports that 32 percent of pregnant women were given prescriptions back then (though more were taking over-the-counter drugs).

  7. Julie says:

    This is helpful. more information for me to work with.

  8. Jillian says:

    I’m not a scientist or a research, but as a woman on medication and a mother of two I am interested. I take medicine to mitigate fairly serious allergies. While I was able to prep for pregnancy by doing things like updating vaccines, there’s no getting around maintenance needs. It was terribly frustrating to hear from my doctors that there was so little data to help us guide our decisions.

    I continued to take allergy medicines through my pregnancies out of necessity. I would have happily participated in a medical trial.

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  13. Ricardo Ataíde says:

    Hi Melinda,

    I enjoyed reading your post and have to say that, from the point of view of a woman that is pregnant (or was), some of your arguments are valid. You are, of course, a woman that has a degree of access to information and a level of education that allows you to make the most informed choices (if not always the right ones). One thing, though, that you didn’t mention in your post was that several drug trials are conducted in pregnant women in settings where the importance of having a drug that works is paramount and does not really compare to the dilema of “should I have a flu shot or not”. I’m talking about women in countries that have malaria, HIV and other such debilitating infections as permanent threats. In those countries, researchers are doing all they can to try and come up with drug regimens that are both safe (for the mother and child) and feasible (economically, ethically, practically). Again, I enjoyed reading your post, but it seems to me that you could have “dug a bit deeper”.

    Sincerely,
    Ricardo Ataíde

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