Should we test drugs on pregnant women?
June 21, 2010 12:37 PM Subscribe
Should we start doing medical research on pregnant women? In the wake of the H1N1 epidemic, in which pregnant women had a disproportionately higher risk of death, the question of including pregnant women in clinical trials has begun to be tentatively breached.
Ever since the thalidomide catastrophe, pregnant women have been virtually excluded from clinical research. But at what cost? Pregnant women end up gritting their teeth and toughing it out without medication through conditions ranging from the common cold and morning sickness to migraines and mental illnesses, and physicians operate largely in the dark when it comes to managing more serious conditions. We can do animal studies, but they aren't always useful; pregnant mammal studies were done with thalidomide and found no problems, for example. (Thalidomide has two optical isomers, one of which is teratogenic and one of which is not. Humans are one of a small number of species which easily converts one isomer to the other in vivo.) We can use computer modeling, a field called computational pharmacokinetics, but the results of such modeling are only as accurate as our models -- and gaining accurate data about human placental transfer is as fraught with ethical minefields as anything else related to human pregnancy. The FDA uses a piecemeal approach to grade drugs for safety in pregnancy, combining cohort studies and animal trials, resulting in a "best guess" system in which very few drugs are identified as truly dangerous (class X) but even fewer are identified as genuinely safe (class A). The New England Journal of Medicine offers another solution, outlining a possible ethical framework for including pregnant women in double-blind clinical trials.
Ever since the thalidomide catastrophe, pregnant women have been virtually excluded from clinical research. But at what cost? Pregnant women end up gritting their teeth and toughing it out without medication through conditions ranging from the common cold and morning sickness to migraines and mental illnesses, and physicians operate largely in the dark when it comes to managing more serious conditions. We can do animal studies, but they aren't always useful; pregnant mammal studies were done with thalidomide and found no problems, for example. (Thalidomide has two optical isomers, one of which is teratogenic and one of which is not. Humans are one of a small number of species which easily converts one isomer to the other in vivo.) We can use computer modeling, a field called computational pharmacokinetics, but the results of such modeling are only as accurate as our models -- and gaining accurate data about human placental transfer is as fraught with ethical minefields as anything else related to human pregnancy. The FDA uses a piecemeal approach to grade drugs for safety in pregnancy, combining cohort studies and animal trials, resulting in a "best guess" system in which very few drugs are identified as truly dangerous (class X) but even fewer are identified as genuinely safe (class A). The New England Journal of Medicine offers another solution, outlining a possible ethical framework for including pregnant women in double-blind clinical trials.
Pregnant women end up gritting their teeth and toughing it out without medication through conditions ranging from the common cold and morning sickness to migraines and mental illnesses, and physicians operate largely in the dark when it comes to managing more serious conditions.
I think that this may be a little hyperbolic. Last time I checked, when pregnant women become ill (e.g., infections, hyperemesis gravidarum, mental illness, etc.) they're hardly turned away with a pat on the back and a lillipop. All medications have an FDA Pregancy Risk Category to guide physicians on for precribing during pregnancy. Books are available that detail what evidence there is for use of particular medications during pregnancy.
Clinical trials are meant to test safety and pharmacokinetics (Phase I), and efficacy (Phase II/III). Until there is proof of safety or efficacy, medications in clinical trials cannot be called safe or efficacious since the studies aren't complete. As such, the risk of the unknown effect on the mother and/or fetus seem to me to be, a priori, greater than the known benefit. Including pregnant women on a case-by-case basis (for example, pregnant women with cancer), on an emergent basis, or in the face of a public health emergency (e.g., for a vaccine) seems reasonable. But KatherynT's statement is a little overblown in my opinion.
In the end, until there's a lot of data to support taking the risk, most physicians will always err on the side of being conservative -- prescribe when you need to (affects life/health of the mother or fetus), hold back when you can (if there is a more conservative, non-pharmacologic way to mitigate symptoms), and when forced, talk to your patient about how much risk she wants to take.
posted by scblackman at 12:48 PM on June 21, 2010 [2 favorites]
I think that this may be a little hyperbolic. Last time I checked, when pregnant women become ill (e.g., infections, hyperemesis gravidarum, mental illness, etc.) they're hardly turned away with a pat on the back and a lillipop. All medications have an FDA Pregancy Risk Category to guide physicians on for precribing during pregnancy. Books are available that detail what evidence there is for use of particular medications during pregnancy.
Clinical trials are meant to test safety and pharmacokinetics (Phase I), and efficacy (Phase II/III). Until there is proof of safety or efficacy, medications in clinical trials cannot be called safe or efficacious since the studies aren't complete. As such, the risk of the unknown effect on the mother and/or fetus seem to me to be, a priori, greater than the known benefit. Including pregnant women on a case-by-case basis (for example, pregnant women with cancer), on an emergent basis, or in the face of a public health emergency (e.g., for a vaccine) seems reasonable. But KatherynT's statement is a little overblown in my opinion.
In the end, until there's a lot of data to support taking the risk, most physicians will always err on the side of being conservative -- prescribe when you need to (affects life/health of the mother or fetus), hold back when you can (if there is a more conservative, non-pharmacologic way to mitigate symptoms), and when forced, talk to your patient about how much risk she wants to take.
posted by scblackman at 12:48 PM on June 21, 2010 [2 favorites]
We're expecting a fourth child at the end of July, and it has always struck me how little is known about medication effects on pregnant women. Seems like all the info out there available to the consumer is practically anecdotal; "Ask your doctor" becomes the default response, and many of the doctors that aren't OB's just won't plain prescribe *anything*, hardly.
If you're talking about including pregnant women in normal studies as part of the general population, the body is so whacked out at that time with hormonal and physical changes that it would really not be useful for most reasonable scenarios.
posted by RikiTikiTavi at 12:51 PM on June 21, 2010
If you're talking about including pregnant women in normal studies as part of the general population, the body is so whacked out at that time with hormonal and physical changes that it would really not be useful for most reasonable scenarios.
posted by RikiTikiTavi at 12:51 PM on June 21, 2010
Pregnant women end up gritting their teeth and toughing it out without medication...
I think that this may be a little hyperbolic.
Not in our experience. Once we get admitted to the women's hospital, it's all good. But the urgent care won't touch a pregnant woman. My wife was at a clinic where they had to essentially pretend she wasn't pregnant in order to treat her bladder infection (they of course prescribed a safe antibiotic). But we've been essentially sent home with tylenol before for stuff.
In the end, until there's a lot of data to support taking the risk, most physicians will always err on the side of being conservative -- prescribe when you need to (affects life/health of the mother or fetus), hold back when you can (if there is a more conservative, non-pharmacologic way to mitigate symptoms), and when forced, talk to your patient about how much risk she wants to take.
I totally agree, and I understand that there is not enough data, and this profession lives and dies by experimental results. And that's a good thing. But talking to the patient about risks just doesn't happen in most situations I've seen. None of the doctors seem to have time for that anymore. And, to be fair, I'm not sure how informed the patients would be about the risks. I mean, there aren't sufficient studies, right? So what are you going to tell them? They don't exactly have what they need to make that decision.
We always wait to go to the doctor until the last possible moment, toughing out illnesses, etc. to make sure it's not going to just heal on it's own. But in our experience the doctors underestimate the amount of pain/discomfort she's experiencing, with the exception of doctors who actually have something related (for example, a migraine sufferer).
posted by RikiTikiTavi at 1:01 PM on June 21, 2010 [3 favorites]
I think that this may be a little hyperbolic.
Not in our experience. Once we get admitted to the women's hospital, it's all good. But the urgent care won't touch a pregnant woman. My wife was at a clinic where they had to essentially pretend she wasn't pregnant in order to treat her bladder infection (they of course prescribed a safe antibiotic). But we've been essentially sent home with tylenol before for stuff.
In the end, until there's a lot of data to support taking the risk, most physicians will always err on the side of being conservative -- prescribe when you need to (affects life/health of the mother or fetus), hold back when you can (if there is a more conservative, non-pharmacologic way to mitigate symptoms), and when forced, talk to your patient about how much risk she wants to take.
I totally agree, and I understand that there is not enough data, and this profession lives and dies by experimental results. And that's a good thing. But talking to the patient about risks just doesn't happen in most situations I've seen. None of the doctors seem to have time for that anymore. And, to be fair, I'm not sure how informed the patients would be about the risks. I mean, there aren't sufficient studies, right? So what are you going to tell them? They don't exactly have what they need to make that decision.
We always wait to go to the doctor until the last possible moment, toughing out illnesses, etc. to make sure it's not going to just heal on it's own. But in our experience the doctors underestimate the amount of pain/discomfort she's experiencing, with the exception of doctors who actually have something related (for example, a migraine sufferer).
posted by RikiTikiTavi at 1:01 PM on June 21, 2010 [3 favorites]
It's not just how much risk the patient wants to take. How can she know? The risks are really unknown because no large scale studies are available.
The driving factor is largely fear on the part of doctors. Since few drugs are approved for use in pregnancy, almost all prescriptions are for non-FDA approved indications. The risks? One "bad baby" case and you can have a malpractice judgment against you in the millions, exceeding your malpractice insurance coverage amount many times over.
In my town, I am the only specialist in my field who will even see pregnant women in the hospital. All the others refuse the consults.
posted by sudogeek at 1:04 PM on June 21, 2010
The driving factor is largely fear on the part of doctors. Since few drugs are approved for use in pregnancy, almost all prescriptions are for non-FDA approved indications. The risks? One "bad baby" case and you can have a malpractice judgment against you in the millions, exceeding your malpractice insurance coverage amount many times over.
In my town, I am the only specialist in my field who will even see pregnant women in the hospital. All the others refuse the consults.
posted by sudogeek at 1:04 PM on June 21, 2010
It's not just how much risk the patient wants to take. How can she know? The risks are really unknown because no large scale studies are available.
Next thing you know, people might want safety studies on vaccines irregardless of the Greater Good argument.
posted by Balisong at 1:16 PM on June 21, 2010
Next thing you know, people might want safety studies on vaccines irregardless of the Greater Good argument.
posted by Balisong at 1:16 PM on June 21, 2010
This is my point exactly. The equation is, essentially, unquantifiable/undefined risk of the medication versus (hopefully) more quantifiable/defined risk of the disease or symptoms.
Take the example of migraine that RikiTikiTavi and KathrynT referred to. Let's say you want to take a triptan (e.g., Imitrex or sumatriptan), a potent drug that causes vasoconstriction and is marked Pregnancy Category C. Your choices are (as I see them), use whatever available data may be out ther to give you a sense (in an uncontrolled and likely underpowered way) of the risk, or weigh whether or not treating the symptoms of the migraine with that particular medication are "worth" any potential risk of causing vasoconstriction in the placenta (or other unexpected/unintended effect) leading to harm to the fetus. Only the patient can assess whether or not a small, hard-to-quantify risk is something they're willing to take. For some women, no risk, no matter how small, is worth taking. For some, a 1% or 2% or 4% chance of an "association" with fetal damage/demise is acceptable (especially when there's always a background rate of fetal damage/demise that prevents causal linkage).
In this case, the physician/practitioner ought to help guide his/her pregnant patient through the thought process.
A clinical trial is different. It is an experiment, and in the early phases (Phase 1, Phase 2), not designed to treat disease. I think that in these cases, the risk is always greater than the benefit because until the drug shows any signs of efficacy (proof-of-concept, Phase 2b), the is no benefit - only potential benefit. Plus, a drug that causes fetal damage/demise may be "killed off" by its developer for that reason alone, and as such, may not be available for non-pregnant patients. Thalidomide went through this -- we discovered, 30 years later, that the drug is good for various types of cancer.
posted by scblackman at 1:16 PM on June 21, 2010
Take the example of migraine that RikiTikiTavi and KathrynT referred to. Let's say you want to take a triptan (e.g., Imitrex or sumatriptan), a potent drug that causes vasoconstriction and is marked Pregnancy Category C. Your choices are (as I see them), use whatever available data may be out ther to give you a sense (in an uncontrolled and likely underpowered way) of the risk, or weigh whether or not treating the symptoms of the migraine with that particular medication are "worth" any potential risk of causing vasoconstriction in the placenta (or other unexpected/unintended effect) leading to harm to the fetus. Only the patient can assess whether or not a small, hard-to-quantify risk is something they're willing to take. For some women, no risk, no matter how small, is worth taking. For some, a 1% or 2% or 4% chance of an "association" with fetal damage/demise is acceptable (especially when there's always a background rate of fetal damage/demise that prevents causal linkage).
In this case, the physician/practitioner ought to help guide his/her pregnant patient through the thought process.
A clinical trial is different. It is an experiment, and in the early phases (Phase 1, Phase 2), not designed to treat disease. I think that in these cases, the risk is always greater than the benefit because until the drug shows any signs of efficacy (proof-of-concept, Phase 2b), the is no benefit - only potential benefit. Plus, a drug that causes fetal damage/demise may be "killed off" by its developer for that reason alone, and as such, may not be available for non-pregnant patients. Thalidomide went through this -- we discovered, 30 years later, that the drug is good for various types of cancer.
posted by scblackman at 1:16 PM on June 21, 2010
Speaking of H1N1: Swine Flu Jumps Back to Pigs and Keeps Evolving
posted by homunculus at 1:42 PM on June 21, 2010
posted by homunculus at 1:42 PM on June 21, 2010
As we investigate having our first child, my wife and I have been appalled at how little concrete information there is on the effects of various antidepressants on a developing fetus.
There's a lot of ass-covering and very little actionable advice.
posted by Robson at 1:43 PM on June 21, 2010
There's a lot of ass-covering and very little actionable advice.
posted by Robson at 1:43 PM on June 21, 2010
In this case, the physician/practitioner ought to help guide his/her pregnant patient through the thought process.
It's really interesting to think about how pregnant women would make decisions regarding risk based on their doctor's advice vs. anecdotal advice they might get from other women who are pregnant or have been pregnant. On AskMe and Jezebel, I've seen discussions where women think the doctor is being too paternalistic and they disregard the doctor's advice (or are generally suspicious of doctors), and openly talk crap about the doctor and their medical training. I don't like to visit Jezebel anymore, but I remember there was a recent post where the some commenter said something like it was her own damn business how much beer and wine they wanted to ingest while pregnant and the doctor didn't know what he/she was talking about.
I see a lot of that type of commentary on the internet. There seems to be a preference for instinct and supportive anecdotes versus complicated explanations regarding risks, and a suspicion of doctors. Would people even trust their doctor's advice or attempt at discussing risk?
posted by anniecat at 1:48 PM on June 21, 2010
It's really interesting to think about how pregnant women would make decisions regarding risk based on their doctor's advice vs. anecdotal advice they might get from other women who are pregnant or have been pregnant. On AskMe and Jezebel, I've seen discussions where women think the doctor is being too paternalistic and they disregard the doctor's advice (or are generally suspicious of doctors), and openly talk crap about the doctor and their medical training. I don't like to visit Jezebel anymore, but I remember there was a recent post where the some commenter said something like it was her own damn business how much beer and wine they wanted to ingest while pregnant and the doctor didn't know what he/she was talking about.
I see a lot of that type of commentary on the internet. There seems to be a preference for instinct and supportive anecdotes versus complicated explanations regarding risks, and a suspicion of doctors. Would people even trust their doctor's advice or attempt at discussing risk?
posted by anniecat at 1:48 PM on June 21, 2010
Kathryn T, do you have a citation for the "pregnant mammal studies" done with thalidomide?
Interestingly almost all basic biomedical research uses male, rather than female, mice.
posted by James Scott-Brown at 1:55 PM on June 21, 2010
Interestingly almost all basic biomedical research uses male, rather than female, mice.
posted by James Scott-Brown at 1:55 PM on June 21, 2010
The UW is also ramping up research on Pharmacology and Pregnant Women.
posted by jeffamaphone at 2:38 PM on June 21, 2010
posted by jeffamaphone at 2:38 PM on June 21, 2010
Interestingly almost all basic biomedical research uses male, rather than female, mice.
That conclusion was challenged by other researchers: Male Mice Not Alone in Research
Our collective experience is that many researchers select less aggressive females because they can be group-housed to save money. This female bias will persist indefinitely given financial constraints on basic biomedical research, especially in academic laboratories.
posted by jjray at 3:05 PM on June 21, 2010
That conclusion was challenged by other researchers: Male Mice Not Alone in Research
Our collective experience is that many researchers select less aggressive females because they can be group-housed to save money. This female bias will persist indefinitely given financial constraints on basic biomedical research, especially in academic laboratories.
posted by jjray at 3:05 PM on June 21, 2010
Isn't it already difficult enough to get women included in medical research? It wasn't until 1993, I think, that NIH mandated the inclusion of women in clinical trials, but I remember reading recently that the mandate hasn't done much good. Ridiculous.
I don't know much about the specifics of medical testing--are there situations here where stem cells might help in the research process?
posted by Fui Non Sum at 3:38 PM on June 21, 2010
I don't know much about the specifics of medical testing--are there situations here where stem cells might help in the research process?
posted by Fui Non Sum at 3:38 PM on June 21, 2010
We already have all kinds of cell cultures that will work fine for bioassay type endeavors, so it's not like we really need to add stem cells to the mix. Unfortunately, patients tend to be whole organisms, so you often have cell based bioassays that make a drug look really good, and then you go to the clinic where your drug doesn't measure up.
posted by Kid Charlemagne at 10:15 PM on June 21, 2010
posted by Kid Charlemagne at 10:15 PM on June 21, 2010
As we investigate having our first child, my wife and I have been appalled at how little concrete information there is on the effects of various antidepressants on a developing fetus.
There's a lot of ass-covering and very little actionable advice.
Disasters like thalidomide tend to make people cautious; maybe overcautious, but if you were a GP who'd prescribed it for a woman with morning sickness, thinking you were doing her a favour, and she'd brought her terribly crippled baby to see you a few months later... how many risks would you ever take in your career after that?
posted by rodgerd at 3:14 AM on June 22, 2010 [1 favorite]
There's a lot of ass-covering and very little actionable advice.
Disasters like thalidomide tend to make people cautious; maybe overcautious, but if you were a GP who'd prescribed it for a woman with morning sickness, thinking you were doing her a favour, and she'd brought her terribly crippled baby to see you a few months later... how many risks would you ever take in your career after that?
posted by rodgerd at 3:14 AM on June 22, 2010 [1 favorite]
scblackman: Pregnant women end up gritting their teeth and toughing it out without medication through conditions ranging from the common cold and morning sickness to migraines and mental illnesses, and physicians operate largely in the dark when it comes to managing more serious conditions.
I think that this may be a little hyperbolic. Last time I checked, when pregnant women become ill (e.g., infections, hyperemesis gravidarum, mental illness, etc.) they're hardly turned away with a pat on the back and a lillipop. All medications have an FDA Pregancy Risk Category to guide physicians on for precribing during pregnancy. Books are available that detail what evidence there is for use of particular medications during pregnancy.
When I developed hypertension, I had the choice of three drugs. None of them particularly good (I doubled my dose each fortnight attempting to keep it down long enough to go into labour naturally - I didn't get there but I did at least reach full term). That's two if you suffer from asthma. Of the two that are left, one has a huge amount of side effects including the high probability of rebound hypertension after stopping. Pregnancy induced hypertension and pre-eclampsia are one of the most common severe issues during pregnancy.
posted by geek anachronism at 3:44 AM on June 22, 2010
I think that this may be a little hyperbolic. Last time I checked, when pregnant women become ill (e.g., infections, hyperemesis gravidarum, mental illness, etc.) they're hardly turned away with a pat on the back and a lillipop. All medications have an FDA Pregancy Risk Category to guide physicians on for precribing during pregnancy. Books are available that detail what evidence there is for use of particular medications during pregnancy.
When I developed hypertension, I had the choice of three drugs. None of them particularly good (I doubled my dose each fortnight attempting to keep it down long enough to go into labour naturally - I didn't get there but I did at least reach full term). That's two if you suffer from asthma. Of the two that are left, one has a huge amount of side effects including the high probability of rebound hypertension after stopping. Pregnancy induced hypertension and pre-eclampsia are one of the most common severe issues during pregnancy.
posted by geek anachronism at 3:44 AM on June 22, 2010
The same paradox exists regarding testing antidepressants on depressed pregnant women. Is it more important to address a mother's depression, which could lead to poor prenatal care - or worse, self-harm by the mother – and poor outcomes for the developing baby? Or is it more important to protect the fetus from possible risks surrounding antidepressants? They are vexing questions for sure.
It'd be nice if the article could try to discuss depression in terms that considered the mother's wellbeing as well as the baby's. Obviously the baby's is important, but there's two of us involved in this here pregnancy thing.
posted by Kit W at 6:08 AM on June 22, 2010 [1 favorite]
It'd be nice if the article could try to discuss depression in terms that considered the mother's wellbeing as well as the baby's. Obviously the baby's is important, but there's two of us involved in this here pregnancy thing.
posted by Kit W at 6:08 AM on June 22, 2010 [1 favorite]
Robson, define your search with "Serotonin syndrome" there are quite a few studies but as always it's about weighing the benefits and rolling a crap shoot. And even then, antidepressants themselves haven't been studied too much about effects since 1) they're fairly new and 2) it is all based on the individual. One person can love Paxil, the other person can feel like they want to kill themselves.
Talk with as many doctors as you can and see if there is a right time for this. Perhaps after most of the development is done? Perhaps wait until the child is born and hold off on breast feeding?
Good luck. It's not an easy decision at all.
posted by stormpooper at 6:44 AM on June 22, 2010
Talk with as many doctors as you can and see if there is a right time for this. Perhaps after most of the development is done? Perhaps wait until the child is born and hold off on breast feeding?
Good luck. It's not an easy decision at all.
posted by stormpooper at 6:44 AM on June 22, 2010
It'd be nice if the article could try to discuss depression in terms that considered the mother's well being as well as the baby's. Obviously the baby's is important, but there's two of us involved in this here pregnancy thing.
I've read this before in an article that I could swear appeared on the blue, but the author, who was advised by her psychiatrist that it was unwise to get pregnant while on antidepressants, was upset that the doctor cared more about the risks to the fetus than her mental health and felt that the doctor thought it was careless of the woman to get pregnant without getting off her antidepressants or telling her so she could inform her of risks.
I, I suppose mistakenly, thought the whole point is to maximize the chances for the healthiest possible outcome for the fetus, especially if it is wanted and there are no plans to abort it or give it up if there's something wrong with it. I guess we're assuming that if something happened to the (wanted) fetus then it would have a negative effect on the mother's well being. I guess the other assumption is that having a child with birth defects and health problems is stressful over the long term as well. I didn't really think of it as two different entities since the fetus can't really have much of a say in the matter at that point on whether it would be okay with having heart defects.
Antidepressants during pregnancy increase risk of spontaneous abortion, study finds
Antidepressants in Pregnancy May Delay Developmental Milestones where it says, "The U.S. Food and Drug Administration and the American College of Obstetricians and Gynecologists (ACOG) have issued warnings about an increased risk of heart defects associated with the use of the Paxil during pregnancy."
posted by anniecat at 6:59 AM on June 22, 2010
As someone on antidepressants who is considering getting pregnant, I've run into this very problem: no one knows the effects of antidepressants on a fetus. They know certain ones are not advised (Paxil as well as MAOIs) and certain ones are "okay" (Wellbutrin and Zoloft), but had very little advice for me about whether I should switch properly working medications to something I'd already been on (Zoloft), or maintain where I was. Going off meds completely is a concern to me because I feel that post-partum depression would be very dangerous for me, but yes, I do very much worry about the effect on a fetus and later the child's development. So I have to weigh whether my mental health- especially during the time it takes to get pregnant- can be balanced without harming my future child. It's really hard. And basically, no one knows or can say what to do, except to tell me that if my body is at a good equilibrium now, with the drug and dose I'm on, to change medications and introduce those stressors could be just as harmful.
posted by questionsandanchors at 10:13 AM on June 22, 2010
posted by questionsandanchors at 10:13 AM on June 22, 2010
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