Part 1 (FDA Categories)
Part 2 (So What Do I Do, Then? Eh?? EH?)
So 2/3 of drugs are Category C and, according to the FDA, the average woman of childbearing age is taking 3 medications.
Say you're pregnant, or about to get pregnant. You go to your doctor to talk about meds. Chances are, your doctor will say, "Oh, well... just to be SAFE, you shouldn't take that! After all, you wouldn't want to hurt your baby!"
This frequently happens over antidepressants- most of which are very safe in pregnancy. Also, I am too lazy to find the articles, but 1) 80% of unmedicated women with a major depressive episode will have postpartum depression and 2) a recent, quite good, study shows that tapering off SSRIs a week or two before the due date does not, in fact, prevent infant respiratory distress. (A month or two is required, which is plenty of time to feel really, really nuts.) Therefore, "stop your meds" is stupid, dangerous, bad advice. For the mother.
This rant is, in fact, relevant. Liability has a lot to do with OB care. If you can convince your medical-professional-of-choice that you are making an informed decision, it reduces their fear that you will sue them.* Plus, they can write it down in your chart and all.
So how do you and your doctor know if something is safe? In order of ease-of-use:
1) Motherisk (pregnancy and breastfeeding): They run trials and write reviews. They also have a hotline. They have good, sensible information on drugs in pregnancy and breastfeeding. Unfortunately, they think one glass of wine MAY HURT YOUR BABY OMG. You can ignore that part if you want.
2) Dr. Jack Newman's book or website (breastfeeding:) Note: I recommend reading through this web page for a truly excellent general summary of when drugs are safe. Example: if they give it to newborns, it's probably safe in breastfeeding and maybe in pregnancy.
3) Common sense. I knew someone whose husband was worried about her taking Tums. They are made of calcium. Like in vitamins. Tylenol? Probably harmless. One glass of wine? Europe's rate of birth defects is no higher than it is here even though about 50% of women report drinking a little while pregnant.** Also, alcohol is proportionally present in breastmilk; if your BAC is 0.02, then 0.02% of your breastmilk is alcohol. If your kid drinks 100 mL of milk right after you drink, they'll get about 0.02 mL of alcohol, which is 0.4 mL of beer, or 8 drops. One cup of coffee in the morning while pregnant? Even March of Dimes, crazy fearmongers though they tend to be, thinks that's safe. Most drugs, about 1% ends up in breastmilk. Think before panicking, that's my motto!
4) The NHS publishes a clinical knowledge summary which is like the Cliff's Notes version of PubMed. (Registration required.) It tends to be conservative, but accurate.
5) There's always PubMed for the hard-core article-readers, (it's an index of all biology and medicine articles published). How do you tell if something's a good study? Well.... that's harder. Is it published in NEJM or Proceedings of the Royal Swedish Academy of Neurotoxicity in Cats? Do the error bars overlap, yet they claim P < 0.05?*** Is it the only article ever claiming that result? Is it a meta-analysis of twenty articles with widely differing methods, controls, and data? If you know a scientist or medical professional... ask them to read up on it for you. We're well practiced in spotting crappy data. Also we have academic-library access to all the darn articles. (Rot in hell, Else.vier.)
* One day, I should perhaps relate my not-very-amusing, three-days-before-Bug's-birth story of double vision, the ER, the MRI, the very cranky neurologist, the ex-military ex-OB specialty ophthalmologist, the lumbar puncture and C-section I didn't get, three most excellent midwives, and a partridge in a fricking pear tree, i.e., how to very firmly refuse treatment even while pregnant. It was, of course, idiopathic.
**Roughly four times the reported alcohol-in-pregnancy rate here, and yet the birth defect rate is no higher. Therefore, if there is an effect, it is lost in the noise. As another side note, one of the most-cited papers on drinking in pregnancy is a CDC study where they defined "moderate drinking" as 3 drinks. A DAY.
*** Mathematically, virtually impossible. I calculated it out once.
Showing posts with label Antidepressants and Pregnancy. Show all posts
Showing posts with label Antidepressants and Pregnancy. Show all posts
Friday, January 21, 2011
Friday, January 14, 2011
Pregnant Humans And Drug Trials
Part 1: FDA Pregnancy Categories: Who Made These UP, Anyhow?
Part 2: What to do, what to do?
Drugs in pregnancy! One of my favorite topics again.
There are currently five categories: A, B, C, D, and X. There is no standardized labeling for lactation. Categories D and X are pretty good: Proven, serious harm in humans. Category X includes retinol, DES, and thalidomide. Category D includes chemo drugs.
Category A is also pretty good, though fairly useless: Proven not to cause harm. They include folic acid and levothyroxine. Great! Folic acid doesn't cause fetal damage! Who knew??
However. B and C are exceedingly useless. What they say is, well, we don't think it'll do anything terrible, maybe, or maybe it will. The FDA states that 2/3 of currently on-the-market drugs are Category C. Tylenol is Category B.
The biggest problem with the system right now- in my opinion- is that it only looks at double-blind studies. In theory, this is an admirable scientific principle. In practice it doesn't work. At high doses, most drugs will harm animals or animal fetuses, and one purpose of animal studies is to determine the dose that causes harm; therefore, most animal studies will show harm. Many, if not most, Category B and C drugs with proven-harm have used a dosage 5-10x the maximum human dose. Try to get that past an IRB for a double-blind study in pregnant humans! In addition, some drugs cannot be double-blinded: insulin, for example, which is a Category B drug.
For functional purposes, these categories tell you almost nothing about whether the drug si safe. Albuterol is Category B. Fluconazole is Category C. Practically all SSRIs are Category C. Blood-pressure medications which are routinely used, as standard-of-care, to treat pregnant women, are Category C.
For many of these drugs, there is a great deal of data in pregnant women, including Drug X vs. Drug Y efficacy studies. There are large pregnancy registries for many, many drugs, which track adverse events, adverse outcomes, and birth defects. However, if it is not double-blind, the FDA will not consider it while assigning categories. If you or your doctor are interested in a drug, well, read through PubMed and look at the registries. Or trust someone's review.
The FDA, by the way, thinks that these categories are confusing and ineffective and wants to change them.
Next: So That Wasn't Helpful, How Do I Know What's Safe Then???
Part 2: What to do, what to do?
Drugs in pregnancy! One of my favorite topics again.
There are currently five categories: A, B, C, D, and X. There is no standardized labeling for lactation. Categories D and X are pretty good: Proven, serious harm in humans. Category X includes retinol, DES, and thalidomide. Category D includes chemo drugs.
Category A is also pretty good, though fairly useless: Proven not to cause harm. They include folic acid and levothyroxine. Great! Folic acid doesn't cause fetal damage! Who knew??
However. B and C are exceedingly useless. What they say is, well, we don't think it'll do anything terrible, maybe, or maybe it will. The FDA states that 2/3 of currently on-the-market drugs are Category C. Tylenol is Category B.
The biggest problem with the system right now- in my opinion- is that it only looks at double-blind studies. In theory, this is an admirable scientific principle. In practice it doesn't work. At high doses, most drugs will harm animals or animal fetuses, and one purpose of animal studies is to determine the dose that causes harm; therefore, most animal studies will show harm. Many, if not most, Category B and C drugs with proven-harm have used a dosage 5-10x the maximum human dose. Try to get that past an IRB for a double-blind study in pregnant humans! In addition, some drugs cannot be double-blinded: insulin, for example, which is a Category B drug.
For functional purposes, these categories tell you almost nothing about whether the drug si safe. Albuterol is Category B. Fluconazole is Category C. Practically all SSRIs are Category C. Blood-pressure medications which are routinely used, as standard-of-care, to treat pregnant women, are Category C.
For many of these drugs, there is a great deal of data in pregnant women, including Drug X vs. Drug Y efficacy studies. There are large pregnancy registries for many, many drugs, which track adverse events, adverse outcomes, and birth defects. However, if it is not double-blind, the FDA will not consider it while assigning categories. If you or your doctor are interested in a drug, well, read through PubMed and look at the registries. Or trust someone's review.
The FDA, by the way, thinks that these categories are confusing and ineffective and wants to change them.
Next: So That Wasn't Helpful, How Do I Know What's Safe Then???
Wednesday, September 15, 2010
Addendum: Antidepressants and Pregnancy
Stopping your drugs 2 weeks before the due date probably doesn't make any difference.
Thursday, February 15, 2007
Ask a Scientist: Antidepressants and Pregnancy (6)
Series: Antidepressants, Pregnancy, Risks
A list of generic and trade names is here.
*****
By the way, the pregnancy-and questions currently outnumber all others about ten to one. Who'd have guessed? Women are curious and underinformed!
6. Maternal risks and consequences of untreated depression
Aside from the obvious things about not being treated for depression (during or after pregnancy)- like not eating right, and never managing to wash the dishes, and being completely unable to take joy in anything, for example- it appears that being depressed affects children's growth and development. I find this entirely unsurprising: interaction with children, including how many words one speaks to them, has a huge impact on their development. (Here is where I would put references to 200 studies about this, if I had time.)
[Here is where I repeat that this is not medical advice, okay? These are my personal opinions.]
Each woman (possibly with her partner) decides what risks she is willing to take in pregnancy, and I'm all for that; the reason I wanted to write this is because so many doctors refuse to treat depression in pregnancy without evaluating the risks or letting the patient decide, and this in a situation where the risks appear to be relatively low (as opposed to, say, isoretinoin, which is associated with a roughly 25% incidence of major birth defects and a high rate of SA).
But especially once one is postpartum, I would argue there is NO reason to leave depression untreated. It is neither ennobling nor noble. It is merely dreadful.
And by the way, I have eliminated from consideration all studies that claim vitamins/ fish oil/ acupuncture will make all MDD patients, and especially women, feel all better. Because I don't do quackery. It exhausts me.
6a. Relapses
Relapses are very common in depression; one study, done over 1.5 years, cites a 40% relapse rate in the control group. They are investigating only one drug, but even in this isolated case, treatment reduces relapses to 26% and increases the time to relapse.
Another study cites a recurrence rate of 65% in controls vs. 27% treated with the same one drug. [And boy, are those control figures, um, depressing, by the way.]
These studies are both in cohorts with MDD. If you have MDD and it's untreated, guess what? It'll probably come back!
A series of small studies in pregnant women found that while half stopped or tried to stop taking ADs while pregnant, 75% of MDD patients "experienced depressive relapse". Of patients who discontinued or decreased AD dose, 61% went back to taking them.
6b. Infant failure to thrive
As previously mentioned, one study comparing 5 SSRIs and venlafaxine shows that maternal depression of >2 months decreases infant weight gain. This is confirmed by other studies, one longitudinal one which finds that 'infants of prenatally depressed mothers showed significantly more growth retardation than controls at all time points.'
A review mentions that extensive evidence shows that persistent deprssion is associated with higher cortisol levels and lower serotonin, and these stress effects are echoed in the infant's 'biochemical profile'. They also mention that prenatal depression is associated with both physical and behavioral complications throughout pregnancy, birth, and infancy. These results are supported by animal studies showing that maternal stress affects pregnancy outcome and offspring development.
To further sweeten the pot, an assortment of studies find that maternal depression and/or other psychiatric conditions are associated with missing prenatal checkups, prematurity, low birth rate, and more NICU stays: i.e., poorer self-and-fetus care during pregnancy, and poorer outcomes in birth.
6c. Parenting problems, attachment, child behavior
Here I'll quote because I couldn't put it any better:
"Depressive symptoms have also been found to be associated with negative parenting behaviors, insecure attachment, and subsequent internalizing behaviors in the child."
"Through children's early adolescence, maternal drug use [Ed: illegal, not prescription] is no more inimical for them than is maternal depression.... [on] mothers' everyday functioning [:] results showed that negative parenting behaviors were linked with multiple adverse child outcomes."
Child difficulty [to the parents] was associated with elevated levels of psychosocial stress, but only for some participants. Parental psychopathological symptoms during pregnancy should thus be considered as a risk factor for elevated and prolonged depression and elevated psychosocial stress in mothers and fathers across the transition to parenthood." So if you're stressed and depressed, your child may be even more of a handful. Eeeek.
"If depression persists into the postpartum period, it can have long-term consequences for both mother and baby. Mothers might go on to develop chronic mood disorders, and untreated postpartum depression can impair mother-infant attachment (level I evidence). Finally, being exposed to a chronically depressed mother can have cognitive, emotional, and behavioural consequences for a child."
Conclusions:
- Introduction
- Spontaneous abortion
- Premature birth
- Congenital or teratogenic defects; that is, malformations in utero
- Cardiac defects
- Antenatal/ postnatal adaptation problems
- Muscle stiffness
- Breathing distress at birth
- Neurological withdrawal symptoms
- Breastfeeding risks
- Infant weight gain
- Infant serotonin levels
- Long-term neurologic development
- Maternal risks of going without treatment
- Relapses
- Infant failure to thrive
- Parenting problems, attachment, child behavior
A list of generic and trade names is here.
*****
By the way, the pregnancy-and questions currently outnumber all others about ten to one. Who'd have guessed? Women are curious and underinformed!
6. Maternal risks and consequences of untreated depression
Aside from the obvious things about not being treated for depression (during or after pregnancy)- like not eating right, and never managing to wash the dishes, and being completely unable to take joy in anything, for example- it appears that being depressed affects children's growth and development. I find this entirely unsurprising: interaction with children, including how many words one speaks to them, has a huge impact on their development. (Here is where I would put references to 200 studies about this, if I had time.)
[Here is where I repeat that this is not medical advice, okay? These are my personal opinions.]
Each woman (possibly with her partner) decides what risks she is willing to take in pregnancy, and I'm all for that; the reason I wanted to write this is because so many doctors refuse to treat depression in pregnancy without evaluating the risks or letting the patient decide, and this in a situation where the risks appear to be relatively low (as opposed to, say, isoretinoin, which is associated with a roughly 25% incidence of major birth defects and a high rate of SA).
But especially once one is postpartum, I would argue there is NO reason to leave depression untreated. It is neither ennobling nor noble. It is merely dreadful.
And by the way, I have eliminated from consideration all studies that claim vitamins/ fish oil/ acupuncture will make all MDD patients, and especially women, feel all better. Because I don't do quackery. It exhausts me.
6a. Relapses
Relapses are very common in depression; one study, done over 1.5 years, cites a 40% relapse rate in the control group. They are investigating only one drug, but even in this isolated case, treatment reduces relapses to 26% and increases the time to relapse.
Another study cites a recurrence rate of 65% in controls vs. 27% treated with the same one drug. [And boy, are those control figures, um, depressing, by the way.]
These studies are both in cohorts with MDD. If you have MDD and it's untreated, guess what? It'll probably come back!
A series of small studies in pregnant women found that while half stopped or tried to stop taking ADs while pregnant, 75% of MDD patients "experienced depressive relapse". Of patients who discontinued or decreased AD dose, 61% went back to taking them.
6b. Infant failure to thrive
As previously mentioned, one study comparing 5 SSRIs and venlafaxine shows that maternal depression of >2 months decreases infant weight gain. This is confirmed by other studies, one longitudinal one which finds that 'infants of prenatally depressed mothers showed significantly more growth retardation than controls at all time points.'
A review mentions that extensive evidence shows that persistent deprssion is associated with higher cortisol levels and lower serotonin, and these stress effects are echoed in the infant's 'biochemical profile'. They also mention that prenatal depression is associated with both physical and behavioral complications throughout pregnancy, birth, and infancy. These results are supported by animal studies showing that maternal stress affects pregnancy outcome and offspring development.
To further sweeten the pot, an assortment of studies find that maternal depression and/or other psychiatric conditions are associated with missing prenatal checkups, prematurity, low birth rate, and more NICU stays: i.e., poorer self-and-fetus care during pregnancy, and poorer outcomes in birth.
6c. Parenting problems, attachment, child behavior
Here I'll quote because I couldn't put it any better:
"Depressive symptoms have also been found to be associated with negative parenting behaviors, insecure attachment, and subsequent internalizing behaviors in the child."
"Through children's early adolescence, maternal drug use [Ed: illegal, not prescription] is no more inimical for them than is maternal depression.... [on] mothers' everyday functioning [:] results showed that negative parenting behaviors were linked with multiple adverse child outcomes."
Child difficulty [to the parents] was associated with elevated levels of psychosocial stress, but only for some participants. Parental psychopathological symptoms during pregnancy should thus be considered as a risk factor for elevated and prolonged depression and elevated psychosocial stress in mothers and fathers across the transition to parenthood." So if you're stressed and depressed, your child may be even more of a handful. Eeeek.
"If depression persists into the postpartum period, it can have long-term consequences for both mother and baby. Mothers might go on to develop chronic mood disorders, and untreated postpartum depression can impair mother-infant attachment (level I evidence). Finally, being exposed to a chronically depressed mother can have cognitive, emotional, and behavioural consequences for a child."
Conclusions:
- Depression is miserable and loathsome.
- Untreated depression in pregnancy is associated with higher risk of poor outcomes.
- Infants with depressed mothers have weight-gain delays.
- Untreated depression after pregnancy is associated with developmental troubles and poor parenting.
- Parental depression interferes with children's physical and emotional development.
Thursday, February 08, 2007
Ask a Scientist: Antidepressants and Pregnancy (5)
Series: Antidepressants, Pregnancy, Risks
A list of generic and trade names is here.
*****
5. Breastfeeding risks
Okay, folks, there are a LOT of articles about this. If you want to see them, search 'breastfeeding antidepressants' on Pubmed. As far as I can tell, they largely come to the same conclusions. So here's a summary of the first 50 or so.
Did you know there's a Journal of Human Lactation??? They have an excellent 2001 review of various ADs in lactation.
Motherisk has a lovely patient-oriented summary about drugs and breastfeeding. (Thanks, Aurelia.)
Summary:
Use of SSRIs and TCAs (except doxepin) is considered safe. Occasional adverse events are reported. They generally resolve once either breastfeeding is stopped, the schedule is altered to minimize infant exposure, or the mother stops taking the drug.
Of the SSRIs, sertraline and paroxetine have very low numbers of adverse events. Mild adverse events are associated with fluoxetine and citalopram (colic, crying, etc.).
Antipsychotics and lithium are not recommended in breastfeeding.
5a. Infant weight gain
A study comparing the 5 most common SSRIs and venlafaxine shows absolutely normal weights in all infants. They note, however, that maternal depression of >2 months DOES make the babies gain less weight.
Paroxetine in 27 mothers has no effect on weight gain or developmental milestones. A meta-analysis of SSRIs (other than fluoxetine) and TCAs also showed no effect on weight gain.
One study on 26 breastfed infants whose mothers took fluoxetine, however, showed an average 1-pound difference in weight gain over 6 months. The JHL review notes that none of the weights, even the lower ones, were below the national mean. Another study notes lower birth weights in fluoxetine usage, but only studies five exposed infants (i.e., not enough to say).
5b. Infant serotonin levels
Unsurprisingly, this isn't exactly studied a lot. One editorial (pdf) summarizes a few studies on the matter: rats exposed to fluoxetine had a 50% occupancy of their serotonin reuptake protein (5-HTT); however, apparently about 80% is necessary for an AD effect. (Also, nobody's quite sure exactly what 5-HTT does or how it relates to depression.)
A human study on fluoxetine says that "most infants may continue to breastfeed without experiencing meaningful changes in" serotonin uptake and metabolism. A small study that lumps together three ADs seems to suggest that newborn serotonin levels are changed by maternal AD use, but stabilize within one month. They go on to suggest that it could have terrible! developmental! consequences but I think they're full of beans (and hand-waving).
5c. Long-term neurologic development
You'll be shocked (shocked!) to learn that basically, nobody has a clue. In infants followed for up to a year, they're perfectly normal. After that, well, neurology is complicated and poorly understood anyways. The best that can be said is that SSRIs and other ADs don't appear to do anything either a) really nasty b) quick or c) much of the time.
Reported infant exposures in breastfeeding
The medical literature says that infant exposure of <10% is largely considered safe. In addition, some data indicate that breastfeeding can alleviate neonatal abstinence syndromes (here in, for example, methadone exposure. Think how much more innocuous sertraline is.).
These exposures and reported adverse effects in lactation are taken from the JHL article and a review in Drug Safety. Both studies note that changing dosage time and breastfeeding times can significantly reduce/ minimize infant exposure.
A modeling study notes that the total infant yearly dose (of fluoxetine) is generally about 1 or 1.5 of the mother's daily dose. This isn't very much. Another meta-analysis summarizes overall exposures for many psychoactive drugs.
Fluoxetine: Infants may receive up to 20% of maternal daily dose (MD). Some reports of extreme infant fussiness which resolve on maternal drug or breastfeeding discontinuation. Other studies indicate no complications in infants. Labelling recommends not using in breastfeeding, but is generally considered low-risk.
Paroxetine: Infant exposure ~3% MD.
Fluvoxamine: May be contraindicted in infants who are taking caffeine (i.e. for apnea). Infant breastmilk dose 0.75%-1.4% MD. Alternatively, undetectable in infant serum.
Citralopram: 0.4%-1.8% MD. No adverse effects reported.
Sertraline: 0.5-2% MD; sometimes undetectable in infant. No known adverse effects. Considered safe and well-studied.
Nefadozone: Adverse event in preterm infant receiving 0.45% of maternal dose; attributed to reduced hepatic function. Calculated to be safe if infant is confirmed to receive less than 10%.
Bupropion: ~0.02% MD; therefore considered very safe in lactating mothers. One case report of seizures; may be avoided if family history of seizure.
Venlafaxine: up to 7.6% MD; metabolized well by infants. No apparent effect on weight. Well-tolerated.
Conclusions:
- Introduction
- Spontaneous abortion
- Premature birth
- Congenital or teratogenic defects; that is, malformations in utero
- Cardiac defects
- Antenatal/ postnatal adaptation problems
- Muscle stiffness
- Breathing distress at birth
- Neurological withdrawal symptoms
- Breastfeeding risks
- Infant weight gain
- Infant serotonin levels
- Long-term neurologic development
- Maternal risks of going without treatment
- Relapses
- Infant failure to thrive
- Parenting problems, attachment, child behavior
A list of generic and trade names is here.
*****
5. Breastfeeding risks
Okay, folks, there are a LOT of articles about this. If you want to see them, search 'breastfeeding antidepressants' on Pubmed. As far as I can tell, they largely come to the same conclusions. So here's a summary of the first 50 or so.
Did you know there's a Journal of Human Lactation??? They have an excellent 2001 review of various ADs in lactation.
Motherisk has a lovely patient-oriented summary about drugs and breastfeeding. (Thanks, Aurelia.)
Summary:
Use of SSRIs and TCAs (except doxepin) is considered safe. Occasional adverse events are reported. They generally resolve once either breastfeeding is stopped, the schedule is altered to minimize infant exposure, or the mother stops taking the drug.
Of the SSRIs, sertraline and paroxetine have very low numbers of adverse events. Mild adverse events are associated with fluoxetine and citalopram (colic, crying, etc.).
Antipsychotics and lithium are not recommended in breastfeeding.
5a. Infant weight gain
A study comparing the 5 most common SSRIs and venlafaxine shows absolutely normal weights in all infants. They note, however, that maternal depression of >2 months DOES make the babies gain less weight.
Paroxetine in 27 mothers has no effect on weight gain or developmental milestones. A meta-analysis of SSRIs (other than fluoxetine) and TCAs also showed no effect on weight gain.
One study on 26 breastfed infants whose mothers took fluoxetine, however, showed an average 1-pound difference in weight gain over 6 months. The JHL review notes that none of the weights, even the lower ones, were below the national mean. Another study notes lower birth weights in fluoxetine usage, but only studies five exposed infants (i.e., not enough to say).
5b. Infant serotonin levels
Unsurprisingly, this isn't exactly studied a lot. One editorial (pdf) summarizes a few studies on the matter: rats exposed to fluoxetine had a 50% occupancy of their serotonin reuptake protein (5-HTT); however, apparently about 80% is necessary for an AD effect. (Also, nobody's quite sure exactly what 5-HTT does or how it relates to depression.)
A human study on fluoxetine says that "most infants may continue to breastfeed without experiencing meaningful changes in" serotonin uptake and metabolism. A small study that lumps together three ADs seems to suggest that newborn serotonin levels are changed by maternal AD use, but stabilize within one month. They go on to suggest that it could have terrible! developmental! consequences but I think they're full of beans (and hand-waving).
5c. Long-term neurologic development
You'll be shocked (shocked!) to learn that basically, nobody has a clue. In infants followed for up to a year, they're perfectly normal. After that, well, neurology is complicated and poorly understood anyways. The best that can be said is that SSRIs and other ADs don't appear to do anything either a) really nasty b) quick or c) much of the time.
Reported infant exposures in breastfeeding
The medical literature says that infant exposure of <10% is largely considered safe. In addition, some data indicate that breastfeeding can alleviate neonatal abstinence syndromes (here in, for example, methadone exposure. Think how much more innocuous sertraline is.).
These exposures and reported adverse effects in lactation are taken from the JHL article and a review in Drug Safety. Both studies note that changing dosage time and breastfeeding times can significantly reduce/ minimize infant exposure.
A modeling study notes that the total infant yearly dose (of fluoxetine) is generally about 1 or 1.5 of the mother's daily dose. This isn't very much. Another meta-analysis summarizes overall exposures for many psychoactive drugs.
Fluoxetine: Infants may receive up to 20% of maternal daily dose (MD). Some reports of extreme infant fussiness which resolve on maternal drug or breastfeeding discontinuation. Other studies indicate no complications in infants. Labelling recommends not using in breastfeeding, but is generally considered low-risk.
Paroxetine: Infant exposure ~3% MD.
Fluvoxamine: May be contraindicted in infants who are taking caffeine (i.e. for apnea). Infant breastmilk dose 0.75%-1.4% MD. Alternatively, undetectable in infant serum.
Citralopram: 0.4%-1.8% MD. No adverse effects reported.
Sertraline: 0.5-2% MD; sometimes undetectable in infant. No known adverse effects. Considered safe and well-studied.
Nefadozone: Adverse event in preterm infant receiving 0.45% of maternal dose; attributed to reduced hepatic function. Calculated to be safe if infant is confirmed to receive less than 10%.
Bupropion: ~0.02% MD; therefore considered very safe in lactating mothers. One case report of seizures; may be avoided if family history of seizure.
Venlafaxine: up to 7.6% MD; metabolized well by infants. No apparent effect on weight. Well-tolerated.
Conclusions:
- Being depressed affects infant weight gain.
- SSRIs and TCAs in breastmilk don't.
- There are no data on long-term neurological consequences.
- In any case, infant AD dosage through breastmilk is very low.
- On the other hand, infant/child exposure to maternal depression definitely has bad effects on weight gain, "emotional and behavioural development", maternal-infant bonding, cognitive development, and children's levels of fear and anxiety.
- Many ADs are well-studied in lactating mothers; few-to-no adverse events are reported. Most are widely considered to be safe.
Monday, February 05, 2007
Ask a Scientist: Antidepressants and Pregnancy (4)
Series: Antidepressants, Pregnancy, Risks
[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]
This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.
A list of generic and trade names is here.
*****
4. Antenatal/ postnatal adaptation problems
Certain post-birth symptoms are associated with maternal antidepressant- usually SSRI, but also venlafaxine- use in the last trimester. They are all categorized as 'neonatal withdrawal [or abstinence] syndrome'. These syndromes rarely lead to anything other than an unpleasant week with a cranky baby, and maybe a couple days in the NICU.
Muscle stiffness and/or convulsions are treated with support and/or low doses of SSRIs. A certain amount of breathing and/or neonatal distress is associated with maternal SSRI usage; it is rarely fatal except in infants with other complications, and is treated supportively.
4a. Muscle stiffness
A recent study looked at reported incidences of seizure-like symptoms in mothers taking SSRIs. They found 93 reported cases of these symptoms in a large adverse-event database and tried to eliminate other factors and drugs that might have caused the symptoms. Then they compared the incidence to the overall incidence in the adverse-event database. 74 cases were 'certain'; of those, 51 involved paroxetine use, 10 fluoxetine, 7 sertraline, and 6 citalopram.
Most of the incidents were neurological (see below); there were 11 total instances of hypertonia and convulsions.
Two case studies on venlafaxine report increased hypertonia (stiffness) in neonates; one treats with a low dose for a week, and the other recommends breastfeeding to mitigate withdrawal.
One case study reports convulsions associated with paroxetine.
4b. Breathing distress at birth (and other distress, ICU)
Third-trimester SSRI use is associated with babies more often having to go the NICU with breathing problems, neonatal lowered heart rate, or other unspecified distress. Various studies estimate the risk at various levels.
A large Canadian cohort of 75,000 mothers taking any of 6 SSRIs showed that 13.9% vs. 7.8% of controls had some neonatal respiratory distress (that is, had to spend some time in the NICU). A Finnish population study likewise showed that, of infants whose mothers bought SSRIs in the 3rd trimester, 15.7% vs. 11.2% for infants whose mothers bought SSRIs in the 1st trimester. A Motherisk study specifically on citralopram found an increased chance of having to go to a special-care nursery.
Another study, the inspiration for a recent mildly hysterical FDA alert, looked for infants with PPHN (a condition where there is high blood pressure in the lungs and therefore oxygen deficit) and then tried to see how many mothers used SSRIs. They found an increased risk of about 6-fold; that is, in their study, from 7/1000 to 37/1000. The problem with this study is they looked for a condition and then tried to check drug usage. It would be better to look among a large cohort of SSRI users (like in the Canadian study) and check for PPHN. Also, they only find 14 cases of PPHN with SSRI use. I find this not terribly credible due to poor design and small sample size.
4c. Neurological withdrawal symptoms
Many newborns with SSRI exposure do manifest neurological signs of a 'neonatal abstinence syndrome.' In addition to the higher incidence of respiratory distress (as above), many infants cry a lot and have trouble sleeping. This number is reported as high as 30% in a small study (60 infants). Of these, 8 had 'severe' and 10 'mild' symptoms. The average duration was about three days.
Another small study examines 76 mothers who took ADs and 90 control. 63% of exposed infants had some neurological symptoms. 75% of these infants resolved within 3 days; premature infants were more strongly affected by SSRI side effects. And yet one more study of 46 infants found much the same: about 30% of infants have mild respiratory distress or twitchiness. (They also found that clonazepam, a benzodiazapene, exacerbated the effect, probably due to metabolic effects.)
Numerous case reports have been published on neonatal withdrawal symptoms in maternal use of citralopram, fluoxetine, paroxetine, and I'm sure other drugs. The above case studies on venlafaxine also report irritability, etc.
One exceedingly crappy case report tries to correlate paroxetine levels in one newborn with- gasp!- pneumothorax. They do not measure maternal paroxetine levels, but cord-blood levels are four times above the normal therapeutic range. And then the infant is irritable in addition to intubated, but gets better within a week. Correlation is NOT causation here.
Conclusions:
- Introduction
- Spontaneous abortion
- Premature birth
- Congenital or teratogenic defects; that is, malformations in utero
- Cardiac defects
- Antenatal/ postnatal adaptation problems
- Muscle stiffness
- Breathing distress at birth
- Neurological withdrawal symptoms
- Breastfeeding risks
- Infant weight gain
- Long-term neurologic development
- Maternal risks of going without treatment
- Relapses
- Infant failure to thrive
- Parenting problems, attachment, child behavior
[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]
This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.
A list of generic and trade names is here.
*****
4. Antenatal/ postnatal adaptation problems
Certain post-birth symptoms are associated with maternal antidepressant- usually SSRI, but also venlafaxine- use in the last trimester. They are all categorized as 'neonatal withdrawal [or abstinence] syndrome'. These syndromes rarely lead to anything other than an unpleasant week with a cranky baby, and maybe a couple days in the NICU.
Muscle stiffness and/or convulsions are treated with support and/or low doses of SSRIs. A certain amount of breathing and/or neonatal distress is associated with maternal SSRI usage; it is rarely fatal except in infants with other complications, and is treated supportively.
4a. Muscle stiffness
A recent study looked at reported incidences of seizure-like symptoms in mothers taking SSRIs. They found 93 reported cases of these symptoms in a large adverse-event database and tried to eliminate other factors and drugs that might have caused the symptoms. Then they compared the incidence to the overall incidence in the adverse-event database. 74 cases were 'certain'; of those, 51 involved paroxetine use, 10 fluoxetine, 7 sertraline, and 6 citalopram.
Most of the incidents were neurological (see below); there were 11 total instances of hypertonia and convulsions.
Two case studies on venlafaxine report increased hypertonia (stiffness) in neonates; one treats with a low dose for a week, and the other recommends breastfeeding to mitigate withdrawal.
One case study reports convulsions associated with paroxetine.
4b. Breathing distress at birth (and other distress, ICU)
Third-trimester SSRI use is associated with babies more often having to go the NICU with breathing problems, neonatal lowered heart rate, or other unspecified distress. Various studies estimate the risk at various levels.
A large Canadian cohort of 75,000 mothers taking any of 6 SSRIs showed that 13.9% vs. 7.8% of controls had some neonatal respiratory distress (that is, had to spend some time in the NICU). A Finnish population study likewise showed that, of infants whose mothers bought SSRIs in the 3rd trimester, 15.7% vs. 11.2% for infants whose mothers bought SSRIs in the 1st trimester. A Motherisk study specifically on citralopram found an increased chance of having to go to a special-care nursery.
Another study, the inspiration for a recent mildly hysterical FDA alert, looked for infants with PPHN (a condition where there is high blood pressure in the lungs and therefore oxygen deficit) and then tried to see how many mothers used SSRIs. They found an increased risk of about 6-fold; that is, in their study, from 7/1000 to 37/1000. The problem with this study is they looked for a condition and then tried to check drug usage. It would be better to look among a large cohort of SSRI users (like in the Canadian study) and check for PPHN. Also, they only find 14 cases of PPHN with SSRI use. I find this not terribly credible due to poor design and small sample size.
4c. Neurological withdrawal symptoms
Many newborns with SSRI exposure do manifest neurological signs of a 'neonatal abstinence syndrome.' In addition to the higher incidence of respiratory distress (as above), many infants cry a lot and have trouble sleeping. This number is reported as high as 30% in a small study (60 infants). Of these, 8 had 'severe' and 10 'mild' symptoms. The average duration was about three days.
Another small study examines 76 mothers who took ADs and 90 control. 63% of exposed infants had some neurological symptoms. 75% of these infants resolved within 3 days; premature infants were more strongly affected by SSRI side effects. And yet one more study of 46 infants found much the same: about 30% of infants have mild respiratory distress or twitchiness. (They also found that clonazepam, a benzodiazapene, exacerbated the effect, probably due to metabolic effects.)
Numerous case reports have been published on neonatal withdrawal symptoms in maternal use of citralopram, fluoxetine, paroxetine, and I'm sure other drugs. The above case studies on venlafaxine also report irritability, etc.
One exceedingly crappy case report tries to correlate paroxetine levels in one newborn with- gasp!- pneumothorax. They do not measure maternal paroxetine levels, but cord-blood levels are four times above the normal therapeutic range. And then the infant is irritable in addition to intubated, but gets better within a week. Correlation is NOT causation here.
Conclusions:
- SSRIs cause some increase in post-natal problems.
- These manifest as mild breathing distress, NICU time, and longer hospital stays.
- Some infants will experience muscle stiffness and, occasionally, convulsions.
- Some incidents of severe respiratory distress are reported.
- Many 3rd-trimester-SSRI-exposed infants will be irritable for several days after birth, due to neurological withdrawal.
- If symptoms are severe, some doctors recommend treating with tapered SSRI doses.
- Breastfeeding may mitigate withdrawal.
- These effects can be worse in premature infants, who are predisposed to breathing distress.
- Motherrisk reminds us that "Among pregnant women, abrupt discontinuation of antidepressants has been associated with withdrawal symptoms, including nausea and vomiting, diarrhea, sweating, anxiety and panic attacks, mood swings, and suicidal thoughts."
- They recommend exposed infants be monitored for a week or so after birth.
- This sounds really alarming, but remember, this is an increase in nonfatal events.
- A review on AD withdrawal in adults tells us that "Most reactions are mild and short-lived and require no treatment other than patient reassurance."
Thursday, February 01, 2007
Ask a Scientist: Antidepressants and Pregnancy (3)
Series: Antidepressants, Pregnancy, Risks
[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]
This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.
A list of generic and trade names is here.
*****
3. Congenital or teratogenic defects; that is, malformations in utero
These studies are often reported as odds ratios (ORs): the chance that X will happen under condition Y, divided by the rate of X without condition Y. Sometimes ORs are high: 2-fold, 4-fold. Remember that the basal rate is important; does it increase from 1% to 2% or 10% to 20%? Is the basal rate noisy; that is, is it small enough that there is doubt what the basal rate really is; could it be 1-3% in reality? So a high OR is not always cause for alarm. (Moral: Read articles carefully.)
It is believed that first-trimester exposure has the most impact on congenital (i.e. pre-birth) deformities; for an example, see this; this is why many of these studies focus on women who took ADs in the first trimester.
For comparison, the CDC runs a long-term birth defect database called the MACDP. Its latest report, from 2004, reports 1.2% cardiac defects and 2.3% all birth defects (including trisomies) among all births in the study.
The same large Finnish database mentioned in Part 1 investigated rate of birth defects among women with SSRI purchases in 1st, 2nd, 3rd, or all trimesters. About 1400 women bought SSRIs in the first trimester, being: citalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine. Most SSRIs had no effect on birth defect incidence. There was a questionable association between 1st-trimester fluoxetine exposure and cardiac defects: 2.3% vs. a reported rate of 0.8% in Finland. After the authors adjusted for other factors, however(they don't specify, but probably things like smoking, family history, cocaine use, etc.), they found no association.
A study of 150 women on venlafaxine (Effexor) detected no defects above the basal level of 1-3% in the general population. A literature review of many other studies says that fluoxetine, sertraline (SSRIs), bupropion, and low doses of paroxetine are not associated with birth defects. A few isolated cases are reported with venlafaxine.
A large study/database (pdf) by Glaxo-Smith-Kline tracking reported defects (incident reporting), especially in bupropion use for all purposes, finds the following incidences (selected data):
All congenital defects:
Bupropion: 3.4%
All other ADs: 2.5%
1st trimester use (smaller cohorts), all defects:
Paroxetine: 4%
Citralopram: 3.2%
Trazodone: 5%
Venlafaxine: 1.9%
Sertraline: 1.4%
Bupropion is associated with a 1.9% incidence of cardiac defects (CDC: 1.2%).
A recent study on the Quebec pregnancy registry also reports that 7% of infants in 1403 women taking paroxetine had congenital defects, and 1.7% had cardiac defects.
CONCLUSIONS:
- Introduction
- Spontaneous abortion
- Premature birth
- Congenital or teratogenic defects; that is, malformations in utero
- Cardiac defects
- Antenatal adaptation problems
- Muscle stiffness
- Breathing distress at birth
- Neurological withdrawal symptoms
- Breastfeeding risks
- Infant weight gain
- Long-term neurologic development
- Maternal risks of going without treatment
- Relapses
- Infant failure to thrive
- Parenting problems, attachment, child behavior
[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]
This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.
A list of generic and trade names is here.
*****
3. Congenital or teratogenic defects; that is, malformations in utero
- All defects; cardiac defects
These studies are often reported as odds ratios (ORs): the chance that X will happen under condition Y, divided by the rate of X without condition Y. Sometimes ORs are high: 2-fold, 4-fold. Remember that the basal rate is important; does it increase from 1% to 2% or 10% to 20%? Is the basal rate noisy; that is, is it small enough that there is doubt what the basal rate really is; could it be 1-3% in reality? So a high OR is not always cause for alarm. (Moral: Read articles carefully.)
It is believed that first-trimester exposure has the most impact on congenital (i.e. pre-birth) deformities; for an example, see this; this is why many of these studies focus on women who took ADs in the first trimester.
For comparison, the CDC runs a long-term birth defect database called the MACDP. Its latest report, from 2004, reports 1.2% cardiac defects and 2.3% all birth defects (including trisomies) among all births in the study.
The same large Finnish database mentioned in Part 1 investigated rate of birth defects among women with SSRI purchases in 1st, 2nd, 3rd, or all trimesters. About 1400 women bought SSRIs in the first trimester, being: citalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine. Most SSRIs had no effect on birth defect incidence. There was a questionable association between 1st-trimester fluoxetine exposure and cardiac defects: 2.3% vs. a reported rate of 0.8% in Finland. After the authors adjusted for other factors, however(they don't specify, but probably things like smoking, family history, cocaine use, etc.), they found no association.
A study of 150 women on venlafaxine (Effexor) detected no defects above the basal level of 1-3% in the general population. A literature review of many other studies says that fluoxetine, sertraline (SSRIs), bupropion, and low doses of paroxetine are not associated with birth defects. A few isolated cases are reported with venlafaxine.
A large study/database (pdf) by Glaxo-Smith-Kline tracking reported defects (incident reporting), especially in bupropion use for all purposes, finds the following incidences (selected data):
All congenital defects:
Bupropion: 3.4%
All other ADs: 2.5%
1st trimester use (smaller cohorts), all defects:
Paroxetine: 4%
Citralopram: 3.2%
Trazodone: 5%
Venlafaxine: 1.9%
Sertraline: 1.4%
Bupropion is associated with a 1.9% incidence of cardiac defects (CDC: 1.2%).
A recent study on the Quebec pregnancy registry also reports that 7% of infants in 1403 women taking paroxetine had congenital defects, and 1.7% had cardiac defects.
CONCLUSIONS:
- SSRIs (except for paroxetine) are probably not associated with increased risk of birth defects, including cardiac defects. Neither is venlafaxine.
- Paroxetine and trazodone are associated with increased risk of birth defects.
- The Quebec study indicates that low doses of paroxetine are NOT associated with increased risk.
- Bupropion may slightly increase cardiac defects; however, the effect is small and therefore not certain.
Monday, January 29, 2007
Ask a Scientist: Antidepressants and Pregnancy (Intro, 1,2)
By request, and most especially for S and B, I am supplying a short and detailed, but not comprehensive, review of some common antidepressants and pregnancy.
Most doctors do not wish to prescribe any drugs for use in pregnancy; many doctors recommend that even Sudafed not be used- just in case!- even though there is an enormous amount of evidence that demonstrates no danger. For all my friends who wish to have adequate documentation with which to beat their doctors over the head, here you go.
This will be a series on Mondays and Thursdays.
For references relating to other drugs, more info, or PDFs, email me.
Series: Antidepressants, Pregnancy, Risks
[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]
This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.
A list of generic and trade names is here.
****
Introduction
Despite the FDA's quite reasonable official stance that the risk/reward should be weighed individually, this attitude seems to be slow to catch on.
The FDA labels pregnancy drugs into five categories: A, B, C, D and X.
The risks discussed arose through incident reporting, animal studies, cohort studies (comparing two more-or-less matched groups), long-term drug tracking by manufacturers (including pregnancy registries), and various medical studies. You will notice, if you read the individual papers, that there is a large amount of variability between studies; human populations are heterogeneous. The smaller or more biased (nonrandom) a sample, the more variation one will expect from study to study.
Relatively few drugs are Class A; even, say, sertraline, which is a relatively old and well-studied AD, is Class C. So is Sudafed. So is Benadryl. This is because it is difficult to demonstrate NO risk, and because many drugs have some small risk associated. A patient might think Class C is a terrible risk in pregnancy, or that there are no studies in humans, but actually there are a lot of studies in pregnant humans. Yet the FDA says there are "no adequate and well-controlled studies in pregnant women" in the drug labelling. In fact, the AAFP says that Benadryl and Sudafed are safe in pregnancy. Overall, the FDA system is confusing, inaccurate, and not very informative; the patient should look up each drug herself to get good information. (The FDA decided in 1997 to replace the A-X categorization with narrative. Aaaaand... not yet.)
After reading a lot of papers, I'd say that the data indicate that many antidepressants are NOT harmful during pregnancy, and patients with depression are better advised to continue treatment. I believe the small risk is worth the benefits. Many doctors will say 'But we don't know what all the risks could be, so it's better not to risk at all, and any risk is too much for your little embryo.' I could not disagree more. We do know what the risks could be: that's why we do studies. Each woman should be able to decide for herself what risk, including small risks, are acceptable to her.
It is always possible, of course, that there are risks these studies have not picked up. The studies could be:
I have a personal interest: depression runs in my family, and SSRIs are my new best friend. But aside from that, I believe in the informative power of research and reject the 'what if... you can't prove a negative' attitude.
****
1. Spontaneous abortion: Risk may increase a little.
For reference, the spontaneous abortion (SA), or miscarriage, rate is reported as around 10% of all confirmed pregnancies. SA rates in these studies vary widely.
A study on 136 women who took bupropion in the first trimester reports that SA incidence increased to 14.7% vs. 4.5%. Tricyclics are reported to have no effect on SA in one study of 689 women; a meta-analysis (an overview of many unrelated studies) finds an overall SA increase to 12.3% from 10% for tricyclics.
The same meta-analysis reports SSRIs raise SA from 8.4% to 12.8%. The authors note that they cannot rule out depression as a contributing factor to SA.
Another single-cohort study cites SAs at 12% for venlafaxine vs. 7% basal, and 10.7% in other SSRIs. These groups are not significantly different from each other.
CONCLUSION: SSRIs, tricyclics, bupropion, and other antidepressants (ADs) may somewhat increase the rate of spontaneous abortion in early pregnancy. Basal SA rate is generally 10% of confirmed pregnancies, though sometimes reported lower among small cohorts. Antidepressant SA risk is apparently raised to 10-15%. This increase may or may not be significant (i.e., real), and is small.
2. Premature Birth: ADs either do or don't increase preterm birth.
There are at least two good, large studies on preterm birth and AD use. The first uses a Swedish birth database which includes 997 mothers who took ADs, out of >500,000 women total. In the general population, 5% of babies are born before 37 weeks; in all AD-medicated mothers it is 10%, and 10% in SSRI users. The second study follows 1,782 mothers who took SSRIs, 360 throughout pregnancy and >1000 with 1st trimester purchases. They find no increase at all in preterm birth and no decrease in birth rate.
CONCLUSION: There is not a lot of data on preterm births. These studies are both large population-based studies, but are not random except in the sense of including all of a registry. It is not possible to say whether preterm births are truly increased by AD usage in pregnancy. It may be slightly increased; one study shows a small effect.
Most doctors do not wish to prescribe any drugs for use in pregnancy; many doctors recommend that even Sudafed not be used- just in case!- even though there is an enormous amount of evidence that demonstrates no danger. For all my friends who wish to have adequate documentation with which to beat their doctors over the head, here you go.
This will be a series on Mondays and Thursdays.
For references relating to other drugs, more info, or PDFs, email me.
Series: Antidepressants, Pregnancy, Risks
- Introduction
- Spontaneous abortion
- Premature birth
- Congenital or teratogenic defects; that is, malformations in utero
- Cardiac defects
- Antenatal adaptation problems
- Muscle stiffness
- Breathing distress at birth
- Neurological withdrawal symptoms
- Breastfeeding risks
- Infant weight gain
- Long-term neurologic development
- Maternal risks of going without treatment
- Relapses
- Infant failure to thrive
- Parenting problems, attachment, child behavior
[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]
This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.
A list of generic and trade names is here.
****
Introduction
Despite the FDA's quite reasonable official stance that the risk/reward should be weighed individually, this attitude seems to be slow to catch on.
The FDA labels pregnancy drugs into five categories: A, B, C, D and X.
| Category | Description |
|---|---|
| A | Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities. |
B | Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. |
C | Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. or No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women. |
| D | Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. |
| X | Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant. |
The risks discussed arose through incident reporting, animal studies, cohort studies (comparing two more-or-less matched groups), long-term drug tracking by manufacturers (including pregnancy registries), and various medical studies. You will notice, if you read the individual papers, that there is a large amount of variability between studies; human populations are heterogeneous. The smaller or more biased (nonrandom) a sample, the more variation one will expect from study to study.
Relatively few drugs are Class A; even, say, sertraline, which is a relatively old and well-studied AD, is Class C. So is Sudafed. So is Benadryl. This is because it is difficult to demonstrate NO risk, and because many drugs have some small risk associated. A patient might think Class C is a terrible risk in pregnancy, or that there are no studies in humans, but actually there are a lot of studies in pregnant humans. Yet the FDA says there are "no adequate and well-controlled studies in pregnant women" in the drug labelling. In fact, the AAFP says that Benadryl and Sudafed are safe in pregnancy. Overall, the FDA system is confusing, inaccurate, and not very informative; the patient should look up each drug herself to get good information. (The FDA decided in 1997 to replace the A-X categorization with narrative. Aaaaand... not yet.)
After reading a lot of papers, I'd say that the data indicate that many antidepressants are NOT harmful during pregnancy, and patients with depression are better advised to continue treatment. I believe the small risk is worth the benefits. Many doctors will say 'But we don't know what all the risks could be, so it's better not to risk at all, and any risk is too much for your little embryo.' I could not disagree more. We do know what the risks could be: that's why we do studies. Each woman should be able to decide for herself what risk, including small risks, are acceptable to her.
It is always possible, of course, that there are risks these studies have not picked up. The studies could be:
- Deliberately biased, by influence from drug companies. I find this unlikely because different studies mainly get similar results.
- Looking for the wrong things. Many studies, however, look for all neurological symptoms or all congenital defects. Previous animal studies have given researchers some idea of what to look for; however, animal models are not perfect models for human disease.
- Using a biased sample. This is possible, although many studies look at thousands of patients. But are they representative of the population? Are affluent white women more likely to take SSRIs? Are there genetic factors in other ethnic groups? (The African-American ethnic group, for example, is known to have a polymorphism that can reduce cardiac drug efficacy.)
- Not picking up some rare conditions because the numbers are too low. This is possible as well; however, if it is the case, it may be either not above background (the naturally occurring level of X) in a reasonable number of patients, and/or it's so rare that it is probably not a major concern.
- Anything else I haven't thought of.
I have a personal interest: depression runs in my family, and SSRIs are my new best friend. But aside from that, I believe in the informative power of research and reject the 'what if... you can't prove a negative' attitude.
****
1. Spontaneous abortion: Risk may increase a little.
For reference, the spontaneous abortion (SA), or miscarriage, rate is reported as around 10% of all confirmed pregnancies. SA rates in these studies vary widely.
A study on 136 women who took bupropion in the first trimester reports that SA incidence increased to 14.7% vs. 4.5%. Tricyclics are reported to have no effect on SA in one study of 689 women; a meta-analysis (an overview of many unrelated studies) finds an overall SA increase to 12.3% from 10% for tricyclics.
The same meta-analysis reports SSRIs raise SA from 8.4% to 12.8%. The authors note that they cannot rule out depression as a contributing factor to SA.
Another single-cohort study cites SAs at 12% for venlafaxine vs. 7% basal, and 10.7% in other SSRIs. These groups are not significantly different from each other.
CONCLUSION: SSRIs, tricyclics, bupropion, and other antidepressants (ADs) may somewhat increase the rate of spontaneous abortion in early pregnancy. Basal SA rate is generally 10% of confirmed pregnancies, though sometimes reported lower among small cohorts. Antidepressant SA risk is apparently raised to 10-15%. This increase may or may not be significant (i.e., real), and is small.
2. Premature Birth: ADs either do or don't increase preterm birth.
There are at least two good, large studies on preterm birth and AD use. The first uses a Swedish birth database which includes 997 mothers who took ADs, out of >500,000 women total. In the general population, 5% of babies are born before 37 weeks; in all AD-medicated mothers it is 10%, and 10% in SSRI users. The second study follows 1,782 mothers who took SSRIs, 360 throughout pregnancy and >1000 with 1st trimester purchases. They find no increase at all in preterm birth and no decrease in birth rate.
CONCLUSION: There is not a lot of data on preterm births. These studies are both large population-based studies, but are not random except in the sense of including all of a registry. It is not possible to say whether preterm births are truly increased by AD usage in pregnancy. It may be slightly increased; one study shows a small effect.
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