Expert: William J. Walker, Pharm.D. - 1/29/2004

Question
Hi,
 I am a 24 yr old woman who was diagnosed with Bipolar Affective Disorder and Panic Disorder/Agoraphobia appx 6 years ago. I also have two protruding disks that are pinching a nerve causing extreme pain and muscle spasms. I recently found out that I am pregnant (appx 3 to 5 weeks). I spoke with my GP who is managing my meds about what I should do but I would like as much advice as possible (my first OBGYN appt is not until Feb 10).

I was taking Lith Carb 300mg BID, Lexapro (not sure of the generic name) 20mg a day, Diazapam 5mg TID and Hydrocodone 7.5mg TID. My dr told me to DC the Lithium but to continue the others.

I am a grad student in psychology and have a great interest in studing/researching medicine esp. psychopharmaceuticals. However, I have yet to find any informative studies on the net and haven't had the chance to go to the library to look at journal articles.

I was hoping that you could give me any advice or info on these meds and their effects on the neonate or any kind of reference materials. Any help would be greatly appreciated. Thanks so much, Jessica S.

Answer
The advice given to you by your physician is actually in accord with what I would tell you as a conclusion to a rather lengthy and involved discussion.    It is also in agreement with the general consensus among psychopharmacologists the world over.    This particular topic has been discussed at length in recent months in an international web based association of practitioners that share ideas and opinions.    I happen to belong to this group of thousands and I can tell you that this advice is well backed by literature references as well as direct experience.    I tell you this up front mainly to set your mind at ease regarding what you were told.

As far as the subject of pregnancy in general with respect to the fetal effects of maternally ingested drugs you should realize that there are so few well documented studies in this area because quite frankly it would be highly unethical to allow such scientific methods in human subjects.   Therefore much of what we do know either comes from anecdotal reports of cases which lack any sort of proper scientific design and therefore uncertain causality statistics.   Or they come from small sample size studies on animal populations which at best can be misleading.   So most of the accepted standards of practice come from some basic fundamental principles and a bit of common sense.   For instance,  we know of some agents the inherent toxicity profiles and perhaps some pharmacological properties that we can quite judiciously draw inferences from and confidently predict certain outcomes based on extrapolation.    In other cases we have seen direct outcomes in a sufficient number that allow for causal linking and therefore utilize experience and observation to fill the void left by inadequate study design.    In other cases still we have enough knowledge about the nature of a compound and it's mechanism of action to deduce that fetal exposure would be catastrophic.

Fetal development has also provided us with some great guidelines in general.    For instance we have learned over the past century of exponential increase in pharmaceutical chemistry that it is mostly within the first trimester that drugs pose the greatest threats.    Because it is during this time that the fetus is developing the organ systems and tissues are differentiating.    The fetus changes the most during this time.   Starting out as a gamete and rapidly maturing into a recognizable life form from a mere grouping of cells.    During times of incredible cellular division and differentiation is also when those cells are most susceptible to even subtle effects of exogenous substances.   As opposed to later trimesters where the fetus really changes very little.   At these later dates the fetus is primarily growing ever larger.   More or less the greatest risks are early on.    Even to the degree that the most dangerous period of all happens to be the time before which many have not even discovered that they are pregnant yet.    Still some drugs can create problems at later stages especially when those effects are related to the drug's behavior within well developed fetal organs.   Or if they happen to impact negatively the healthy growth of the fetus which could cause the fetus to face risk upon birthing.

The holistic focus of alternative medicine and the embracing of natural methods of child birthing has also given us a renewed respect for this fetal development.   To the degree that some maintain a more extreme position of recommending total avoidance of pharmaceuticals whenever possible during pregnancy.   I might add that this kind of thinking can become very popular when the child in question is your own.    For it is true on some levels that no circulating exogenous chemical can be 100% safe to the fetus.    It can safely be said that this is quite true.   The challenge here is in defining what amount of said danger is actually significant enough to be noticeable.    

And we cannot exclude the other side of this balance.   In other words in every case of considering a drug for use during pregnancy there are two distinct factors at play.   Risk and benefit.    Clinically the task at hand is to quantify both singularly and then stratify those results against each other.   In the end we must make some very difficult choices as we balance out the relative risks from the relative benefits.   And in only a precious few cases do we actually begin with a completely unacceptable risk level no matter what the benefit.   Most of the time what we are considering is far more complicated in that the risks are relative and maybe even unlikely.   And the benefits are typically significant because if they were not then we would not even be considering the decision at all.   So the task then is determining whether or not the loss of benefit itself would present a far greater risk overall than would ever occur as a result.

Having said all of that I can now tell you that there is really ample evidence to suggest that there are tremendous risks to the fetus in cases of untreated bipolar disease.   Depression alone can lead to fetal demise.    Clinical standards of care are such that these forms of mental illness are best when maternal treatments are maintained during pregnancy.   The same can be said of frank pain syndromes but to a lesser degree of evidence.    The key to proper treatment is not a question whether or not to treat but rather what to rely on as effective treatment.    We do have many choices at hand so we are not limited.    

Now for some specifics.    Lithium is the most effective agent there is for treating mania and bipolar disease.   However it is very harsh on renal tissue and thyroid tissue.    In fetal development these two organs,  the kidneys and the thyroid,   are at risk with lithium.  In the first trimester it should absolutely be avoided.   I even recommend that this agent be avoided entirely throughout pregnancy and during lactation as well.    In my opinion this agent should not be employed in fertile females of child bearing age anyway.    

SSRI agents,   such as escitalopram (Lexapro),   are actually rather safe.    They can be maintained during pregnancy just fine.   Although not completely void of some impact on the fetus we have not seen definitive problems.   The problem that we do see though is that bipolar disease that is treated with SSRI agents alone is at risk of developing into a raging mania.    Not good.  For you or the fetus.    Most clinicians would agree that in bipolars you either avoid SSRI altogether or at least combine them with a mood stabilizer.   Since you suffer from panic disorder along with bipolar the SSRI makes sense.   But you really should replace the lithium with another safer mood stabilizer.   That becomes tricky.    Mainly because those that are the best in efficacy,  such as divalproex (Depakote),   are also not recommended during pregnancy.   And those that are actually on the safe side,   such as gabapentin (Neurontin),   are really not very effective at all.

Finally,   narcotic analgesics are considered to be quite safe to the fetus as far as teratogencicity is concerned.    Hydrocodone is no exception.    But there are several other reasons why I think that this drug needs to go.   First is the fact that a regular and sustained maternal use of narcotic analgesics will cause the fetus to become narcotic dependent.    The child will grow and develop in the womb with a constant narcotic presence.   This can result in a most nasty cold turkey withdrawal experience at birth.    A most hellacious way to enter the world.    Second is the fact that hydrocodone as a narcotic agent combines with acetaminophen.    While acetaminophen itself is not directly harmful to the fetus it is a potential detriment to hepatic cells.    What we cannot state for sure is how deleterious acetaminophen can be to the developing fetal liver when it is present in a constant fashion.    As far as pain management is concerned alone I am not fond of using this two agent product but that is even more pronounced as a concern additionally for the fetus.    And last is the fact that hydrocodone is an extremely short acting narcotic that rapidly metabolizes down to hydromorphone (Dilaudid) in the liver and this is another very potent and very short acting narcotic.   The point being that hydrocodone is one of the worst possible choices for a rational long term pain management regimen for the simple fact that it does not last for the entire duration between doses and the potency coupled with rapid rise in blood levels creates for an extremely harsh dependency syndrome.    In the patient yes but also happens to the fetus.    Now mind you I am not saying that you need to suffer pain.   But if you require chronic narcotic analgesic therapy then my recommendation is to employ a rational regimen.   Using a regularly scheduled long acting narcotic that is not combined with acetaminophen.   Perhaps morphine as MS Contin,   oxycodone as OxyContin,  or even fentanyl as Duragesic patches.    There is another option utilizing methadone as an analgesic because it is longer acting.   The point being that such rational therapeutics will decrease the potential for narcotic craving and drug seeking behaviors and result in a lower potential for fetal withdrawals at birth.

I have a similar overall feeling about the diazepam.    In the event that your panic disorder is so debilitating that it requires long term therapy on a benzodiazepine agent like diazepam then perhaps this choice is better than lorazepam or certainly alprazolam.    But the same problems are at hand here.   These drugs cause severely harsh dependency syndromes and withdrawal is most excruciating.   Some of the worst there is.    Fetal exposures that are sustained will again result in a dependent fetus and abrupt withdrawal at birth.    Even more insidious is the frightening notion that it might be possible for benzos to produce a syndrome similar to FAS (fetal alcohol syndrome) which is a form of mental retardation in infants born to chronic alcohol drinking mothers.     There are no dramatically conclusive reports as such as there is with ethanol but on the other hand we have much data to support the notion that benzos behave quite similarly to ethanol.   I would simply recommend that this agent be ever so slowly tapered down and then stopped.    Replace it with another option for the next year or so.