Is there any evidence that folate supplementation lowers the risk of valproate caused neural tube defects? I think of this as common clinical knowledge, but does anyone know of a good study that looks at this?
Neural Tube-Depakote-Folate
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Most recent paper I have handy (not able to pubmed at moment) is AJP 2004 review Management of Bipolar Disorder in Pregnancy and the Postpartum Period . At least at that time , there had been no studies in use of folate as prophylaxis in expectant mothers on anticonvulsants. They simply cite the general thought and AAN recs.
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I was just discussing this with some neurologists today, and the consensus was that there's no conclusive human evidence (although there is some evidence in animal studies). The epileptologists at my institution generally think that the risk of neural tube defects is still high either way, and you need to consider that in your clinical decision-making. Even if you can show that the risk goes from 1% to 0.5%, that difference may be statistically significant, but I'm not sure if that's a big enough difference to make a distinction between treating and not treating.
I think it's a bigger concern in epilepsy because of the potentially catastrophic effects of switching seizure meds too quickly. In psych, we have more options - monitor closely, switch to an antipsychotic, switch to lithium, use a short-term benzo, etc. Also, remember that the neural tube closes pretty early in pregnancy (weeks 4-6, IIRC), so it's not a long period during which you have to find other ways to manage the illness.
I think it's a bigger concern in epilepsy because of the potentially catastrophic effects of switching seizure meds too quickly. In psych, we have more options - monitor closely, switch to an antipsychotic, switch to lithium, use a short-term benzo, etc. Also, remember that the neural tube closes pretty early in pregnancy (weeks 4-6, IIRC), so it's not a long period during which you have to find other ways to manage the illness.
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I think the reason it's a bigger concern in epilepsy is because the seizure, especially status epilepticus, can cause hypoxia to the fetus. So there is a physiological risk at stake with or without the medications. I have heard psychiatrists make the same argument - that the mother being off her meds and becoming manic is a risk to the fetus as well, which I would certainly agree with - but that risk is surely harder to define and quantify.
As far as the original question, how could such an experiment be done? Depakote is a last choice seizure medication in pregnancy, and an even worse choice for bipolar (as Shan explained above, there are many alternatives.) It seems like it would be unethical to conduct that kind of experiment.
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Yeah, but bipolar disorder is an episodic illness, and epilepsy is not. Even off meds, most patients won't develop a manic episode in any randomly-sampled period of a few weeks. Patients with epilepsy, on the other hand, will often develop seizures as soon as their meds get to a subtherapeutic level. And, as you say, the risk associated with mania is harder to quantify.
My point was that I'm comfortable leaving the neurologists to debate this point. Once they come to a conclusion about it, I'll follow their recommendations. Until then, I've got plenty of other tools for managing bipolar disorder in pregnancy.
It won't be done as a prospective randomized trial of course, but we could get useful data retrospectively. One way would be to compare the incidence of neural tube defects in patients treated with depakote who took folate vs. patients who didn't. The selection bias would be significant, because only a small subset of the population takes depakote + folate (we'd usually only recommend folate supplementation if the patient was planning to get pregnant, and if the patient was planning to get pregnant, we probably would have stopped the depakote... so we're looking at the small subset of people who would be at high risk of seizure without depakote)... but it'd be interesting to see the data.
