Folic acid supplementation in women with epilepsy

Folic acid supplementation is recommended for all women with epilepsy who may become pregnant. However, there is no agreed-upon dose for women with epilepsy taking antiseizure medication, and there may be risks of high-dose (>1 mg/day) folic acid supplementation. Dr. Bruna Nucera spoke with Dr. Marte Helene Bjørk about the risks and benefits of folic acid supplementation and what this means for pregnant women with epilepsy.

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Transcript

 [00:00:00] Dr. Bruna Nucera: So today, we will talk about folic acid supplementation in women with epilepsy during pregnancy. We know that folic acid is recommended for all women with epilepsy who intend to become pregnant. Folic acid is a necessary coenzyme for the development of white and red blood cells and several central nervous system functions.

However, there is no agreement for an optimal pre conceptual dose for women with epilepsy taking antiseizure medication, and no precise indication. My name is Bruna Nucera. I'm an adult epileptologist from Italy, and with me we have Professor Bjørk. Please introduce yourself.

[00:00:46] Dr. Marte Bjørk: Hello, I'm Marte Helene Bjørk.

I am a consultant neurologist from Haukeland University Hospital, which is in Bergen in Norway. I'm a professor at the University of Bergen, where I chair the Bergen Epilepsy Research Group, an interdisciplinary research group specifically interested in finding the safest and the best treatment for individuals in childbearing age that have epilepsy.

[00:01:16] Dr. Bruna Nucera: Thank you, Professor Bjørk for accepting my invitation for this podcast. My first question is, could you discuss the range of folic acid recommendation for women with epilepsy provided by various global organizations? 

[00:01:30] Dr. Marte Bjørk: Yeah, thank you. That's a really good question because there are so many different recommendations, but I think that the most important one is that one that we have from the World Health Organization recommending every woman that intend to be pregnant to take at least a 0.4 milligrams of folic acid before she gets pregnant in the pre conceptional period and also throughout the first trimester, the first 12 to 13 weeks of pregnancy. And also the WHO, they have another recommendation stating that individuals that are in childbearing age and that could get pregnant should have a folate level that is sufficiently high, around 27 micro mole of folate, or if you use red blood cell folate, 907, which is more like an individual approach to make sure that the folate level is sufficient to avoid neural tube defects. 

Regarding epilepsy, there are a lot of recommendations, but the most recent one is from the American Academy of Neurology, which say that Individuals that will try to get pregnant they need to use at least 0.4 milligram, but they don't state exactly what dose, just at least 0.4. The International League Against Epilepsy, they don't have an official guideline, but they have issued a recommendation paper stating that they recommend women that are using antiseizure medications to use at least 0. 4 milligram even if they're not currently planning pregnancy, because we know that unplanned pregnancies are extremely common. Half of the pregnancy around the world is unplanned. Even more in individuals with epilepsy. And the problem is that when you realize that you are pregnant, it's too late to probably have a benefit from folic acid supplements. And folate deficiencies are very common, probably even more common in people that are taking antiseizure medications. 

Apart from that, there's various national recommendations ranging from 0. 4 to 5 milligrams. And there was a survey of the different ILAE chapters, I think it was published in 2020, where most at that time tended to use around 4 milligrams, in the different chapters. That seems to have changed slightly the last couple of years, moving to lower doses. 

[00:04:11] Dr. Bruna Nucera: But why is there no agreement about the optimal dosage for folic acid?

[00:04:18] Dr. Marte Bjørk: The problem is that there are no randomized controlled trials. The reason why we started using high doses in the first place was that there was a study that included women that had an increased risk of neural tube defects, usually because they had a previous pregnancy with a neural tube defect. And they were given in a randomized manner 4 milligrams or a lower dose, 0. 4 milligrams, or multivitamin, and there were a benefit with the higher doses, but that wasn't specifically done in women with epilepsy.

But because they are also a high-risk pregnancy, we sort of adapted that dose without very good documentation that it would benefit people that are pregnant using antiseizure medications. But we do know that antiseizure medication is associated with lower folate levels. And we also know that a lot of the adverse outcomes associated with using antiseizure medications, they overlap with [outcomes associated with] folate deficiencies. Such as spontaneous abortions, neural tube defects, some pregnancy complications, and some neurodevelopmental disorders that are more frequent in folate deficiency and also after taking antiseizure medications. So that's the rationale for using, for recommending higher doses, but we don't really have documentation that higher doses is better than a medium dose or a low dose of 0.4 milligram. 

I mean, when I'm talking about higher doses I'm talking about doses of 1 milligram or higher. There's no high-level evidence that can tell us that that's beneficial. So that is the problem. Also, it's very hard to interpret the data that we have because there's various observational studies and some show a benefit and some show actually an adverse effect of folate. And the problem is accounting for all the various confounders that are associated with folic acid supplements, which makes it very hard to interpret. For example, using folic acid supplements is associated with having a planned pregnancy. In women with epilepsy, it can also be associated with using more anti-seizure medications with a higher risk profile. And so if you have a an individual using valproate in a high dose and it's a planned pregnancy, and even if it's not a planned pregnancy, when she comes to you and she's already pregnant, we tend to at least like to recommend having a higher dose of folic acid because it's sort of the only thing that we can do.

So it's a lot of confounders that's hard to account for. 

[00:07:02] Dr. Bruna Nucera: You conducted a study regarding cancer risk in children of mothers with epilepsy and high-dose folic acid use during pregnancy, published in JAMA Neurology in November 2022, in which you found that prenatal exposure to high-dose folic acid was associated with an increased risk of cancer in children of mothers with epilepsy. Could you please briefly discuss the main findings, strengths and limitations of the study and overall the clinical implication of these results? 

[00:07:34] Dr. Marte Bjørk: Yeah, thank you. Well actually we have done two studies in cancer and high-dose folic acid, one in children and one in the mothers.

And the reason for that is that in previous research outside of epilepsy, there's been a concern that since folic acid, folate, is necessary for cell division and cell growth, then having then it potentially could be associated with cancer development because cancers need folate to develop, to divide cells and develop. So, in other fields, there's been a concern with using high dose folic acid. So that's why we did the study. 

What we did was to get the registry data from all births in the Nordic countries, which is Norway, Sweden, and Denmark, Finland, and Iceland.

And we were able to get data for folic acid for three Scandinavian countries. And around 20,000 women had pregnancies and had epilepsy. And of those, around 6, 000 used high dose folic acid [>1 mg daily]. And we had, I think, around 18 children that had a cancer, a childhood cancer. But that was higher than what was expected within women with epilepsy, and also within women with epilepsy using anti-seizure medications.  The hazard ratio was between two and three higher if the women used anti-seizure medications. However, we could not find such a risk for women using high-dose folic acid and did not have epilepsy or antiseizure medication use. 

 This study was published in JAMA Neurology in 2022, and we did another study was published in Epilepsia last year, where we looked at cancer in women that had been using folic acid at least in one pregnancy, and we assessed the risk of cancer using folic acid supplements as a time-varying covariate. We found also in that population, a slight increased risk of maternal cancer, which was, after doing a lot of sensitivity analysis and adjustments, mostly associated with non-Hodgkin lymphoma. 

I must state that there's only been these publications on cancer in women with epilepsy and they need to be replicated. And I will especially underline the fact that we have, even in a population that was more than 3 million births, we had only 18 children that had been exposed for maternal epilepsy and high-dose folic acid and got cancer. So the number is really small. The absolute risk is very small, even though the relative risk is increased, and the same goes for the women. There was a really large population and the absolute risk of cancer is very low.

[00:10:37] Dr. Bruna Nucera: Thank you. Can you talk about the dangers of over interpreting an association, in this case, between rates of childhood cancer, maternal folic acid use among women with epilepsy taking antiseizure medication? 

[00:10:52] Dr. Marte Bjørk: It's a very important question, and it's especially important in these large observational studies.

And I think that there's many things to take into account, especially that using folic acid is a marker for also using antiseizure medications. The reason why you are using high-dose folic acid is most likely the antiseizure medications and not that you are, for example, folate deficient.

And using antiseizure medications, of course, is associated with the underlying morbidity that caused the epilepsy and also with socioeconomic parameters and a different lifestyle because you are chronically sick. 

Since we had this large cohort and we knew that publishing these results would question the use of folic acid supplements, which also could have beneficial effects, we did do a whole year of extra analysis to make sure that we accounted for a lot of potential confounders. Most importantly, we did sensitivity analysis within women that were using antiseizure medications, comparing those with antiseizure medications and without folic acid and with repeated prescriptions of antiseizure medications with those that had folic acid and antiseizure medications. And that increased the hazard ratio, showing that the more certain we are that the women have epilepsy and are using antiseizure medications, the stronger the hazard ratio. 

We also did sensitivity analyses removing women that had preexisting cancers. Because of course, if you have some sort of heritable cancer and that's why you have epilepsy, there are some conditions for that to happen, then maybe the child could inherit it. We didn't see any effect of doing that. And we also adjusted for a range of confounders that are associated with both having epilepsy, having antiseizure medications, and using folic acid. So we were not able to adjust away or find another underlying effect or an underlying factor that could drive these associations.

But then again, it's only 18 children and there could be sort of random noise or unmeasured confounding that we were not able to account for using this registry data, which is limited with their ability… they are proxies, right? Because we use prescriptions that have been filled by the mothers and we use diagnosis that has been put in by the hospitals and they're not been clinically assessed like in a smaller clinical study. Then again, there's no possibility of doing a very thorough clinical study with 3 million people. 

[00:13:45] Dr. Bruna Nucera: And from other human and animal studies that you know, what are the benefits and the risks of an high dose of folate? 

[00:13:54] Dr. Marte Bjørk: I think a very common risk which is necessary to be aware of is that if you give a high-dose folic acid supplement, you need to also measure the level of B12, because if you have a B12 deficiency and you give high-dose folic acid, that could give adverse effects. So you need to measure that and then consider supplementing both vitamins.

There are also other important B vitamins that are connected in the metabolism of folic acid. Homocysteine is a good marker of deficiencies of of other B vitamins.

There are observational studies that have shown a benefit of folic acid also for malformations in children of mothers with epilepsy. But most have not found an association and reduced risks of malformations, and it's been investigated in many observational studies. The problem in many of these is that we don't really know exactly when the folic acid was taken: the date the person took the folate, the date they started taking supplements are often not available, and that's the main limitations of most of this research, because folic acid is not like another drug, it's a vitamin. 

So when you take the supplement, first you need to start taking the supplement and then the supplement has to be absorbed by the body and metabolized into active folate. And then the folate storages has to be sort of building. And then that takes time. From the time the woman starts taking the supplements till she has a good folate status, that takes a while. Even if you started taking folate maybe three weeks into the pregnancy, it will be several weeks before the folate is high, if it's a low-dose supplement.

And then when you stop taking it, the half-life is around 100 days, which also makes it hard to understand what was actually the exposure. So, that's some of the challenges that we face in this line of research. 

Regarding the benefits, the most documented benefit is for neuropsychological outcomes in children that has been exposed to antiseizure medications, where we have found in the Norwegian Mother and Child Cohort Study and also In the NEAD and MONEAD study, they have seen signals that folic acid supplements can improve neuropsychological outcomes, are associated with better neuropsychological outcomes, in children that has been exposed to antiseizure medications. It’s seen recently, actually, in the last publication from the MONEAD study. There's also been other studies that have not found an association of improved neuropsychological status, and even studies that have shown, especially in the general population, that using very high levels of folate is associated with worse neuropsychological outcomes.

It's of course possible that there are limitations with this research, for example, that you haven't good data on when the woman started taking supplements and the dose of those supplements.

[00:17:08] Dr. Bruna Nucera: And how to communicate the risk and the benefits of folic acid supplementation to a woman with epilepsy who is planning a pregnancy? 

[00:17:18] Dr. Marte Bjørk: That was much easier before when we could just sort of say that folic acid is probably good for you, so just take a lot of it. Now I think it's harder. I try to be as honest as possible and just try to explain that we think that it could help. It's especially important to not be folate deficient, but also explain that there are some data, though, with very low actual risk, that have shown that it could be harmful with very high doses.

What we do in my clinic is to measure the folate in the women to try and individualize the dose, which I think makes sense to them because then I can explain that we make sure that you don't take more than you actually need. So we think that we can steer clear of any complications.

Of course, that's not been formally tested, but since there are so many individual factors that can determine one's folate status, then it makes sense to individualize the dose based on the actual measurements of folate. And what I see is that there are great variations on how much folic acid you need to take to increase the folate levels. And that you seem to depend both on inherent factors and also on the on diet and on the dose and type of antiseizure medications. I try to give them as much as they need, but not more. 

[00:18:46] Dr. Bruna Nucera: Okay, and what may be future lines of research that can help us finally find an answer on the dosage of folic acid supplementation to recommend to our patients?

[00:19:00] Dr. Marte Bjørk: Well, I think that the dream is to have a randomized control study measuring high dose versus low dose. That's ethically maybe questionable, but maybe not because we already have very different doses in different countries, but I think that within a country that has a certain recommendation, it's hard to do a randomized controlled study. So then we are again left with observational studies and I think that it should be tested whether individualizing the dose as a strategy is associated with the same possible benefits and no increased risks. 

I think that at least any folic acid research needs to take into account that you need detailed information on when the woman started taking folic acid and on her individual risk factors for low folate and the dose. Sort of pooling everyone that has taken folic acid supplements sometime in pregnancy or even within the first trimester, it's very hard to have a concrete answer to whether that's beneficial or not. That is more likely to confuse matters. I think that at least in observational studies, these details need to be adequately recorded. 

[00:20:14] Dr. Bruna Nucera: Thank you again for your time and for accepting my invitation. Is there something else that you would like to tell our listeners or young epileptologists like me?

[00:20:26] Dr. Marte Bjørk: Thank you for the opportunity to talk about folic acid and for the invitation, which is really nice. And I also thank my research group and the SCAN-AED consortium for contributing and collaborating all of these years with this data. And I sincerely hope that there are other people like you, you or other young epileptologists that want to sort of take up this line of research and try and find us the right answer. That would be really nice. So that's my final words.