Antiseizure medications are some of the most common teratogenic drugs given to women of child-bearing age. Kimford Meador, MD, FAAN, Stanford University, Stanford, CA, shares the 3-year neuropsychological outcome results of the MONEAD study (NCT01730170), examining the neurodevelopmental effects of fetal antiseizure medication exposure. The prospective multi-center study enrolled women with epilepsy and healthy women during pregnancy and followed the children to age 3. Most women with epilepsy were taking lamotrigine or levetiracetam during their pregnancy. The primary outcome of verbal abilities at age 3 did not differ between children of healthy women and children of women with epilepsy, and exposure-dependent antiseizure medication effects were not seen. Follow-up of the children is ongoing. This interview took place during the American Academy of Neurology (AAN) 2021 Annual Meeting.
Transcript (edited for clarity)
So this is a long-term NIH-funded multi-center study that began in 1999 with the NEAD study, and now we’re in the MONEAD study, which is a new cohort, an extension of the old study, but a new cohort of women. And the reason we’re doing the new cohort is that drug use has just changed for anti-seizure medications from 2000 to now. So the drugs that are being used now are somewhat different to some of the ones that were implicated as having a lot of risks for children, like valproate and phenobarbital not being used as much...
So this is a long-term NIH-funded multi-center study that began in 1999 with the NEAD study, and now we’re in the MONEAD study, which is a new cohort, an extension of the old study, but a new cohort of women. And the reason we’re doing the new cohort is that drug use has just changed for anti-seizure medications from 2000 to now. So the drugs that are being used now are somewhat different to some of the ones that were implicated as having a lot of risks for children, like valproate and phenobarbital not being used as much. Our intent was to look at what was happening now. And we enroll the women when they’re pregnant and then follow the children out ultimately to six years of age.
But this is our initial results from our three-year-old outcome, where our main outcome was the verbal abilities. And then we also looked at the measures similar to full-scale IQ. And on both of those, we did not find any differences between the children of women with epilepsy that were taking these medications versus children of healthy women. So this is a very good finding to reassure women with epilepsy. And we did not find a dose exposure effect, except from a secondary analysis which found a marginally significant finding for levetiracetam. But I wouldn’t put too much into that now. We need to follow the children further. We need other cohorts.
I think the major limitation of this study, even though it’s got a lot of strengths, prospective, and we’re following all these things during pregnancy and after the birth that are potential confounders of controlling for all those factors, the major limitation is that the cohort is predominantly made up of women that were taking either lamotrigine or levetiracetam or the two together. We have other drugs in there, but they’re the majority of the drugs that are used. And so it adds reassurance that those drugs are safe during pregnancy in regards to the children’s cognitive behavioral outcomes.
There are many of the drugs still we don’t know very much about. I would say we have over 30 any seizure medications, and of those is only a handful, five to eight, that we really understand well what their risks to good or bad are during pregnancy, and most of the others we don’t. So there’s a great need to continue to monitor these other drugs, both in human studies and animal models, to understand the behavioral effects.
It is a teratogenic effect, just like you get a malformation from the teratogenic effects of the drugs. So these are one of the most common types of teratogenic drugs that are given to women of childbearing age. And so it’s a rock and a hard place sometimes for the women. Most of the women cannot just come off the medication, because then they have convulsions and risks for that for their life and for the baby’s life, and for their lifestyle and disability and all those kind of things. So we need to be able to use drugs that control the seizures, because that’s a risk in and of itself, but also try to understand better what are your risks for children.
The other major thing I think is that we don’t understand the mechanisms completely, and teratogens work on a susceptible genetic substrate, and we don’t understand that right now. We have very few clues about what is this susceptible genetic substrate, other than the fact that if a woman takes a drug and they have a baby born and that baby has problems, the risk for the next baby, if she stays on the same drug, is pretty high, it’s elevated over the general population of women with epilepsy.
But again, the really good news so far is, at least for these drugs that we’re looking at here, it shows that women with epilepsy can have healthy, normal babies. And our other findings are, overall, that there were not major complications during the pregnancy. So there is some risk, but it’s pretty low in general. It’s no reason for a woman not to have a baby if she has epilepsy and is taking medication, she should feel that she can. But she needs to talk to her doctor well before the pregnancy, make sure she’s on a safe drug and planning ahead, doing things like taking folate. Periconceptional folate has been shown to help the outcomes in children of women who are taking anticonvulsant drugs.
The six-year-old results are more indicative of skill performance and ultimate cognitive abilities as an adult. We can also do more detailed testing at six years of age, because the children are more easily tested at six than at three. So we can look at other things like memory and attention and executive function, language, and spatial abilities. So we’ll be able to get a broader array of things. Also by six, some diagnoses for behavioral problems like autism may not be present at three, but then recognized by six. So most of those diagnoses would be there at six too. So we think six provides a very good age for outcome measures. It’s very predictive of long-term results in the children.
Grants: NIH/NINDS 2U01-NS038455-11A1. Meador (Multi-PI). “Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs.”*
NIH/NINDS R01NS088748-01. Drane (PI). “Dissecting the Cognitive Roles of Hippocampus & Other Temporal Lobe Structures.” Role: Co-I.
Medtronics. Halpern (PI). “Stereotactic Laser Ablation for Temporal Lobe Epilepsy (SLATE).” Role: Co-I.
Eisai Inc. Razavi (PI). “Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Perampanel as Monotherapy or First Adjunctive Therapy in Subjects With Partial Onset Seizures With or Without Secondarily Generalized Seizures or With Primary Generalized Tonic-Clonic Seizures.” Role: Co-I.
Sunovion Pharma. Meador (PI). “Cognitive and Behavioral Effects of Eslicarbazepine Acetate and Carbamazepine in Healthy Adults.” Consultant (no personal income): Epilepsy Consortium (funds paid to my university)* for Eisai, GW Pharmaceuticals, Medtronics, NeuroPace, Novartis, Supernus, Upsher Smith Labs, UCB Pharma, and Vivus Pharm. Other: Clinical income: EEG procedures and patient care*
*Items with asterisk involve income > $10,000 for recent years.