Epigraph Vol. 24 Issue 4, Fall 2022
Research Recap: Medication effects on infant development
Infants exposed in utero to valproate or phenobarbital monotherapy, or to any polytherapy, had an increased risk of developmental delay, according to the results of a recent study. Dr. Bruna Nucera interviews Dr. Sanjeev Thomas about the results, as well as ongoing work from the Kerala Registry of Epilepsy in Pregnancy.
Listen below or download the episode.
A recent publication in Epileptic Disorders reported data from more than 1,300 infants whose mothers are enrolled in the Kerala Registry of Epilepsy in Pregnancy, a regional registry in southern India. Most mothers were taking anti-seizure medications during pregnancy, though about 100 of them were not. Their babies were evaluated for mental and motor development just after 1 year of age. Among other results, the study found that exposures to valproate monotherapy, to phenobarbital monotherapy, and to polytherapy were associated with a relatively high risk of developmental delay.
Dr. Bruna Nucera spoke with Dr. Sanjeev Thomas about the findings and implications of the study.
Dr. Nucera: Today we are talking about your recent article published in Epileptic Disorders. So let’s start with the interview and I ask you to introduce yourself.
Dr. Sanjeev: My name is Dr Sanjeev Thomas – I’m an epileptologist and a neurologist working in India. Most of my career I was working in Sree Chitra Thirunal Institute for Medical Sciences and Technology in Thiruvananthapuram. This is where we did this research in the past. Last year I have moved to another institution as the director of the Institute of Communicative and Cognitive Neurosciences (Trivandrum), where also we are looking at the developmental outcomes of children. So. Good to be in this podcast.
Dr. Nucera: Please provide some background on the topic of your research and explain why this study was done.
Dr. Sanjeev: There are about 50 million people with epilepsy across the world and a quarter of them are women in reproductive age groups. The main concern for women during the reproductive period is what will happen to their child if they continue to take antiepileptic medications or anti-seizure medications during pregnancy.
At the beginning of my career, I did not have a proper answer to this question, especially based on our own experience. So in 1998, we started the Kerala Registry of Epilepsy in Pregnancy to systematically look at the reproductive outcome of women with epilepsy and the long-term outcomes of children born to them.
In this registry we recruit women in the preconception period, that is when they are planning a pregnancy, or in the first trimester of pregnancy. And we follow up looking for any prenatal screening, for any malformations, and also looking at the control of seizures during pregnancy, and at the time of childbirth onwards we were looking at the babies.
At birth, a physical examination is carried out by the attending physician and at three months of age, all babies are examined in our registry for physical defects, and an echocardiogram and an abdominal ultrasound is done to look for any internal malformations which we might have missed. Then at one year, we look at developmental outcomes—motor and mental development of these babies. After that, as per our protocol, all babies are examined at 6 years of age and 12 years of age and 18 years of age. So this cohort is being followed for a very long period. The oldest children in our cohort are around 21, 22 years. This particular paper is looking at the developmental outcome at 1 year of age, or just after 1 year.
Dr. Nucera: Thank you. So how were the data collected for this study?
Dr. Sanjeev: As per our protocol, all children have to be brought to the clinic after one year. If somebody doesn’t turn up, we send mail to them, or contact them on the phone and ask them to come. They are examined by a developmental pediatrician. We have a very good developmental pediatric center on the same campus, so we are collaborating with them. And if you notice, half of the others in this publication are actually faculty from that site.
So the information they have is that the mother has epilepsy and might have been on some medications. We don’t give any information about whether they were on medicines or if so, what were the medicines they were taking. They have to do the developmental assessment, which is standardized in our place as developmental assessment of children, Indian infants, DASI, which is an adaptation of the Bailey scale of development. So they do the developmental assessment and then give the information back to us.
Dr. Nucera: What were the main findings of the study?
Dr. Sanjeev: We were basically looking at the effect of antiepileptic drugs, whether the anti-seizure medications had any adverse effects. In our series we adjusted for several confounders, like maternal age, birth weight of the baby, the type of epilepsy the mother had.
In our study we were actually having a small number of children who were not exposed to any anti-seizure medications during pregnancy, they were around 110. Then we had a larger group, around 800+, who were on monotherapy, and 400+ who were on polytherapy. The monotherapy was mostly the traditional anti-epileptic drugs, like carbamazepine, phenytoin, phenobarbitone and valproate, and the newer anti-epileptic drugs like oxcarbazepine, lamotrigine, and levetiracetam. For the polytherapy, essentially, we had half of them on valproate plus some other medicines, and another group on multiple drugs but not valproate.
Then we looked at their developmental outcome, motor and mental developmental outcome. The striking abnormalities there were actually a significant drop in the quotients, mental as well as motor development quotients, for those exposed to valproate monotherapy and any polytherapy. Within the polytherapy group, those who were exposed to valproate and other drugs had maximum impact. But those, polytherapy with other medicines also had a significant impact.
For the mental development, phenobarbitone-monotherapy-exposed children also had a significant impact.
For carbamazepine, phenytoin, actually they were intermediate, and they had slight impairment but not very significant.
Among the newer drugs, levetiracetam had a significantly better outcome. Their scores were actually slightly more than the unexposed group. At least we can say that the newer anti-epileptic drug exposure did not influence the mental and motor developmental outcome when examined at 1 year.
So we have three sets of outcomes: Significant impairment with phenobarbital and valproate as monotherapy, and any polytherapy, particularly valproate plus another medicine. And the least or the best outcomes were from the newer drugs like levetiracetam.
Dr. Nucera: Thank you, thank you so much. What are the implications of your research – clinical implications?
Dr. Sanjeev: Until maybe a decade ago, we were not very seriously considering the cognitive adverse effects of exposure to anti-seizure medications during pregnancy. Most of us were talking about malformation risk and how do we reduce it and those things. So we were focusing on therapy in the first trimester, so after first trimester, you know, you can manage with any drug, it doesn’t matter because organogenesis is over and it shouldn’t really cause any harm. However, with the significant effect on the cognitive outcome, the exposure during the entire pregnancy, particularly in the second and third trimesters, becomes more important. So it is not only the first trimester, all three trimester exposures are equally important. This is the first point.
Second is that we now have the capability to modify or intervene and improve the outcome if you plan pregnancy ahead, and also avoid offending medications like valproate, polytherapy, and phenobarbitone, and if possible, try to manage with the newer drugs like levetiracetam or lamotrigine, there is a good possibility that the children will have no adverse outcome as far as mental and motor development is concerned.
Dr. Nucera: Can you briefly discussed the study’s strengths and limitations?
Dr. Sanjeev: The strength of the study is that it is a very rigorous protocol, starting from preconception through the entire pregnancy and afterwards also. So exposure to medications like anti-seizure medications or other medications, we had a systematic prospective data from the pre-pregnancy period on. And the information was updated on a monthly basis during the entire pregnancy. What was the dose used, what were the seizure counts, and whether it was continuing or not. And after delivery, three more months, so altogether 12 months of anti-seizure medication was very rigorously being monitored.
The weakness of the study I would say is that we don’t have drug blood levels. It is strictly on the basis of the total dose that is consumed. In India we don’t have that facility on a larger scale, so it is not part of our protocol. Most of the pregnancy registries do not have blood levels as a part of their protocol.
We had a very good follow up of around 71% of children. The dropout was mostly because some of our children did not turn up for the evaluation at the right time. Some children did not cooperate – they were very restless and in a hospital environment they were not comfortable, and they couldn’t complete the testing.
Dr. Nucera: Are there next steps in this line of research?
Dr. Sanjeev: The first stage of our cognitive evaluation is at 1 year of age, and the second one is at 6 years of age, when the children are examined for IQ and their language outcome, as well as EEG. Then again, the same series is being repeated at 12 years and 18 years of age. We have published our data for these intervals also, where again we have shown that developmental outcomes like IQ and language outcomes are significantly impaired in children exposed to anti-seizure medications, particularly to valproate and polytherapy.
Now when we say there is an impairment, there are two questions. If you demonstrate a 5- or 6-point drop in a developmental outcome, does it matter? Does it influence their real-life performance?
We looked at the educational outcome of children who are grown now and found that – this is a paper we recently published – we had a group who had reached 18-plus. They are eligible for university studies. There were 99 children in our cohort who were in this older age group and 28% of them had joined university for one or the other courses. Whereas for our Kerala state, it is 37% who enroll in university. So that is a significantly lower percentage. Even in lower classes they had more absences, they were using more scribes to write their exams, the dropout rate was higher, so there definitely was a setback in their educational performance. So I think even when we say there is only a 5-point or 6-point drop, it translates into a significant educational obstacle or barrier. So this is a very important point.
Another thing is, when we say there is an impairment in their function, is it that there are environmental factors – neglect, social, economic factors that mean they aren’t able to do it? So we looked at the brain volume. We did some detailed quantitative analysis in a small group of children with impairment – that is, children with exposure to anti-seizure medications and impaired cognitive function, and found that they had lower gray matter volume, their cerebral cortex was thinner than others, and particularly this was in the peri opercular area where the language functions are.
So there is an anatomic structural correlate for this impairment. And this is lingering. What we saw at 1 year is persisting right up to 20 or 21 years of age. So it is not something reversible or something transient – this is a significant problem that persists for a long period of time. It’s a very serious matter.
Research mentioned in this episode
Other epilepsy pregnancy registries
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