Background & General Information

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Most Women with epilepsy have normal pregnancies, but appear to be at risk for problems during pregnancy (e.g., seizures, change in medications, depression, c-sections) and adverse outcomes in their children (e.g., lower birth weight, thinking, or behavioral problems). The purpose of this observational study is to establish the risk and determine the factors which contribute to those risks.

Researchers want to know if epilepsy or the medicines that mothers-to-be must take to control seizures have a negative impact on the outcome of their pregnancy (e.g., OB complications, deptression, seizures, or effects on their child).

The study will enroll and follow 550 women.  350 mothers with epilepsy, 100 pregnant women without epilepsy, and 100 women with epilepsy who are not pregnant will be enrolled in the study at 19 clinical sites across the United States.  The latter two groups will serve as comparision groups to the women with epilepsy during pregnancy for the different outcomes. Researchers want to determine what impact different anti-epilepsy drugs, including the most commonly prescribed medicines: carbamazepine (Tegretol®, Carbatrol®), lamotrigine (Lamictal®), and levetiracetam (Keppra®), have on the mother’s epilepsy during pregnancy. In addition, they also want to determine the impact on the development of children exposed to these medications during pregnancy.

One of the key questions that this study is exploring is if the medicines the mothers-to-be must take to control seizures have a negative, lasting impact on their babies’ developing brains. "A really important aspect of this study is to find out if there is a difference between these drugs; are some of these drugs better for the child in the long-term than other drugs?" said Dr. Kimford J. Meador of Emory University, who is one of the two principal investigators of the MONEAD study. "If that's true, then we will want women to try to use the drugs which have reduced adverse effects. It would dramatically alter how we prescribe drugs. But right now we don't know enough for most anti-epilepsy medications."

adult holding infant's hand

It was not long ago when clinicians were unable to recommend one AED over another in regards to possible risk to the child.  One of the most important findings replicated across several pregnancy registries around the world is the elevated risk of birth defects associated with the anti-epilepsy medication, valproate (Depakote). Further, the NEAD study directed by Dr. Meador demonstrated that children exposed in utero to valproate were at increased risk of cognitive impairment. These findings were pivotal in the FDA adding a warning to valproate (FDA warning). Just recently, in fact, valproate was designated as a category X medication for use in pregnant women to treat migraines indicating that the risks associated with using valproate during pregnancy clearly outweigh any therapeutic benefit (FDA Warning-Migraine Treatment). The MONEAD study is an extension of the NEAD study and will address new anti-epilepsy drugs and new questions to improve pregnancy outcomes in women with epilepsy.

Photo acknowledgement - Simona Blalint
Mother, Father and Infant in park/picture by Simona Balint

“The information that we have gained from large pregnancy registries around the world has allowed us to make better medication choices to lower the risk of birth defects in the children born to our patients with epilepsy, but we still lack key information about how to manage the medicines once the woman becomes pregnant,” said Dr. Page B. Pennell of Harvard University, Brigham and Women’s Hospital, the other principal investigator of the MONEAD study. Epilepsy is a condition that can be very well controlled with modern medications, but it is imperative to appreciate the impact that findings of the MONEAD study will have to lower the risks imparted to developing fetuses in mothers with epilepsy.

"We do know that the vast majority of women with epilepsy have healthy children," Dr. Meador said. "We are talking about a relatively small increased risk, but we want to reduce that risk as much as possible. We want them to have the same lack of risk other children have."

Dr. Meador emphasized that most women with epilepsy can have healthy children and that they should continue taking their medication while pregnant. “However, it is not nearly enough to just continue the medications at the same doses without consideration of the changes that pregnancy causes drug metabolism, which can reduce blood levels of the drug and increase the risk for seizures. It would be a shame to expose the developing baby to both the medicine and increased seizures,” Dr. Pennell reported. “Previous studies have shown that adjustment of the dose of the medicine lamotrigine is necessary to prevent seizure worsening, but we lack this detailed information for many of our other medicines.”  The MONEAD study will not only measure the changes in drug levels, but what impact it has on the women’s seizure frequency and severity, and if those seizures have a negative impact on the developing child.

"In a woman who has significant seizures, the risk from the seizures themselves is worse than the risk of the drugs," Dr. Meador said. “Seizures during pregnancy could lead to injury or death in both the mother and the fetus.”  But the MONEAD study wants to objectively assess multiple anti-epilepsy drugs, which control seizures by reducing neuronal excitability in the mother, impact normal nerve growth and connections in her developing baby's brain. "During development, that excitability may be very important in terms of how nerves grow and connect," Dr. Meador said.

Also, development may be impacted by free radicals released by these drugs which bind to the body's basic building blocks including protein, DNA and RNA. "The body typically can repair some of this type of damage, but if it gets overloaded with damage it may not be able to and there may be long-term consequences," Dr. Meador said. "But it's also possible that the children rebound from these drug effects and it really doesn’t have any long-term effect."

It is known that these types of drugs pass through the placenta from the mother to the baby. Children of women with epilepsy have an approximately 4-6% risk of anatomical birth defects, compared to the 2-3 % overall risk of major congenital malformations in the general population. A separate nationwide study, the North American AED Pregnancy Registry, is trying to determine if the risk for anatomical birth defects differ across AEDs: http://www.aedpregnancyregistry.org/.

picture of DNA strand being affected by free radicals In contrast, the MONEAD study will determine if the risks of behavioral and cognitive problems differ across AEDs. Additionally, MONEAD will determine the amount of exposure to the child through measurement of the medicine concentration in the umbilical cord blood at birth and in the child’s blood stream after birth if they are breastfeeding. “A more detailed pharmacokinetic model of the amount of medication exposure in the MONEAD study will help us to determine how not only the type of medicine, but also the amount of the medicine, can potentially impact the child’s growth and neurodevelopment,” added Dr. Pennell.
Pre-pregnancy planning should include proper selection and dosing of the AED, as well as multivitamins and folate supplements. These efforts are thought to reduce the risk of anatomical birth defects. The MONEAD group wants to learn how to do reduce the risks for behavioral and cognitive problems.

picture of four stages of developing brainStudies have shown that animals exposed to even lower levels of these drugs in the womb have a decreased capacity to think and learn. "They don't learn things as fast, they don't respond as rapidly to cognitive tests. Our concern is that this also might be a problem for women with epilepsy and their children," Dr. Meador said.
So, the MONEAD study is looking for objective data, such as the child's IQ and predicted IQ based on the parents’ to determine any lasting impact these drugs have on the child's ability to think and learn. Researchers at 19 study sites in the U.S. are collecting data on mothers, maternal relatives, fathers, and babies in an effort to determine the impact of these medications.

Additionally, the MONEAD study will monitor women enrolled for symptoms of depression and anxiety during pregnancy and postpartum. Dr. Pennell reported, “In a prior small study in a single clinic, we saw a signal for possible increased risk for postpartum depression in women with epilepsy. Collecting this information in these larger groups of women from multiple sites will allow us to see if this finding is true. This would change the way we screen and treat our patients if there is an elevated risk for postpartum depression.”

picture of neurons Much of the data collected for the MONEAD study is the type normally accumulated during any pregnancy, but the MONEAD study is looking at other parameters as well, such as the mother's seizure frequency and blood levels of the medication. The MONEAD team is performing IQ tests on mothers, fathers and a maternal relative to get a predictive IQ for the baby.  Beginning at about age 2, children receive extensive neuropsychological testing to determine how they are developing compared to children that have never been exposed to AEDs. The study also will gather data on the children’s nutritional status and general health, noting milestones such as when children begin to walk and talk. Contributing risk factors, such as low socioeconomic status and poor diet, also are also considered.

Ultimately, the findings from the MONEAD study will allow women with epilepsy and the clinicians caring for them make better informed choices about the best anti-epilepsy drugs to use during pregnancy and how to adjust the doses to keep the mother’s seizures well-controlled and to minimize any negative effects on the mother and on the child’s growth and development. It is only through the generous participation of women in these different targeted groups that we can begin to provide better answers and ultimately improve the medical care of women with epilepsy during this critical time in their lives.