Newer antiseizure drugs safe for pregnancy, Stanford Medicine-led study shows

Two common antiseizure medications, lamotrigine and levetiracetam, are safe to use during pregnancy, according to a Stanford Medicine-led study.

The research, which was published online Nov. 25 in JAMA Neurology, is the first to evaluate the drugs’ long-term effects on children born to mothers who took one or both medications for epilepsy while pregnant. The findings confirm that these two drugs offer a safe alternative to older antiseizure medications such as valproate that are known to be harmful to fetuses.

The study’s main finding was that verbal ability at age 6 was normal in children whose mothers had used one or both of the drugs during pregnancy. The study also measured a variety of other cognitive and psychosocial outcomes in 6-year-olds and found no statistically significant differences.

“For these newer drugs, lamotrigine and levetiracetam, the outcomes look very good,” said the study’s lead author, Kimford Meador, MD, professor of neurology and neurological sciences. “We didn’t see any difference in outcomes between the children of women with epilepsy who took the newer medications and the children of healthy women, which is very encouraging.”

Women with epilepsy need care from neurologists and obstetricians who are skilled in managing the disease during pregnancy, Meador said, adding that with the right care, “Well over 90% of women with epilepsy will have normal pregnancies and normal children.”

Meador is also the clinical director of the Stanford Comprehensive Epilepsy Center.

A fraught history

Historically, people with epilepsy were strongly discouraged — if not legally banned — from having children.

“There were laws in the 1950s, in 18 U.S. states, to sterilize women and men with epilepsy,” Meador said. “It was part of the eugenics movement.”

As a medical student in the 1970s, Meador cared for an epilepsy patient who had received a hysterectomy, decades earlier, for this reason. When he watched the patient interact with her extended family during her hospitalization, the young Meador was struck by the sense of loss his patient had experienced.

“It was clear to me that she loved children,” Meador said. “She had poured out a lot of her life to her nieces and nephews and had been denied the opportunity to have children because of ignorance, basically.”

The challenges of medicating

It is important to prevent as many seizures as possible during pregnancy, as seizures can harm both the mother and the fetus. But keeping seizures under control comes with challenges. Studies by Meador and colleagues in the 1990s showed that a commonly used antiseizure medication called valproate was a poor choice during pregnancy because it confers significant risk to the children for conditions such as autism and lower IQ as well as impairment to other cognitive abilities. These findings led to government warning labels for valproate. In addition, research by others showed valproate increased congenital malformations. After the research was published, use of valproate in pregnancy declined.

Patients who switch antiseizure medications may experience more seizures during the transition to a new drug, so changing treatments during pregnancy is not ideal either. And even when women stay on the same drugs throughout pregnancy, their bodies are changing. Pregnancy speeds up metabolism, doubling the rate at which many of these drugs are cleared from the body and thus lowering the amount of drug present in the blood. To prevent seizures, physicians must closely monitor medication levels and increase the dose so that blood levels stay steady.

Tracking long-term outcomes

For the study, researchers enrolled women during their pregnancies, followed them and their children for several years, and examined multiple outcomes in mothers and their children. The newest data documents outcomes at age 6 from 298 children of women with epilepsy and a comparison group of 89 children of healthy women. The team previously published data on the same children at 2, 3 and 4.5 years of age.

The women in the study were pregnant between 2012 and 2016. Those with epilepsy were being treated at 20 epilepsy centers around the United States; they received care that they and their physicians chose and that followed standard practice for the disease. During their pregnancies, most women with epilepsy were taking either lamotrigine (43.6%) or levetiracetam (34.5%), or a combination of these medications; others were taking different antiseizure drugs. During the first trimester of pregnancy, most of the women in the study also took folate, a B vitamin that is known to reduce risk for certain birth defects among the general population.

The researchers monitored the mothers’ blood levels of antiseizure medications throughout pregnancy, especially during the third trimester, when the fetal brain is growing most rapidly. They wanted to see whether the child’s maximum exposure to antiseizure medication in the third trimester of pregnancy was linked to their verbal abilities later on.

The researchers were primarily concerned with verbal ability at age 6 because prior studies suggested that verbal skills could be affected by exposure to antiseizure drugs. They measured verbal ability via standardized tests.

The children also completed standard tests of other neurological and psychological abilities, including general intelligence, visuospatial ability, memory, executive function, motor skills, processing speed and behavior.

Verbal abilities preserved

The researchers found no difference in verbal abilities between children of women with and without epilepsy at age 6. This remained true after adjusting for multiple factors that can influence children’s verbal skill. The significant factors included the mother’s IQ, age and education level; whether the child was exposed in utero to acetaminophen (known by the brand name Tylenol); and the child’s sex, ethnicity and whether they were small for gestational age at birth.

Verbal ability was somewhat influenced by medication level in the mother’s blood in the third trimester, with nuances depending on which drug the mother had taken, the study found. 

“It looked like there was a positive effect [on verbal ability] of higher doses for lamotrigine, but this was due primarily to increases up to mid-range, and not the highest doses,” Meador said. “For levetiracetam, we saw a negative effect: At higher dosages, [verbal] performance went down. These findings should be taken with caution because the study did not randomly assign patients to seizure drugs, so the findings require replication,” he added.

The study also found links between prenatal exposure to acetaminophen and impaired neurodevelopmental outcomes. “This is a medication that used to be thought of as very safe during pregnancy,” Meador said, adding that other recent studies have also shown similar risks.

Folate early in pregnancy was found to be helpful. Women are typically told to take folate supplements in early pregnancy to prevent major structural birth defects such as spina bifida, but new findings, including from this study, are also showing that folate supplementation has other benefits for children of women with epilepsy. “We have found that folic acid supplementation improved both cognition and behavior at age 6,” Meador said.

Future directions

There are many epilepsy drugs on the market whose risks are unknown. It is critical that scientists continue uncovering how they influence the developing brain, Meador said. Finding a medication that controls a patient’s seizures can require trial and error, and lamotrigine and levetiracetam don’t work for everyone.

“The next choice is either to use a drug that we know has higher risk or to use a drug where we don’t know the risk,” Meador said. “And that’s a pretty bad situation. It is a clear health care disparity.”

He emphasized the need for further research to understand which underlying genetic signatures make patients more vulnerable to poor outcomes from antiseizure medications. “Drugs that cause birth defects work in a dose-dependent manner, so the higher the dose, the worse the severity, but they also work on a susceptible genotype, and we don’t understand yet what the genes are in humans that put you more at risk.”

The research was supported by grants (U01-NS038455 and U01-NS050659) from the National Institute of Neurological Disorders and Stroke.

Scientists also contributed to the research from Pediatric Neuropsychology International, Emory University School of Medicine, the Emmes Company, University of Minnesota, Brigham and Women’s Hospital, Harvard Medical School, Northwestern University, University of Southern California, Minnesota Epilepsy Group, University of Cincinnati, Wake Forest University, Northwell Health, Columbia University, New York University Comprehensive Epilepsy Center, University of Washington, Geisinger Medical Center, University of Pittsburgh, and the MONEAD Investigator Group.