Article In Brief
In an observational study, breastfeeding appeared to be safe for infants of mothers with epilepsy who took antiepileptic drugs. The babies appeared to have minimal exposure to the drugs and normal neurodevelopmental outcomes.
A new large-scale, prospective cohort study provides supporting evidence to encourage breastfeeding by mothers who receive antiepileptic drug (AED) therapy.
AED concentrations in the infants' blood samples were significantly lower than the levels in maternal blood, as reported by the results of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study published online December 30, 2019 in JAMA Neurology.
Although it is known that a significant part of AED exposure occurs during pregnancy, the study authors noted that for most of these medications, the amount of exposure in infants via breastfeeding was unclear. Prior studies found no adverse neurodevelopmental effects in infants who were breastfed while their mothers were taking AEDs, according to the children's IQ scores at age 3. But until the MONEAD study, there had been limited data on exposure through breast milk.
“In general, breastfeeding by women who are on antiepileptic drugs has often been discouraged because of the lack of information, which can lead to overamplified fear by physicians and families,” the senior study author Page B. Pennell, MD, FAES, vice chair of academic affairs in neurology at Harvard Medical School, told Neurology Today.
Whether AEDs could pose harm to infants is “a reasonable question” for researchers, physicians, and patients to ask because “breastfeeding is a choice.” More data on safety would be comforting in making that choice, said Dr. Pennell, who is also director of research for the division of epilepsy at Brigham and Women's Hospital.
The study authors indicated that “the American Academy of Pediatrics recommends breastfeeding as the sole nutrition for the first six months of life, given the multiple benefits to both the child and mother. Benefits for children who are breastfed include a reduced risk of severe lower respiratory tract infections, atopic dermatitis, asthma, acute otitis media, nonspecific gastroenteritis, obesity, type 1 and 2 diabetes, childhood leukemia, sudden child death syndrome, and necrotizing enterocolitis, as well as possible positive cognitive effects.”
Study Design, Findings
In the study, researchers measured drug concentrations to estimate overall medication exposure and account for pharmacokinetic processes—drug absorption, distribution, metabolism, and elimination, said Angela K. Birnbaum, PhD, FAES, the study's corresponding author and professor and director of graduate studies in experimental and clinical pharmacology at the University of Minnesota's College of Pharmacy.
“The reliability of the drug concentrations was verified through the use of validated drug assays, quality control samples, and rerunning of patient samples on subsequent runs,” Dr. Birnbaum told Neurology Today.
The observational investigation enrolled a total of 351 pregnant women (from 865 screened and 503 eligible individuals) across 20 US sites, along with their 345 infants. Enrollment was restricted to women with epilepsy who were 14 to 45 years old, had pregnancies of less than 20 weeks' gestation, and whose IQ scores measured more than 70 points.
Breastfeeding occurred in 222 (64.3 percent) of the 345 infants. Researchers followed the mothers through pregnancy and for nine postpartum months. Their infants were enrolled in the study at birth.
Data collection for this analysis spanned from December 2012 to October 2016, and it resulted in 164 matching infant-mother concentration pairs from 138 infants. Neurodevelopmental follow-up is being conducted in children until 6 years of age.
During the same visit, five to 20 weeks after birth, infants and mothers underwent blood sample collection. Researchers quantified the percentage of infant-to-mother concentration of AEDs.
When concentrations in infants were less than the lower measurable limit, researchers used the value corresponding to half of the lower limit in calculations. They also recorded the total duration of all daily breastfeeding times or the volume of pumped breast milk consumed from a bottle, or both.
Researchers measured participants' levels of carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and/or zonisamide. About 49 percent of all seven AED concentrations in nursing infants were below the lower limit of quantification. The median percentage of infant-to-mother concentration ranged from 0.3 percent to 44.2 percent.
As in clinical practice, lamotrigine and levetiracetam were the most commonly used AEDs in the study. In multiple linear regression models, maternal concentration was substantially linked to lamotrigine concentration in infants (p<.001).
“However, the maternal levetiracetam concentration was not associated with levetiracetam concentration in infants, possibly influenced by the many infant samples that were below the measurable limit,” Dr. Pennell told Neurology Today.
Researchers did not perform this analysis for the other AEDs, citing too few concentrations in infants that were greater than the lower limit of quantification.
The study was supported by the National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Human Development.
“The authors should be commended for this ambitious undertaking to provide detailed, objective, quantitative, and direct data on the impact of antiepilepsy drugs on breastfeeding of infants,” said Esther Bui, MD, FRCPC, a neurologist with the epilepsy program at the Krembil Brain Institute and assistant professor of neurology and a specialist in epilepsy and electroencephalography at the University of Toronto.
“The time during pregnancy and postpartum stages for many women with epilepsy is filled with anxiety, vulnerability, and uncertainty,” probably even more than for other expectant and new mothers, Dr. Bui added. “This study provides another important beacon of light to guide women and their physicians in making informed decisions in the best interest of their child that best reflects their values.”
Dr. Bui said the study had a number of strengths, including an impressively large enrollment and their evaluation of the most commonly prescribed AEDs in women of childbearing age. She pointed out that the analysis provided direct and quantitative values of drug levels in infants as well as moms within minutes or hours of one another.
The study's weaknesses stem partly from its observational design. However, conducting “a randomized, controlled study would be exceedingly difficult and unethical in this population,” said Dr. Bui, who is also director of the epilepsy fellowship and director of the women's neurology fellowship at Toronto Western Hospital.
In addition, as the authors acknowledged, only two drugs (lamotrigine and levetiracetam) had sufficient numbers of trial participants to perform statistical analysis. The other drugs (carbamazepine, oxcarbazepine, topiramate, valproic acid, and zonisamide) were taken by much smaller segments of participants. Furthermore, because only a single blood sample was drawn to avoid excessive discomfort to the infants, longitudinal values were not available to assess total antiepileptic drug exposure, Dr. Bui said.
Even so, “women can be more reassured that there is objective evidence to support breastfeeding” while taking antiepileptic drugs, she said. Breastfeeding was associated with only a small fraction of anti-epileptic drug levels in infants when compared to the mothers' serum levels. Depending on the drug, in the MONEAD study, this figure ranged from 0.3 percent to 44 percent, Dr. Bui noted.
“The findings reaffirm observational data that there are no clear adverse neurodevelopmental health outcomes in children breastfed by mothers taking antiepileptic drugs, and possibly positive neurocognitive outcomes,” she said.
Nonetheless, studies have documented that women with epilepsy are less inclined to breastfeed their infants than other new mothers. They are also less likely to have access to lactation experts after giving birth. Perceived concerns include drug exposure through breast milk and the potential for sleep deprivation, which may exacerbate seizures, said William D. Gaillard, MD, FAES, president of the American Epilepsy Society and chief of the divisions of child neurology and of epilepsy and neurophysiology at Children's National Hospital in Washington, DC.
As the study's authors found, drug exposure during lactation was minimal, and certainly less than in utero, he said. The benefits of breastfeeding to infants would be significant, as outlined by the American Academy of Pediatrics, said Dr. Gaillard, who is also director of the comprehensive pediatric epilepsy program at Children's National.
If seizures intensify due to sleep deprivation, the researchers emphasized that there are strategies to minimize these risks. In the past decade, there has been increasing awareness of epilepsy's effects and treatments on new mothers and their infants, and the study “is a welcome contribution to this arena,” Dr. Gaillard said.
“The hope is that these data will change practice by encouraging treating neurologists to educate and support breastfeeding in their patients who are new mothers,” he said.
“While assuaging fears and concerns,” such research findings “set the foundation for further study,” including the investigation of factors that contribute to less breastfeeding among mothers with epilepsy and barriers to expanded and accurate education. “It will also be important to understand which maternal populations are less likely to breastfeed their babies,” Dr. Gaillard said.
Furthermore, Dr. Gaillard noted that “there is incomplete knowledge about the presence of some AEDs in breast milk and ensuing potential exposure to infants.” Although the presence is either known or believed to be from low to negligible, he said this needs additional clarification.
The MONEAD trial's significance lies in being the largest ever to analyze the safety of breastfeeding of infants by mothers requiring antiepileptic drug therapy, said Mona Sazgar, MD, FAES, clinical professor in the department of neurology and the comprehensive epilepsy program at the University of California Irvine Health.
“We've never had this many mothers and infants studied in one single report. It's a very strong study of the most important seizure medications that women with epilepsy take,” Dr. Sazgar said.
“The practice of epilepsy specialists has been to inform patients about the potential benefits of seizure freedom during pregnancy and the postpartum period when women stay on seizure medications, versus the risk of infant exposure to antiepileptic drugs. For most seizure medications, the general idea was that the benefits outweigh the risks.
“This study provides credible data regarding infant safety when [they are] exposed to seizure medications through breastfeeding,” she added. “As neurologists, we are excited about the results, which are very reassuring and in keeping with our previous clinical practice.”
Dr. Birnbaum has received research support from the National Institutes of Health (NIH), Epilepsy Foundation, Supernus Pharmaceuticals, and Veloxis Pharmaceuticals and is also a coinventor of a patent for intravenous carbamazepine (Lundbeck Pharmaceuticals). Dr. Pennell has received research support from the NIH and the Epilepsy Foundation and honoraria and travel support from the American Epilepsy Society, AAN, Epilepsy Foundation, NIH, and academic institutions for continuing medical education lectures. Dr. Sazgar serves on the speaker bureau of several pharmaceutical companies, including Eisai, UCB Pharma, and Sunovion, and receives honorarium for her talks. Drs. Bui and Gaillard disclosed no competing interests.