A new study provided reassuring findings for women who wish to breast-feed their infants but are taking antiepileptic drugs (AEDs).
Investigators analyzed the infant-to-mother concentration of AEDS at 5 and 20 weeks postpartum in blood samples of 164 breast-feeding women taking these agents and their babies.
Close to half of AED concentrations in nursing infants were less than the lower limit of quantifications (LLoQ) and substantially lower than maternal blood concentrations.
“We looked systematically at large groups of children, and what we found was that the overall levels were lower than in the mother, and many were very low, below even a detectable level in the blood,” investigator Kimford Meador, MD, professor of neurology at Stanford University School of Medicine and Stanford Neuroscience Health Center, California, told Medscape Medical News.
“Given no adverse effects of breast-feeding and the known benefits of breast- feeding — reducing risks of depression, cancer, diabetes, and infections, to name a few — I encourage mothers to breast-feed if they want to and can, even if they are taking anticonvulsants. I haven’t seen any untoward effects in 20 years in my patients,” Meador reported.
The study was published online December 30 in JAMA Neurology.
“For a long time some physicians have been advising patients with epilepsy not to breast-feed if they are taking anticonvulsants out of concern that it might cause problems in the baby,” Meador said.
His group conducted an earlier study in a cohort of children who had been breastfed by mothers taking AEDs, following the children until age 6 years and comparing them to children who had not been breast-fed.
“We found that at age 6, the IQ in the children who had been breast-fed was even higher than in those who had not been breast-fed,” he noted.
However, animal studies had suggested that some AEDs taken by mothers during pregnancy might have adverse effects on developing fetal neurons during the third trimester, similar to the effects of alcohol that lead to fetal alcohol syndrome.
It was also concerning if “using drugs that might cause apoptosis might be risky for neonates.”
Although previous studies have focused on the levels of AEDs in breast milk as “surrogate markers for the levels of AEDs in the babies, there has never been an extensive study looking at blood levels of mothers and nursing children, looking at the levels in the child,” he said.
To investigate the question, the researchers conducted The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study of outcomes for women with epilepsy and their children during pregnancy and in the postpartum period.
Participants were required to be between age 14 and 45 years, be pregnant for less than 20 weeks’ gestation, and have IQ scores > 70 points. They were followed through pregnancy and for 9 postpartum months.
Between 5 and 20 weeks after birth, the researchers collected blood samples from breast-fed infants and their mothers.
Over half of the 345 infants (64.3%) born to 351 pregnant women with epilepsy (median [range] 42 [8 – 4 years] 87.4% white) were breast-fed.
The final sample with available data consisted of 164 infant-mother concentration dyads, including 135 mothers and 138 infants, with 3 pairs of twins (51.9% female, median [range] age 13 [5 – 20] weeks).
More mothers were being treated with monotherapy than with polypharmacy, but no differences in blood concentrations were found between breast-fed infants whose mothers were receiving polytherapy and those receiving monotherapy.
Roughly half (49.3%) of the infants had AED concentrations less than the LLoQ, and none of the infants whose mothers were taking carbamazepine, oxcarbazepine, valproic acid, or topiramate had drug concentrations greater than the LLoQ.
The authors point out, however, that the LLoQ is lower for lamotrigine than for some other AED concentrations, and note that if the LLoQ value for lamotrigine is adjusted to be similar to levetiracetam, the percentage of infants with lamotrigine concentrations greater than the LLoQ decreased to 54.3%.
The median percentages of infant-to-mother AED concentration were:
Lamotrigine: 28.9% (0.6% – 90.3%)
Levetiracetam: 5.3% (2.1% – 20.4%)
Zonisamide: 44.2% (35.2% – 125.3%)
Carbamazepine: 5.7% (3.7% – 8.4%)
Carbamazepine epoxide: 5.4% (0.9% – 9.6%)
Oxcarbazepine: 0.3% (0.2% – 0.9%)
Topiramate: 17.2% (12.4% – 22.0%)
Valproic acid: 21.4% (17.9% – 24.9%)
Linear regression models, including data from the 52 mother-infant pairs in which mothers were taking lamotrigine, found that maternal concentrations were significantly associated with plasma lamotrigine concentrations in the infants (Pearson correlation coefficient, 0.58; P < .001).
In the 16 mother-infant pairs in which the mothers were taking levetiracetam, maternal levetiracetam concentrations were not associated with concentrations in the infants.
The researchers did not perform these linear regressions in the other AEDs “because there were too few concentrations in infants that were greater than LLoQ,” they explain.
Meador noted that valproic acid is associated with adverse outcomes in infants whose mothers were taking it during pregnancy, but “even drugs like valproic acid don’t pose an additional risk during breast-feeding,” he said.
Nevertheless, although “the vast majority of children born to these mothers do not get affected by these drugs, they’re at increased risk, particularly for some drugs more than others. But still, the majority of babies are normal,” Meador commented.
“The reason we are doing this research is to get that risk down, understand which drugs are risky, which factors work together, so we can design approaches in the future for improving outcomes for babies.”
Confirmatory and Reassuring
Commenting on the study for Medscape Medical News, Torbjörn Tomson, MD, PhD, senior professor in the Department of Clinical Neuroscience at Karolinska Institutet in Stockholm, Sweden, said the results are “largely confirmatory and reassuring: drug concentrations in the breast-fed infants are considerably lower than in the mothers and also lower than what they can be assumed to have been exposed to in utero.” Tomson was not involved with the study.
Also commenting on the study for Medscape Medical News, Emilio Perucca, MD, PhD, professor of clinical pharmacology at the University of Pavia, Italy, said a contribution of the study is that the “number of infant-mother pairs included in this study is larger than [in] earlier studies, and therefore the results have great strength.”
Perucca, who was not associated with the current research, noted that “more recently introduced AEDs, such as lacosamide, were not assessed.”
Still, “overall these findings confirm that breast-feeding by women taking AEDs is generally safe and should be encouraged.”
Meador added that his group has recently published two studies on related topics, one focusing on the protective effects of periconceptual folate on cognition in offspring of pregnant women taking AEDs and the second examining malformations in offspring of pregnant women taking AEDs.
“The most important message is that we should be thinking about these things early,” he said.
“Don’t wait until a woman is planning to get pregnant [to prescribe folate] because many pregnancies are unplanned,” he emphasized. “Think about potential pregnancy in all women of childbearing potential, even adolescents, even if they don’t want to have a child at that point.”
The study was supported by grants from the National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Development. Meador has received research support from the National Institutes of Health and Sunovion Pharmaceuticals and travel support from UCB Pharma. The Epilepsy Study Consortium pays Meador’s university for his research consultant time for Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. The other authors’ disclosures are listed on the original article. Tomson and Perucca have disclosed no relevant financial relationships.
JAMA Neurology. Published online December 30, 2019. Abstract