Women with bipolar disorder are vulnerable to postpartum illness, and it is generally recommended that mothers continue treatment with a mood stabilizer throughout the postpartum period to reduce their risk of relapse; however, this recommendation is complicated by the fact that all mood stabilizers are secreted into the breast milk, although their concentrations appear to vary considerably (Chaudron and Jefferson, 2000). At this point, lamotrigine (Lamictal) is one of the most commonly used mood stabilizers in reproductive-aged women with bipolar disorder and has become a first-line treatment for childbearing women with epilepsy.
Lamotrigine Levels in the Nursing Infant
The plasma levels of 10 breastfed infants of 9 mothers taking lamotrigine during pregnancy and postpartum were monitored after birth (Öhman et al, 2000). Transplacentally acquired plasma levels were similar to maternal plasma levels at birth. Infant serum levels dropped over the first 72 hours of life. Infant plasma levels at 2 to 3 weeks postpartum averaged 1.7 mg/L (range 0.5 to 3.3 mg/L) before nursing and 1.5 mg/L (range <0.5 to 2.5 mg/L) after nursing. Infant plasma levels ranged from 23% to 50% of the mothers’ plasma levels.
Newport and colleagues and includes a total of 30 women taking lamotrigine and their nursing infants. The authors reported that milk/plasma ratios were highly variable, ranging from 5.7% to 147.1%. The mean milk/plasma ratio was 41.3%. This type of variability has been reported in studies of antidepressants and other medications in nursing infants, indicating that milk/plasma ratios may be of limited utility in estimating the extent of exposure in the nursing infant.
Using measurements of maternal and infant plasma lamotrigine concentrations, it was estimated that the relative infant dose (RID) of lamotrigine was 9.2% and that the theoretical infant dose (TID) was 0.51 mg/kg per day. This RID of 9.2% is lower than the RID cutoff of 10% frequently used as an empiric cutoff for assuming safety during lactation. The authors caution, however, that clinicians should be advised that this rule of thumb is arbitrary and has not been objectively verified. Nonetheless, it is reassuring that this dose is considerably lower than the dose of lamotrigine used to treat seizures in infants.
As one would expect, the concentration of lamotrigine in breast milk was positively correlated with the mother’s daily dosage of lamotrigine. Levels of lamotrigine in the breast milk peak at about four hours after ingestion of the medication and return to steady state levels within 24 hours.
Kacirova and colleagues (2019) examined 38 infants breastfed by mothers taking lamotrigine alone or with drugs that induce (n = 4) or inhibit (n = 4) lamotrigine’s metabolism. The mean infant serum lamotrigine concentration was 1.6 mg/L (range <0.66 to 3.8 mg/L). Infant serum concentrations were highly correlated with maternal serum concentrations, with a mean ratio of infant to maternal serum concentrations of 0.34.
In a multicenter study, Birnbaum and colleagues (2020) assessed serum lamotrigine levels in 70 mother-infant pairs. All but 7 of the infants had blood levels of lamotrigine above the lower limit of quantification (0.1 mg/L). The authors estimated the average infant lamotrigine serum concentration to be 1.6 mg/L (range 0.05 to 8.5 mg/L). Average infant blood levels were 28.9% (range 0.6 to 90.3%) of blood levels in the mother.
Adverse Events in the Nursing Infant
Data regarding the risk for adverse events comes largely from case reports. The vast majority of these case reports indicate that the infants and children breastfed by mothers taking lamotrigine do not experience serious adverse events and exhibit normal development. In larger case series, such as the one from Newport and colleagues, no adverse events were observed in the nursing infants. Specifically, none of the nursing infants developed a rash or demonstrated evidence suggestive of Stevens Johnson Syndrome.
There have been occasional case reports of a serious adverse event in a breastfed infant. In one case, a 16-day-old infant experienced apneic episodes, followed by a cyanotic episode requiring resuscitation. The mother had used increasing doses of lamotrigine during her pregnancy, and at the time of her infant’s apneic episodes, she was taking 850 mg/day. The neonatal lamotrigine serum concentration was in the high therapeutic range. After the termination of breastfeeding, the infant recovered fully. Given that the mother was taking a dose of lamotrigine that was two to three times higher than the dose typically used, this case most likely represents an unusual event.
Another case report documented weight loss and hypernatremic dehydration because of inadequate milk intake in a 12-day-old exclusively breastfed infant (Morin et al, 2017). The mother was taking lamotrigine 250 mg daily, aripiprazole 15 mg, sertraline 100 mg orally, and levothyroxine 50 mcg. This case highlights the complexity in identifying medication-associated adverse events in this setting. The mother was taking multiple medications. It is possible that one or more of those medications could have decreased milk production in the mother or may have impacted the baby’s appetite or ability to nurse effectively. On the other hand, hypothyroidism has been associated with low milk production, and dehydration can occur in exclusively breastfed infants. While the authors considered the mother’s medications as a possible cause for the dehydration and related problems, it is not possible to conclude that lamotrigine, or any of the other medications, caused this particular complication.
While various studies have addressed the short-term safety of antiepileptic drugs (AEDs) in nursing infants, few have systematically assessed the long-term effects of exposure to these drugs on cognitive development. In a prospective study from Meador and colleagues which included 78 breastfed children exposed to AEDs (including but not limited to lamotrigine), no adverse effects of AED exposure through breast milk were observed in children at 6 years of age. In fact, breastfed children exhibited higher IQ and enhanced verbal abilities.
In a prospective cohort study from Norway, Velby and colleagues (2013) followed the infants born to mothers taking antiepileptic drugs during pregnancy and lactation. In this study, 71 mothers were taking lamotrigine monotherapy. Infants were assessed at 6, 18 and 36 months of age. Developmental outcomes were better in breastfeeding infants exposed to lamotrigine versus children who were not breastfed or breastfed for less than six months.
While the majority of professional and nutritional organizations support breast milk as the ideal form of nutrition for the infant in the first year of life, women taking psychotropic medications, such as lamotrigine, must weigh the benefits of breastfeeding against the risks of exposure to medication. More research is required to better assess the safety of lamotrigine in nursing infants; however, these findings are reassuring. Lamotrigine levels were detected in most infants assessed; however, the risk of adverse events is very low.
Ruta Nonacs, MD, PhD
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