Anticonvulsant
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Women with epilepsy may have a higher risk of delivering an infant with a malformation than those who do not have this condition. Reproduction studies with lamotrigine in two animal species showed evidence, in the presence of maternal toxicity, of developmental toxicity (growth restriction, behavioral deficits, and death) but not structural anomalies. Moreover, at least two reviews have concluded that this anticonvulsant may be associated with a lower risk of teratogenicity (1,2). However, a recent report has shown a significant risk for oral clefts following 1st trimester exposure (3). A 2012 review concluded that the absolute risk of lamotrigine-induced cleft lip and palate or cleft palate alone was between 0.1% and 0.4% (4). In addition, a significant increase in the risk for major defects has been reported when lamotrigine was combined with valproate (5).
FETAL RISK SUMMARY
Lamotrigine is an anticonvulsant, chemically unrelated to existing antiepileptic drugs, that is used as adjunctive therapy for the treatment of partial seizures in patients with epilepsy. It is also indicated for the maintenance treatment of bipolar disorder to delay the time to occurrence of mood episodes. Protein binding is moderate (about 55%) and the agent is metabolized to inactive metabolites (6).
Lamotrigine was not teratogenic in animal reproductive studies involving mice, rats, and rabbits using oral doses that were 1.2, 0.5, and 1.1 times, respectively, the highest usual human maintenance dose (500 mg/day) based on BSA (HUHMD). However, maternal toxicity and secondary fetal toxicity consisting of reduced fetal weight and/or delayed ossification were observed at these doses in mice and rats but not in rabbits. Behavioral deficits were observed in the offspring of rats dosed with 0.1 and 0.5 times the HUHMD during organogenesis. No structural defects were observed after IV bolus doses in rats and rabbits, but an increased incidence of intrauterine fetal death occurred in rats dosed at 0.6 times the HUHMD. Similarly, an increase in fetal deaths occurred in rats dosed orally at 0.1, 0.14, or 0.3 times the HUHMD during the latter part of gestation. These doses were maternally toxic (decreased food consumption and weight). Postnatal deaths also were observed with the two highest doses (6).
No evidence of carcinogenicity was observed in 2-year studies in mice and rats. In multiple other tests, there was no evidence of mutagenicity or clastogenicity, and no impairment of fertility in rats (6).
Lamotrigine reduces fetal folate levels in rats, an effect known to be associated with malformations in animals and humans (6). Human fetal folate levels have apparently not been investigated, but in studies with nonpregnant humans, the drug’s inhibitory action of dihydrofolate reductase did not significantly reduce folate levels (7). Serum folate and red blood cell folate concentrations were within the 95% confidence interval (CI) of the baseline values.
Lamotrigine crosses the human placenta (8–10). A 24-year-old woman had been treated before and throughout gestation with the anticonvulsant (300 mg/day) in combination with valproic acid (8). The latter drug was discontinued during the 3rd week of pregnancy. Her lamotrigine serum levels decreased from 17.8 mcg/mL (2 weeks after her last dose of valproic acid) to 2.52 mcg/mL at week 34, but she remained seizure-free throughout pregnancy. She delivered a healthy, 3620-g male infant at 39 weeks’ gestation. The umbilical cord blood lamotrigine concentration was 3.26 mcg/mL, indicating a probable cord:maternal serum ratio of 1 (maternal serum level at delivery not reported). On the second day after delivery and a few hours after commencing suckling, the serum concentrations in the infant and mother were 2.79 and 3.88 mcg/mL, respectively, a ratio of 0.7. A 1997 case report found that maternal lamotrigine plasma levels decreased during pregnancy (9). The woman in that case delivered a healthy infant (weight and sex not given) at term. At delivery, the umbilical cord:maternal plasma ratio was 1.2.
In a 2000 report, maternal and cord plasma concentrations of lamotrigine were determined at term delivery in nine women (10 pregnancies; 1 woman with 2 pregnancies also reported in reference 3) (10). Maternal and cord plasma levels were similar. At 72 hours postpartum, median lamotrigine plasma levels in the infants were 75% of the cord plasma levels (range 50%–100%). The placental transfer is consistent with the low molecular weight (about 256). Moreover, during the first 2 weeks after delivery, the median increase in maternal plasma concentration/dose ratio was 170%, a significant increase (10).
A 2004 report described 12 pregnancies in which women were treated with lamotrigine monotherapy for epilepsy (11). An increase in seizure frequency and/or severity occurred in nine pregnancies, attributed to a gradual decrease in the serum-to-dose ratio to 40% of baseline. Consequently, the doses were increased in seven pregnancies. Three to ten days after delivery, toxic symptoms (dizziness, diplopia, or ataxia) occurred in three of the women with dose increases. Lamotrigine serum levels were 12–14 mcg/mL, a high normal range. The symptoms resolved when the dose was decreased (11).
A 2005 abstract reported 62 pregnancy outcomes after exposure to gabapentin, lamotrigine, or topiramate (12). The study included a blinded dysmorphology examination. Nineteen women used lamotrigine, one of whom had a major malformation: coarctation of the aorta with anomalous left coronary artery, frontal hair upsweep, and a long philtrum (monotherapy for seizures). Of the nine infants examined by a dysmorphologist, none had more than one feature consistent with anticonvulsant embryopathy (12).
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was closed to new enrollments in June 2009 and the final report was issued in July 2010 (5). The final report covers pregnancy exposures from September 1992 through March 2010. There were 3416 pregnancies registered prospectively (reported to the Registry before the pregnancy outcome was known), 2444 were closed with known outcomes, and 972 (28.5%) were lost to follow-up. In the 2444 known pregnancy outcomes, there were 43 sets of twins, 1 set of triplets and 1 set of quadruplets, for a total of 2492 fetal outcomes. Among the 1817 fetal outcomes involving lamotrigine monotherapy, there were 1636 live births (defects not reported but cannot be ruled out), 98 spontaneous abortions (SABs), 33 elective abortions (EABs), and 10 fetal deaths without defects. Major birth defects were observed in 36 live births, 3 EABs, and 1 fetal death. Excluding SABs, EABs, and fetal deaths without defects, the earliest exposure by trimester was 1554 (1st), 95 (2nd), 18 (3rd), and 5 not specified. Major birth defects were observed in 35 1st trimester exposures (31 live births, 1 fetal death, and 3 EABs), 4 live births in the 2nd trimester, and 1 live birth in the 3rd trimester. The rate of major birth defects in the 1st trimester exposures was 2.2% (35/1558 excluding fetal deaths and EABs without defects). The sample size of 1558 was sufficient to detect, with 80% power, at least a 1.39- to 1.48-fold increase over baseline in the overall rate of major birth defects (5).
Polytherapy (lamotrigine plus at least one other AED) with valproate involved 173 outcomes: 159 live births, 6 SABs, 6 EABs, and 2 fetal deaths. Among 161 1st trimester exposures, there were 14 live births and 2 EABs with birth defects, 6 SABs, and 139 outcomes without defects (134 live births, 4 EABs, and 1 fetal death). Excluding the 6 SABs, and the 4 EABs and 1 fetal death without defects, the rate of birth defects in the 1st trimester exposures was 10.7% (16/150). Polytherapy without valproate involved 502 outcomes: 457 live births, 22 SABs, 20 EABs, and 3 fetal deaths. Among 474 1st trimester exposures, there were 11 live births and 1 EAB with birth defects, 22 SABs, and 440 outcomes without defects (418 live births, 19 EABs, and 3 fetal deaths). Excluding the 22 SABs, and the 10 EABs and 3 fetal deaths without defects, the rate of birth defects in the 1st trimester exposures was 2.8% (12/430) (5).
The Registry listed the major birth defects observed in the monotherapy and polytherapy groups and concluded that there was no consistent pattern among the defects. Although the data were insufficient to reach a definite conclusion, the Registry found no evidence of a dose–response effect with daily doses of lamotrigine up to 1200 mg/day (5).
Retrospective cases (reported to the Registry after the pregnancy outcome was known) are often biased (only adverse outcomes are reported), but they are useful in identifying specific patterns of anomalies suggestive of a common cause. There were 164 pregnancies with birth defects reported retrospectively to the Registry, 142 involving earliest exposure to lamotrigine in the 1st trimester, 4 with earliest exposure in the 2nd trimester, and 18 with an unspecified trimester of exposure. Lamotrigine monotherapy was used in 94 pregnancies, while 70 involved polytherapy (5).
As of 1996, the FDA had received three disparate reports of birth defects, in which lamotrigine was used in combination with other anticonvulsants during the affected pregnancy (F. Rosa, personal communication, FDA, 1996).
A 1998 noninterventional, observational cohort study described the outcomes of pregnancies in women who had been prescribed ≥1 of 34 newly marketed drugs by general practitioners in England (13). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 of the pregnancies (78%), a newly marketed drug was thought to have taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Lamotrigine was taken during the 1st trimester in 59 pregnancies. The outcomes of these pregnancies included 10 SABs, 1 missed abortion, 9 EABs, 35 normal newborns (4 premature), and 4 newborns with congenital malformations. The malformations observed were ventricular septal defect; congenital respiratory stridor; palatal cleft (soft palate only), hypospadias, and undescended testes (mother had convulsions early in gestation); and abdominal distension with possible congenital intestinal obstruction. In three of these cases, lamotrigine was given in various combinations with other anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital, and/or sodium valproate). In addition, the study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed due to the timing of the questionnaires (13).
A significant association between lamotrigine and isolated, nonsyndromic oral clefts has been reported (3). The findings were published in May 2006 and presented at the June 2006 annual meeting of the Teratology Society in Tucson, Arizona. The cases were collected between 1997 and 2006 by the North American Antiepileptic Drug Pregnancy Registry (North American AED Pregnancy Registry). Among 564 infants (including live births, stillbirths, and elective terminations for anomalies) exposed to lamotrigine monotherapy in the 1st trimester, 15 had major malformations. The prevalence was 2.7% (95% CI 1.5%–4.3%) compared with 1.62% in an unexposed comparison group (N = 221,746 births) (relative risk [RR] 1.7; 95% CI 1.0–2.7). Five infants in the lamotrigine-exposed group had oral clefts (8.9/1000 births): three isolated cleft palate and two isolated cleft lip. None had a recognized syndrome (3).
In the comparison group, the prevalence of the two defects was 1:6160 (0.16/1000) and 1:4820 (0.21/1000), respectively. The RRs attributed to lamotrigine for cleft palate and cleft lip were 32.8 (95% CI 10.6–101.3) and 17.1 (95% CI 4.3–68.2), respectively. The authors thought that the low rates of oral clefts in the comparison group reflected the limited identification of syndromes associated with cleft lip and/or palate. In five other registries that reported 1623 lamotrigine-exposed infants, four infants had oral clefts for a frequency of 2.5/1000 compared with 0.37/1000 in the comparison group. The combined findings showed a significant risk of oral clefts following 1st trimester exposure to lamotrigine monotherapy (3).
An update to the North American AED Pregnancy Registry was published in 2008 (14). Among 684 infants exposed in utero to lamotrigine monotherapy, 16 (2.3%) had major malformations identified at birth, well within the normal background rate. However, five infants (7.3/1000) had oral clefts: three with isolated cleft palate and one each with isolated cleft lip or cleft lip and palate. The rate was 10.4 times the rate among a comparison group of 206,224 unexposed infants (0.7/1000). A comparison also was made with 1623 infants exposed to lamotrigine monotherapy who had enrolled in five other registries. In that group there were four infants with oral clefts (2.5/1000) (RR 3.8, 95% CI 1.4–10.0) (14).
In a population-based case–control study, the EUROCAT Antiepileptic Drug Working Group evaluated data for 3.9 million births from 19 registries covering the period 1995–2005 (15). The data included congenital anomalies among live births, stillbirths, and terminations of pregnancy after prenatal diagnosis. Cases were 5511 nonsyndromic oral clefts, 4571 of whom were isolated oral clefts. In these, there were 1969 cases of cleft palate, 1532 of whom were isolated cleft palate. Controls were 80,052 nonchromosomal, nonepileptic, non-AED-use pregnancies. In the cases, there were 40 pregnancies exposed to lamotrigine monotherapy. Comparisons were made between the monotherapy and the control group for oral clefts relative to other malformations, for isolated oral clefts, cleft palate, and isolated cleft palate. None of the comparisons reached statistical significance. However, when the same comparisons were made between any AED use and no AED use, significant results were found for oral clefts relative to other malformations, cleft palate, and isolated cleft palate (15).
An editorial discussed the results from the above two studies, noting the small number of oral cleft cases in the two reports (five in the North American Registry and three in the EUROCAT) study (16). The editorial also listed the limitations in both. The conclusion was that although the overall risk for oral clefts from lamotrigine monotherapy was low, there was a specific signal that required clarification by additional studies.
A 2013 study reported dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age after fetal valproate exposure (17). Analysis showed that IQ was significantly lower for valproate (mean 97, 95% CI 94–101) than for carbamazepine (mean 105, 95% CI 102–108; p = 0.0015), lamotrigine (mean 108, 95% CI 105–110; p = 0.0003), or phenytoin (mean 108, 95% CI 104–112; p = 0.0006). Mean IQs were higher in children whose mothers had taken folic acid (mean 108, 95% CI 106–111) compared with children whose mothers had not taken the vitamin (mean 101, 95% CI 98–104; p = 0.0009) (17).
In a 2009 case report, a 38-year-old woman took lamotrigine during the latter portion of one pregnancy and throughout another pregnancy (18). Both infants appeared to be normal, although a benign peripheral pulmonary stenosis was discovered at 16 days of age in the second infant. This infant also had an apneic episode and became cyanotic (see Breastfeeding Summary).
A 2006 review of prophylactic therapy of bipolar disorder briefly described the effects in pregnancy and breastfeeding of a number of drugs, including lamotrigine (19). Untreated pregnant and nursing women with the disorder are at an increased risk of poor obstetrical outcomes and relapse of affective symptoms. Although the limited data prevented conclusions on the relative safety of the drugs, the author did state that each case needed to be considered separately (19).
A study published in 2009 examined the effect of AEDs on the head circumference in newborns (20). Significant reductions in mean birth-weight-adjusted mean head circumference (bw-adj-HC) was noted for monotherapy with carbamazepine and valproic acid. No effect on bw-adj-HC was observed with gabapentin, phenytoin, clonazepam, and lamotrigine. A significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 standard deviations below the mean) was noted after any AED polytherapy but not after any monotherapy, including carbamazepine and valproic acid. The potential effects of these findings on child development warrant study (20).
The pharmacokinetics of lamotrigine were described in 2002 (21). The clearance of the drug increases by >50% starting early in pregnancy and reverts to the nonpregnant state quickly after delivery. Lamotrigine blood levels should be checked before, during, and after pregnancy.
BREASTFEEDING SUMMARY
Lamotrigine is excreted into breast milk (6,8–10,18,22–25). A 24-year-old mother who had been treated throughout gestation with lamotrigine (see details above) began nursing her infant on the 2nd day after delivery (8). At this time, she was taking 300 mg/day, decreased to 200 mg/day approximately 6 weeks postpartum to lessen the drug exposure of the infant. From day 2 to day 145 after delivery, 11 maternal serum and 9 milk samples (about 2–3 hours after the morning dose) were drawn, with lamotrigine serum concentrations ranging from 3.59 to 9.61 mcg/mL and milk levels ranging from 1.26 to 6.51 mcg/mL. The mean milk:serum ratio was 0.56 with a high correlation (r = 0.959, p <0.01) between the serum and milk. The infant’s serum levels (about 1–2 hours after breastfeeding), determined at the same times as the mother’s, ranged from <0.2 mcg/mL (during weaning) to 2.79 mcg/mL. No adverse effects were observed in the nursing infant either during breastfeeding or during weaning (8).
A 60-kg woman took lamotrigine 200 mg/day throughout gestation and during nursing (9). Two weeks after delivery, the milk:maternal plasma ratio was 0.6. The infant’s plasma level, which had been similar to the mother’s at birth, was now 25% of the maternal levels. No adverse effects were observed in the nursing infant (9).
In a 2000 report, nine women (10 pregnancies, one woman with two pregnancies also reported in reference 3) received lamotrigine throughout gestation (see Fetal Risk Summary above) and continued the drug during breastfeeding (10). The median milk:maternal plasma ratio 2–3 weeks after delivery was 0.61 (range 0.47–0.77). The lamotrigine plasma concentrations in the infants were approximately 30% (range 23%–50%) of the corresponding maternal plasma levels. The estimated infant lamotrigine dose was ≥0.2–1 mg/kg/day, assuming a milk intake of 150 mL/kg/day, about 9% of the weight-adjusted maternal daily dose. Because of the slow elimination in the infant (most likely due to reduced hepatic glucuronidation capacity), the marked increase in maternal plasma lamotrigine concentrations that occurred after birth (see Fetal Risk Summary above), and the fact that infant drug levels may not have reached steady-state concentrations, the infant exposure could eventually result in therapeutic plasma lamotrigine levels. No adverse effect in the nursing infants was observed (10).
A 38-year-old woman took lamotrigine throughout her third pregnancy for a seizure disorder caused by a pilocytic astrocytoma 6 years earlier (18). Although the brain tumor had been removed surgically, she had residual epilepsy that was treated with lamotrigine. In her second pregnancy, she started daily lamotrigine 550 mg toward the end of the pregnancy, and then gradually reduced the dose while breastfeeding to 425 mg. The highest serum concentration, measured at 45 days postpartum, was 8.96 mcg/mL. No adverse effects were observed in the fully breastfed infant. In her third pregnancy, the mother’s daily dose was increased from 450 mg (pregestation) to 875 mg (term). The dose at term was 10.9 mg/kg/day. Serum concentrations during this interval were 5.12 mcg/mL (pregestation), 3.30 mcg/mL (3rd trimester), and 4.53 mcg/mL (day of birth). She had a focal epileptic seizure during the 5th gestational month and a generalized tonic–clonic seizure shortly after delivery. She took her last 875-mg dose 20.5 hours before giving birth to a full-term, 4200-g male infant with Apgar scores of 9 and 9. Because of the latest seizure, a dose reduction was not started until the 2nd week. The infant was exclusively breastfed. His lamotrigine concentration approximately 12.5 hours after birth was 7.71 mcg/mL (proposed pediatric therapeutic range 1–5 mcg/mL). At age 3 days, his serum concentration was 5.81 mcg/mL. At 16 days of age, his breathing became irregular and strenuous and he had a brief episode of apnea. Three hours after the first apneic episode, he became cyanotic while nursing. The mother, a physician, successfully resuscitated him and took him to the hospital. On admission, his lamotrigine serum concentration was 4.87 mcg/mL (4 hours after the mother’s 850-mg dose and 3 hours after nursing). Except for periodic sinus tachycardia (170–180 beats/minute) and a benign peripheral pulmonary stenosis, his examination and laboratory tests were normal. Breastfeeding was discontinued on postpartum day 17. The mother’s lamotrigine serum concentration at this time was 14.93 mcg/mL. Her dose was decreased to 600 mg on postpartum day 22, and then gradually reduced to 525 mg by day 64. Using a milk concentration of 7.68 mcg/mL obtained on day 22, the theoretical infant dose (1.15 mg/kg/day) as a percentage of the mother’s weight-adjusted dose was 13%. The milk:plasma ratio determined 4 times during postpartum days 22–64 was 0.79–0.96. Based on blood samples obtained 22 and 25 days after birth, the estimated lamotrigine half-life in the infant was 56 hours, about twice that seen in adults. The infant had no further apneic or cyanotic episodes and was developing normally at 7 months of age. The authors could not determine why the infant developed apnea but concluded that lamotrigine was the probable cause (18).
A 2004 study reported lamotrigine serum concentrations in four nursing infants, all of whom had been exposed throughout pregnancy (22). All the women had full-term deliveries of healthy babies. The doses on day 10 postpartum, the sampling day, were 200–800 mg/day. The infant: maternal plasma concentration ratios were 0.2, 0.2, 0.43, and ≤0.17 (infant <1 mcg/mL and maternal 5.2 mcg/mL), respectively. For the first two cases, sampling was repeated at 2 months of age with nearly identical ratios of 0.22 and 0.23, respectively, but both nursing infants were being supplemented with formula 2–3 times per day. No adverse effects were observed in the infants, but the authors were concerned because of the drug concentrations reaching “therapeutic ranges” (22).
A 2005 case report described a woman treated for epilepsy with partial seizures with 300 mg/day lamotrigine throughout pregnancy and during breastfeeding (23). The healthy, 3.3-kg male infant was spontaneous delivered at term with Apgar scores of 8 and 9. Development of the infant was normal during the first 4 breastfed months and no toxicity was observed (23).
A 2006 report quantified the amount of lamotrigine in the breast milk of six mothers and in the plasma of their breast-fed infants (mean age 4.1 months; range 0.4–5.1 months) (24). The mothers, who obtained the milk samples by hand expression, were taking a mean dose of 400 mg/day (range 75–800 mg) for epilepsy (N = 5) or bipolar disorder (N = 1). The duration of treatment before the study was not stated. The mean maternal dose based on body weight was 6.3 mg/kg/day, whereas the mean absolute infant dose was 0.45 mg/kg/day. The daily infant dose relative to the mother’s weight-adjusted dose was 7.6%. The mean infant plasma concentration of lamotrigine was 0.60 mg/L, a level that was a mean of 18% of the maternal plasma concentration. The mothers and physicians observed no adverse effects in the infants (24).
A 2008 report described steady-state lamotrigine concentrations in 26 women who were breastfeeding while taking the drug (25). The mean age of the infants was 13.0 weeks and the mean maternal dose was 5.93 mg/kg/day. The mean breast milk concentration was 3.38 mcg/mL (based on sampling from one breast every 4 hours for 24 hours) and the milk:plasma ratio was 0.413. The mean theoretical infant dose was 0.51 mg/kg/day and the relative infant dose was 9.2%. No adverse events were noted among the mothers or their nursing infants, but seven infants had elevated platelet counts without adverse clinical consequences (25).
As with any drug, a mother who must take lamotrigine to control her disease and who chooses to nurse her infant should carefully monitor the infant for adverse effects. Some anticonvulsants have produced adverse effects in nursing infants (see Phenobarbital and Primidone); whereas others are considered compatible with breastfeeding. (See Carbamazepine, Phenytoin, and Valproic Acid.) No adverse effects have been seen in nursing infants of mothers taking lamotrigine. Monitoring infant lamotrigine concentrations should be considered, as well as close monitoring for sedation and rash (26).
In a 2010 study, 199 children who had been breastfed while their mothers were taking a single antiepileptic drug (carbamazepine, lamotrigine, phenytoin, or valproate) were evaluated at 3 years of age cognitive outcome (27). Mean adjusted IQ scores for exposed children were 99 (95% CI 96–103), whereas the mean adjusted IQ scores of nonbreastfed infants were 98 (95% CI 95–101).
Because of the potential for therapeutic serum concentrations in the infant, the American Academy of Pediatrics classifies lamotrigine as a drug for which the effect on a nursing infant is unknown but may be of concern (28).
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