Anticonvulsant
PREGNANCY RECOMMENDATION: Human and Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
A 2012 review concluded that the use of topiramate during pregnancy was associated with a two- to threefold increased risk of malformations, largely due to an increased risk for cleft lip with or without cleft palate (1). Another 2012 study found significant effects on cognitive functions and other matters (see below) (2). Consistent with previous anticonvulsants studies, the risk of birth defects appears to be increased when topiramate is combined with other antiepileptics. Topiramate does not produce epoxide metabolites (3). Because these intermediate arene oxide metabolites have been associated with teratogenicity (see Carbamazepine, Phenytoin, and Valproic Acid), this may indicate a lower risk of teratogenicity compared with other agents. The effect of topiramate on folic acid levels or metabolism is unknown (3). Until this information is available, the safest course is to start folic acid supplementation (4–5 mg/day) before conception, as is done with other antiepileptic agents. Topiramate should be avoided, if possible, during the 1st trimester but, if required, monotherapy with the lowest effective dose is preferred. The risk for neonatal hypocalcemic seizures following in utero exposure to topiramate requires further study.
FETAL RISK SUMMARY
Topiramate, a sulfamate-substituted monosaccharide, is an antiepileptic agent indicated as adjunctive therapy in patients with partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. The drug undergoes partial metabolism to six metabolites, none of which constitutes more than 5% of the dose, with approximately 70% of the dose eliminated unchanged in the urine. Only 13%–17% is bound to human plasma proteins and the mean plasma elimination half-life is 21 hours. Topiramate is a weak carbonic anhydrase inhibitor, but this activity is not thought to be a major contributing factor to its antiepileptic action (4).
Reproduction studies with topiramate have been conducted in mice, rats, and rabbits. In pregnant mice, oral doses, 0.2–5 times the recommended human dose (400 mg/day) based on BSA (RHD), administered during organogenesis increased the incidence of fetal malformations at all doses. The primary anomalies were craniofacial defects. At the highest dose (5 times the RHD), reduced fetal body weights and ossification were evident, but this dose also caused maternal toxicity (decreased body weight gain) (4).
Topiramate at doses of 0.005–12.5 times the RHD was administered to pregnant rats during organogenesis. At ≥10 times the RHD, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased. In addition, in the postnatal portion of the study, pups exposed to topiramate during organogenesis exhibited delayed physical development (doses 10 times the RHD) and persistent reductions in body weight gain (doses ≥1 times the RHD). The teratogenic dose (≥10 times the RHD) produced clinical signs of maternal toxicity. At ≥2.5 times the RHD, reduced maternal weight gain was evident. However, fetotoxicity (reduced fetal body weight and increased incidence of structural variations) was observed at half the RHD. Pregnant rats also were treated during the latter part of gestation and throughout lactation with doses ranging from 0.005 to 5 times the RHD. No drug-related effects on gestation length or parturition were observed at any studied dose. At ≥0.05 times the RHD, reductions in pre- and/or postweaning body weight gain were observed. At 5 times the RHD, offspring exhibited decreased viability and delayed physical development (4).
Pregnant rabbits were administered oral doses during organogenesis that were approximately 0.6–11 times the RHD. At ≥2 times the RHD, embryo and fetal mortality was observed, but maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) also were evident. At 6 times the RHD, teratogenic effects, primarily rib and vertebral malformations, were observed (4).
Topiramate crosses the placenta to the fetus with cord and maternal plasma drug levels approximately equivalent at term (5,6). Diffusion across the placenta to the embryo early in gestation has not been studied. The molecular weight (about 339), the relatively lack of protein binding and low metabolism, and the prolonged plasma elimination half-life favor transfer of the drug to the embryo and fetus.
Postmarketing experience has been reported by the manufacturer (4). Without providing specific details, the manufacturer stated that cases of hypospadias had been observed in male infants exposed in utero to the drug, with or without other anticonvulsants. A causal relationship with topiramate has not been established (4).
A 2003 reference cited details from pregnancy exposure during clinical trials (5). Among 28 pregnancies, all involving polytherapy (other anticonvulsants not specified), there was “one malformation and two children with anomalies.” In addition, the outcomes of 139 pregnancies identified during postmarketing surveillance were 87 live births, 23 elective abortions, and 29 lost to follow-up. The patient’s anticonvulsant therapy was not specified. Five cases of hypospadias were observed, presumably in the live births (5).
In cases reported in a 2002 publication, five women were treated with topiramate (100–400 mg/day) combined with either carbamazepine (four cases) or valproic acid (one case) throughout gestation (6). All five newborns were healthy, normal infants. Birth weights of three infants ranged from 3520 to 3855 g, whereas the other two, both delivered from smoking mothers, had lower weights: 3160 g (6 cigarettes/day) and 2720 g (10 cigarettes/day), respectively. Cord blood levels of topiramate (average 8.1 microM) were nearly equivalent to the maternal plasma concentration at delivery (average 8.4 microM) (6).
A 2002 review cited a case of a pregnant patient who had been treated with topiramate (1400 mg/day) monotherapy throughout gestation (7). The growth-restricted newborn had several minor anomalies, including generalized hirsutism, a third fontanelle, short nose with anteverted nares, blunted distal phalanges and nails, and fifth nail hypoplasia. The similarity of some of these anomalies to those observed with other anticonvulsants suggested to the authors that genetic factors might have been involved (7).
A 2006 report from the United Kingdom Epilepsy and Pregnancy Register provided information on 35 pregnancies treated with topiramate for epilepsy, 28 of which involved monotherapy (8). Two newborns, both exposed to monotherapy, had major congenital malformations (rate 7.1%, 95% confidence interval [CI] 2.0%–22.6%); one with cleft lip–palate and the other with hypospadias.
A second report from the above Register described the outcomes of 203 pregnancies exposed to topiramate (70 monotherapy and 133 polytherapy) (9). The outcomes of this prospective (enrolled before the outcome was known) observational study were 18 spontaneous abortions (SABs), 5 elective abortions, 2 stillbirths, and 178 live births (62 monotherapy and 116 polytherapy). The mean topiramate dose in the two groups was 245 mg (range 50–800 mg) and 299 mg (range 25–1000 mg), respectively, whereas the mean gestational age at delivery and the birth weight was 39.2 and 38.8 weeks, and 3168 and 3062 g, respectively. Three (4.8%, 95% CI 1.7%–18.2%) major anomalies were observed in the monotherapy group (daily dose): cleft lip and bilateral cleft palate (200 mg); hypospadias (400 mg); and cleft lip and palate (600 mg). There also were five (8.1%) infants with minor malformations who had been exposed to doses of 50–750 mg/day. Among the 116 live births exposed to polytherapy, 13 (11.2%, 95% CI 6.7%–18.2%) had major defects (daily dose): left hydronephrosis, dysmorphic (800 mg); pyloric stenosis (3 cases) (75, 150, 800 mg); hernia and hydrocele (250 mg); anal atresia (175 mg); tracheoesophageal fistula (150 mg); hypospadias (50 mg); cleft palate, crossed toes (500 mg); bilateral dislocated hips (400 mg); Harold type II talipes, plagiocephaly (350 mg); congenital dislocated hip (500 mg); and left cleft lip and palate (250 mg). The other anticonvulsants were carbamazepine, clobazam, ethosuximide, lamotrigine, levetiracetam, phenobarbital, sodium valproate, and vigabitrin. Minor defects, including two infants with glandular or mild hypospadias, were observed in 10 (8.6%) infants exposed to polytherapy. In the combined groups, four oral clefts (2.2%, 95% 0.9%–5.6%) were observed, and among 78 male infants, 4 had hypospadias (5.1%, 95% CI 0.2%–10.1%). The rate of oral clefts was 11 times the background rate (9).
A teratogen information service (TIS) in Israel reported the outcomes of 52 pregnancies that were exposed to topiramate including in the 1st trimester (10). Compared with 212 controls not exposed to teratogens, there were statistically significant differences in SABs (11.3% vs. 2.8%, p = 0.017), birth weight (2932 vs. 3300 g, p = 0.024), and birth weight of single term infants (3084 vs. 3356 g, p = 0.001). After adjustment of the abortion data for gestational age when the TIS was called, maternal age, previous miscarriages, and smoking, regression analysis revealed that gestational age at initial TIS contact was a significant predictor and did not support a drug effect. The total number of major birth defects (4/41, 9.8%) was not statistically different from controls (7/206, 3.4%) (p = 0.090), but the possibility of a small increased risk could not be excluded because of the sample size. However, two of the anomalies were genetic in origin and were not caused by drugs. The other cases were pulmonary artery stenosis (topiramate 475 mg/day) and multiple brain cysts with neonatal seizures (topiramate 50 mg/day plus valproic acid 800 mg/day and clonazepam 1 mg/day). The reason for the low birth weight was unknown (10).
In the 2007 report from the Australian Registry of Antiepileptic Drugs in Pregnancy, no malformations were observed in the offspring of 15 pregnancies treated with topiramate monotherapy in the 1st trimester (11).
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was first published in January 1997. The final report was published in July 2010 (12). The Registry is now closed. Among 54 prospectively enrolled pregnancies exposed to topiramate and lamotrigine, with or without other anticonvulsants, 48 were exposed in the 1st trimester resulting in 40 live births, 2 birth defects, 3 SABs, and 3 EABs. There were six exposures in the 2nd/3rd trimesters resulting in five live births and one birth defect (12).
A 2007 report described two siblings that developed hypocalcemic seizures shortly after birth from a mother taking topiramate throughout pregnancy (13). The mother had developed seizures during her first pregnancy at age 20 and had been treated with valproic acid. Following that pregnancy, her anticonvulsant therapy had been changed to topiramate, 200 mg twice daily. Seven years later she became pregnant a second time and gave birth to a normal appearing, 3153-g male infant that was formula fed. Seizures began on day 3 of life and were associated with hypocalcemia, hypomagnesemia, and hyperphosphatemia but normal parathyroid hormone concentrations. Other laboratory parameters were within normal limits. He was treated with IV calcium and a low-phosphorus formula, and was discharged home at age 14 days on phenobarbital. At age 6 months, phenobarbital was discontinued. His development and neurologic examination were normal at 1 year of age. The mother subsequently delivered a normal baby girl (weight not specified) at term that was formula fed. During this pregnancy, her third, she had taken topiramate 100 mg twice daily. Seizures were noted at age 7 days and were associated with the same electrolyte and hormone abnormalities as in the first case. The infant was treated with IV calcium, magnesium, phenobarbital, and a change in the formula. No further seizures occurred after age 8 days, and she was discharged home on short-term courses of oral calcium and phenobarbital. Her neurological examination was normal at 2 months of age. Because there was no identifiable biochemical etiology for the seizures in the two infants, the seizures were attributed to hypocalcemia caused by hypoparathyroidism. It was proposed that in utero exposure to topiramate led to hypoparathyroidism and subsequent hypocalcemia via effects on protein kinase A signaling (13).
In a 2012 study, 9 children of preschool age (3–7 years) exposed during pregnancy to topiramate were compared with 18 children not exposed (2). The two groups were compared on developmental measures of visual, fine and gross motor function, and behavior and cognitive functions. The exposed group performed significantly worse than controls in almost all measures, including verbal, nonverbal, and general IQ scores (2).
A dose-related interaction between topiramate and a combined oral contraceptive (ethinylestradiol 35 mcg/northethindrone 1 mg) has been reported (4,14). At a dose of 400 mg/day, peak levels of the estrogen were decreased. At 800 mg/day, estrogen bioavailability was reduced and clearance increased. Norethindrone clearance was also increased at 800 mg/day. The concurrent use of these agents could reduce the efficacy of the contraceptive, possibly requiring a higher-dose contraceptive combination (14).
Topiramate is known to induce hepatic enzymes and may increase the incidence of early hemorrhagic disease of the newborn by depleting fetal vitamin K stores. Although vitamin K1 (see Phytonadione) does not readily cross the placenta, 10 mg/day of the vitamin may be given orally to the mother in the last 4 weeks of pregnancy. In addition, 1 mg of vitamin K1 should be given IV or IM to the infant at birth (15).
BREASTFEEDING SUMMARY
Topiramate is excreted into breast milk. This is consistent with the low molecular weight (about 339), protein binding (13%–17%), and metabolism (about 30%), and the prolonged plasma elimination half-life (21 hours).
Three women who had been treated with topiramate throughout pregnancy (see above) and continued during nursing were studied (6). The daily doses were 150, 200, and 200 mg/day. The mean milk:plasma ratio 3 weeks after delivery was 0.86 (range 0.67–1.1). In one case, 3 months after delivery, the ratio was 0.69. The minimum weight-adjusted infant doses, based on 150 mL/kg of milk per day, were about 0.1–0.7 mg/kg/day or 3%–23% of the maternal doses. Plasma concentrations of topiramate in two infants at 3 weeks of age, before and after nursing, were 1.4 and 1.3 microM, and 1.6 and 1.9 microM, respectively. The latter infant had a topiramate plasma concentration of 2.1 microM at 3 months of age. (Note: Possible antiepileptic effects of topiramate on cultured neurons are concentration-dependent within the range of 1 to 200 microM [3]). Plasma levels in the third infant were undetectable at 2 and 4 weeks postdelivery. The elimination half-life in the infants was estimated to be about 24 hours compared with 20–30 hours among healthy adult controls. No adverse effects of the exposure were observed (6).
In pediatric patients (ages 2–16 years), common adverse effects (most occurred twice as often or more than those in placebo-treated patients) associated with topiramate were fatigue, somnolence, difficulty with concentration/attention, aggressive reaction, confusion, difficulty with memory, ataxia, purpura, epistaxis, infections (viral and pneumonia), and anorexia and weight decrease (4). (Patients also were receiving one or two other anticonvulsants.) The potential for these or other adverse effects in a nursing infant cannot be assessed with the available data. Therefore, nursing women who are being treated with topiramate, particularly those receiving high doses, should be advised to monitor their infants for signs of toxicity and for changes in alertness, behavior, and feeding habits.
References
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12.The Lamotrigine Pregnancy Registry. Final Report. September 1, 1992 through March 31, 2010. GlaxcoSmithKline, July 2010.
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