topiramate and Teratogenesis

Antiseizure medications (ASMs) are frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders. Possible teratogenic effects are therefore of wide concern and the risks imposed by the medications must be weighed against the risk with the disorder treated. It is our objective to update family practitioners on the implications of starting ASM for women with epilepsy during childbearing age. We hypothesized that clinicians would prescribe ASM based on avoiding teratogenesis and treating associated comorbidities simultaneously.. The study cohort was derived from women veterans with epilepsy (WVWE) prescribed ASM who received Veterans Health Administration care for at least 3 years in Veterans Health Administration between fiscal years (FY)01 and FY19. Regimens were classified as monotherapy or polytherapy. Multivariant logistic regression examined the association between demographics, military characteristics, physical/psychiatric comorbidities, neurological care, and use of each ASM.. Among 2,283 WVWE, in ages between 17 and 45, the majority (61%) received monotherapy in FY19. Commonly prescribed ASM included 29% gabapentin, 27% topiramate, 20% lamotrigine, 16% levetiracetam, and 8% valproate (VPA). Comorbid diagnosis of headache predicted use of topiramate and VPA, bipolar disease predicted use of LMT and VPA, pain predicted gabapentin, and schizophrenia was associated with VPAs use. Women receiving levetiracetam and lamotrigine were significantly more likely to receive neurology care previously.. The presence of medical comorbidities influences the selection of ASM. VPAs use in WVWE during childbearing age continues, despite the high teratogenic risk, especially in women with bipolar disorder and headaches. Multidisciplinary care integrating family practice doctors, mental health, and neurology can prevent the enduring problem of teratogenesis in women taking ASM.

Topics: Adolescent; Adult; Anticonvulsants; Epilepsy; Female; Gabapentin; Humans; Lamotrigine; Levetiracetam; Middle Aged; Pain; Pharmaceutical Preparations; Teratogenesis; Topiramate; Valproic Acid; Veterans; Young Adult

Topiramate is commonly used for treating epilepsy in both children and adults. Recent clinical data suggests that administration of topiramate to women during pregnancy increases the risk of oral clefts in their offspring. To better understand the potential effects of topiramate, we dosed adult female zebrafish with topiramate, and investigated the altered morphologies in adult females and their offspring. It showed that topiramate-treated female fish had reduced oocyte maturation, and the survival rates of their offspring were seriously decreased during embryogenesis. In addition, around 23% of offspring displayed cartilage malformation in the craniofacial area, such as loss of ceratobranchial cartilages as well as impaired ceratohyal, Meckel's cartilage and ethmoid plate development. Moreover, mineralization of ceratohyal, Meckel's cartilage, and vertebrae were downregulated during bone development. Taken together, we concluded that topiramate impaired oogenesis in the maternal reproductive system, and then caused offspring cartilage malformation or bone dysplasia.

Topics: Animals; Body Weight; Chondrogenesis; Craniofacial Abnormalities; Female; Fructose; Models, Animal; Oocytes; Oogenesis; Teratogenesis; Teratogens; Topiramate; Zebrafish

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

Topics: Acetamides; Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Ethosuximide; Female; Fructose; Humans; Lacosamide; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Teratogenesis; Topiramate; Triazines; United States; Valproic Acid; Zebrafish