Teratogenic effects of carbamazepine on embryonic eye development in pregnant mice.
BACKGROUND
Carbamazepine is an antiepileptic drug used widely for the treatment of epileptic seizures and neuropathic pain. Several malformations in humans, mainly neural tube defects, have been reported as a consequence of its use during pregnancy. The association between maternal use of carbamazepine and congenital eye malformations is not very well understood.


OBJECTIVE
The purpose of this study was to examine this association after intraperitoneal injection of carbamazepine during the period of organogenesis in mice.


METHODS
Balb/c timed-pregnant mice were divided into 4 experimental and control groups. Two experimental groups received daily intraperitoneal injections of 15 mg/kg (group I) or 30 mg/kg (group II) of carbamazepine on gestational days 6 to 15. Two control groups received normal saline or Tween 20 (polysorbate 20). Dams underwent Cesarean section on gestational day 18 and embryos were harvested. External examination for eye malformations, routine histological processing of malformed fetuses to study eye morphology, and skeletal staining were performed.


RESULTS
The mean weight and crown-rump of the fetuses in both experimental groups were significantly reduced compared with those of the control groups. Various malformations were detected such as brachygnathia, calvarial deformity, vertebral deformity, short tail, and brachydactyly. Premature opening of one or both eyes with mild to severe exophthalmos occurred in the 2 experimental groups. Deformed lens, retinal folds with undeveloped layers, and corneal folds with absence of surface epithelium were detected in both experimental groups.


CONCLUSIONS
This study, to the best of our knowledge, showed for the first time that intraperitoneal administration of carbamazepine at clinically comparable doses during organogenesis can induce several eye malformations in mice. The implication of these results needs to be considered when carbamazepine is administered during human pregnancy.
Afshar
Mohammad
M
Department of Anatomy, Birjand University of Medical Sciences, Birjand, Iran.
Moallem
Seyed Adel
SA
Houshang Mohammadpour
Amir
A
Shiravi
Abdolhossein
A
Majid Jalalian
Seyed
S
Jafar Golalipour
Mohammad
M
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000473:pathology; D000015:Abnormalities, Multiple / Q000209:etiology* / Q000473:pathology; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D002220:Carbamazepine / Q000008:administration & dosage / Q000633:toxicity*; D018568:Crown-Rump Length; D004435:Eating; D005123:Eye / Q000187:drug effects* / Q000196:embryology; D005124:Eye Abnormalities / Q000139:chemically induced*; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D005865:Gestational Age; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009139:Musculoskeletal Abnormalities / Q000139:chemically induced; D038081:Organogenesis / Q000187:drug effects; D011247:Pregnancy; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*
D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D013723:Teratogens; D002220:Carbamazepine