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Published on: July 29, 2019
Experimental studies on reproductive toxicologic effects of lamotrigine in mice
R Padmanabhan1, Y M Abdulrazzaq, S M A Bastaki
1Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates. padmanabhanr@uaeu.ac.ae
Background:
Virtually all antiepileptic drugs (AED) tested so far have been found to be teratogenic. The second generation AED possess a number of therapeutic advantages over the older ones. There are, however, very little data on their effects on embryonic development. A recent report suggests that lamotrigine (LTG) can be teratogenic to human fetuses. With only a few cases of prenatal exposure to LTG in the record, however, it has not been possible to establish a recognizable pattern of malformations in the infants of LTG-treated mothers.
Objectives:
The objectives of the present study were to evaluate the reproductive toxic effects of LTG .
Results:
Single (50-200 mg/kg) or multiple doses (25, 50, 75 mg/kg) of LTG were administered by intraperitoneal (i.p.) injection (note that the therapeutic administration is oral) to groups of TO mice on gestation day (GD) 7 or 8. Fetuses were collected on GD 18. Maternal toxic effects including a dose-related mortality, a high incidence of abortion, embryo lethality, congenital malformations and intrauterine growth retardation (IUGR) were observed in the LTG-treated group. Administration of LTG in multiple low doses resulted in a better maternal survival and increased incidence of embryonic resorption and malformations with increasing dose; IUGR was significant but not dose-dependent. The malformations characteristic of the LTG multiple low dose group fetuses included maxillary-mandibular hypoplasia, exencephaly, cleft palate, median facial cleft, urogenital anomalies and varying degrees of caudal regression. Skeletal malformations and developmental delay of the skeleton were observed both in single and multiple dose groups.
Conclusions:
The results of this study indicate that LTG administered i.p. at high doses can induce intrauterine growth retardation and at low multiple doses causes a dose-dependent increase in embryonic resorption, craniofacial and caudal malformations as well as maternal toxicity in the mouse. Previous studies in other laboratories have used oral route of exposure and concluded that there are no teratogenic effects of LTG at dose levels that are not maternally toxic.
Insights
Lamotrigine (LTG), an antiepileptic drug, can cause significant embryonic developmental toxicity, including malformations and growth retardation in mice. These findings highlight potential risks of LTG exposure during pregnancy.
Area of Science:
- Developmental toxicology
- Pharmacology
- Teratology
Background:
- Antiepileptic drugs (AEDs) are often teratogenic, posing risks to fetal development.
- Limited data exist on the embryonic effects of second-generation AEDs like lamotrigine (LTG).
- Previous reports suggest LTG may be teratogenic, but patterns of malformation are not well-established.
Purpose of the Study:
- To evaluate the reproductive toxic effects of lamotrigine (LTG) in a mouse model.
- To investigate dose-dependent teratogenic effects and maternal toxicity associated with LTG exposure.
Main Methods:
- TO mice were administered single or multiple doses of LTG via intraperitoneal injection on gestation days 7 or 8.
- Fetuses were collected on gestation day 18 for examination.
- Maternal toxicity, embryo lethality, abortion, congenital malformations, and intrauterine growth retardation (IUGR) were assessed.
Main Results:
- LTG administration induced maternal toxicity, including mortality, abortion, and embryo lethality.
- Observed fetal malformations included maxillary-mandibular hypoplasia, exencephaly, cleft palate, and caudal regression.
- Both single high doses and multiple low doses of LTG resulted in significant IUGR and skeletal malformations.
Conclusions:
- LTG administered intraperitoneally can cause IUGR and maternal toxicity in mice.
- Multiple low doses of LTG increased embryonic resorption and induced dose-dependent craniofacial and caudal malformations.
- These findings contrast with studies using oral LTG administration, suggesting route of administration impacts teratogenic potential.
