Phenytoin induced malformations, fetal hyperglycaemia: a role for arachidonic acid?

Howe A, Farrell E, Oakes DJ and Ritchie H

School of Medical Sciences, Univeristy of Sydney.

Background: Phenytoin (Phe) controls epilepsy, so women must remain on the drug during pregnancy. It is a human teratogen causing cleft lip and maxillary hypoplasia. Using an animal model developed by the authors, a teratogenic dose of phenytoin was associated with acute maternal hyperglycaemia and an increased risk of malformations. A previous study demonstrated increased serum levels of arachidonic acid (AA) were associated with decreased malformations in offspring of diabetic rats (Reece et al., 1996. Am J of Obst and Gyn, 175(4): 818-823). Aim: To determine whether dosing with AA ameliorates the teratogenic effects of phenytoin. Method: Pregnant rats were given a teratogenic dose of Phe during the critical period of craniofacial development followed by an injection of arachidonic acid (PheAA) or insulin (PheIns). Control rats received either Phe or AA. Blood glucose levels were measured at 2, 4 and 24 hrs later. At the end of pregnancy, fetuses were examined for the presence of malformations. Malformations ranged from cleft lip to moderate or severe maxillary hypoplasia. Result: Phe and PheAA rats showed increased glucose levels (2 and 8 hrs) in the dams and fetus, unlike PheIns or controls (saline, or AA only) rats. Treatment produced cleft lip and maxillary hypoplasia in all the Phe exposed embryos. Co-administration of insulin (PheIns) reduced both clefting and severity of maxillary hypoplasia, whereas, co-treatment with AA (PheAA) reduced the rate but not severity of malformations. Conclusion:Results indicate reduced hyperglycaemia (by insulin) was associated with reduced rate and severity of Phe- induced malformations. AA did not reduce, but in fact, increased the severity of Phe- induced malformations. This suggests acute hyperglycaemia (and associated malformations) induced in our model is not related to the AA deficiency that occurs with the chronic hyperglycaemia reported in both in vitro and in vivo models of diabetic embryopathy.