Prothrombin and PIVKA‐II Levels in Cord Blood from Newborn Exposed to Anticonvulsants During Pregnancy

Abstract

Summary:Purpose: To determine whether anticonvulsant exposure during human pregnancy caused an increase of the abnormal form of prothrombin, known as PIVKA-I1 (prothrombin induced by vitamin K absence for factor 11), and a decrease in total prothrombin, in the blood of the newborn.Methods: Cord blood was collected from the placenta at the time of parturition from 12 women who had received anticonvulsant therapy during pregnancy and from 11 control women.Results: PIVKA-I1 was present in cord blood from control mothers at low or nondetectable levels. In the same samples, total prothrombin concentrations were -50% of adult levels, but there was wide variation between individuals. Exposure to carbamazepine (CBZ) alone during pregnancy was associated It has been known for a number of years that maternal use of the anticonvulsants (AEDs) phenobarbital (PB; and derivatives), phenytoin (PHT), and carbamazepine (CBZ) is sometimes associated with bleeding in the neonate (1-5). Furthermore, each of these drugs is associated with an abnormal facial appearance in some of the exposed neonates. Typically there is a small, depressed nose and midfacial hypoplasia (6-8). The similarity between this facial appearance and the facies of children exposed to warfarin prenatally (9), and the tendency for both groups to have neonatal bleeding, has led to the suggestion that these defects are the result of AEDinduced vitamin K deficiency in the embryo (9,lO). The primary pharmacologic effect of warfarin is to block vitamin K recycling, which results in an effective vitamin K deficiency.There is some evidence that vitamin K may be necessary for normal prenatal midfacial growth (1 1 ) as well as

Canadian Paediatric Surveillance Program confirms low incidence of hemorrhagic disease of the newborn in Canada

“…Although there is evidence of vitamin K deficiency in the cord blood from newborns exposed to anticonvulsants (and antituberculous drugs) during pregnancy (24), there were no reports of such occurrence during the four years experience in Canada. Somewhat surprisingly, one classic and two late HDNB were reported in spite of intramuscular vitamin K administration following birth.…”

Experimental studies on reproductive toxicologic effects of lamotrigine in mice

“…Hemorrhagic lesions of the tail similar to those observed here were also reported in a VPA‐study (Padmanabhan and Ahmed, 1996). These taken together with human studies involving phenytoin (Howe et al, 1995) and carbamazepine (Howe et al, 1999) would suggest that AEDs might cause congenital malformations via a common mechanism of fetal hemorrhage, possibly involving vitamin K deficiency (Howe et al, 1999). Disturbance to the caudal eminence in the retinoic acid and VPA‐treated mouse embryos seems to be initiated by hemorrhage and subsequent vascular disruption sequence (Padmanabhan, 1998).…”

Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate

“…[10][11][12] There is, however, no evidence that these biochemical changes are associated with a risk for clinical bleeding. These series, consisting of 12 to 25 patients each, show that newborn infants exposed to maternal enzyme-inducing AED may exhibit elevated concentrations of PIVKA II (protein induced by vitamin K absence of factor II), which is an indirect marker of deficient vitamin K production.…”

“…[2][3][4][5][6] Since 1958, Ͼ40 cases of neonatal bleeding associated with maternal anticonvulsant therapy have accumulated. 3,[10][11][12] Enzyme-inducing AED such as phenobarbital, phenytoin, and carbamazepine cross the placenta and increase the rate of oxidative degradation of vitamin K in the fetus. 3,[10][11][12] Enzyme-inducing AED such as phenobarbital, phenytoin, and carbamazepine cross the placenta and increase the rate of oxidative degradation of vitamin K in the fetus.…”