PREGNANCY IN THE WOMAN WITH EPILEPSY/
of monitoring levels needs to be tailored to each situa-tion,including increased monitoring for worseningseizure control,adverse effects,and compliance issues.Several factors contribute to the decline in AEDlevels during pregnancy.
Impaired absorption is onecause,although relatively uncommon.The volume of dis-tribution increases throughout pregnancy,but this wouldnot account for the relatively lesser reduction in free lev-els compared with total levels.The most important con-tributing mechanisms are thought to be decreased albu-min concentration,reduced plasma protein binding,andincreased drug clearance.The decline in albumin con-centration and plasma protein binding creates an in-creased percentage of unbound AED,which in turn pro- videsan increased proportion of the drug available formetabolic degradation.In addition,the increased sexsteroid hormone levels may cause an induction of thehepatic microsomal enzymes and contribute to the in-creased clearance of AEDs.
Women with epilepsy do have an increased risk of cer-tain obstetrical complications.There is an approximately twofold increased risk of vaginal bleeding,anemia,hy-peremesis gravidarum,abruptio placentae,eclampsia,premature rupture of membranes,induced labor,and ce-sareansection.
Weak uterine contractions have beendescribed in women taking AEDs,which may accountfor the twofold increased use of interventions duringlabor and delivery including induction,mechanical rup-ture of membranes,forceps or vacuum assistance,andcesarean sections.
Offspring of women with epilepsy are at an increasedrisk for intrauterine growth retardation,major congeni-tal malformations,minor anomalies,microcephaly,cog-nitive dysfunction,and infant mortality.
The term“fetal anticonvulsant syndrome”is used to include vari-ous combinations of these findings and has been de-scribed with virtually all of the AEDs.
Intrauterine growth retardation results in low birth weight (<2500 g) in 7 to 10% of infants born to women with epilepsy
and is even more prevalent in infantsexposed to polytherapy.
Minor anomalies are definedas structural deviations from the norm that do not con-stitute a threat to health.Major malformations are de-fined as abnormalities of an essential anatomical struc-ture present at birth that interfere significantly withfunction or require major intervention,or both.
Minor anomalies affect 6 to 20% of infants born to women with epilepsy,which is an approximately two-fold increased rate compared with the general popula-tion.
Minor anomalies include distal digital and nailhypoplasia,and the craniofacial anomalies including oc-ular hypertelorism,broad nasal bridge,short upturnednose,altered lips,epicanthal folds,abnormal ears,andlow hairline.
Many of the craniofacial anomalies areoutgrown by age 5 years.
Major malformations occur at a rate of 2 to 3% in thegeneral population;reported rates in offspring of women with epilepsy range from 1.25 to 11.5%,with the com-bined estimates yielding a rate of 4 to 6%
Major malformations (Table1) associated with AEDsinclude congenital heart disease,cleft lip/palate,andneural tube defects.
Urogenital defects also occur ata higher rate of 1.7% of newborns and commonly in- volve glandular hypospadias.The congenital heart de-fects include atrial septal defect,ventricular septal de-fect,tetralogy of Fallot,coarctation of the aorta,patentductus arteriosus,and pulmonary stenosis.The neuraltube defects usually consist of spina bifida and notanencephaly but tend to be severe open defects fre-quently complicated by hydrocephaly and other midlinedefects.
Carbamazepine (CBZ) and valproate (VPA)are selectively associated with neural tube defects at arate of 10 and 20 times that in the general population,respectively.
One analysis of pooled data from fiveprospective studies suggested that the absolute risk withVPA monotherapy may be as high as 3.8% for neuraltube defects and that offspring of women receiving
Table 1Major Malformations in Infants ofWomen with Epilepsy
MalformationGeneral PopulationInfants ofWomen with Epilepsy
Congenital heart0.5%1.5–2%Cleft lip/palate0.15%1.4%Neural tube defect0.1%1–2% (VPA)0.5–1% (CBZ)
CBZ, carbamazepine; VPA, valproate.