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Epilepsia y Embarazo 1

Epilepsia y Embarazo 1

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299
Epilepsy;Co-Editors in Chief,Robert M.Pascuzzi,M.D.,Karen L.Roos,M.D.;Guest Editor,Martha J.Morrell,M.D.
Seminars in Neurology 
,Volume 22,Number 3,2002.Address for correspondence and reprint requests:Page B.Pennell,M.D.,Emory University School of Medicine, WMB 6000,1639 Pierce Drive,Atlanta,GA 30322.
1
Emory Epilepsy Monitoring Unit,Emory University School of Medicine,Atlanta,Georgia.Copyright © 2002 by Thieme Medical Publishers,Inc.,333 Seventh Avenue,New York,NY 10001,USA.Tel:+1(212) 584-4662.0271-8235,p;2002,22,03,299,308,ftx,en;sin00206x.
Pregnancy in the Woman with Epilepsy:Maternal and Fetal Outcomes
Page B. Pennell, M.D.
1
ABSTRACT
Pregnancy in women with epilepsy is associated with increased obstetric risksand increased adverse neonatal outcomes.Prior to conception,folic acid should be ad-ministered and the antiepileptic drug (AED) regimen should be optimized.Effectivecontrol of maternal seizures with the least risk to the fetus is the goal,preferably using AED monotherapy.Periodic monitoring of total and free AED levels is recommended. The “fetal anticonvulsant syndrome”has been described with all of the AEDs and in-cludes major malformations,minor anomalies,microcephaly,cognitive impairment,in-trauterine growth retardation,and infant mortality.The most common major malforma-tions are cleft lip/palate,heart defects,and neural tube defects.Prenatal screening shouldbe offered.Supplemental vitamin K 
1
should be given to the mother and newborn to pre- vent neonatal hemorrhagic disorder.Careful planning and management of any pregnancy in women with epilepsy are essential to increase the likelihood of a healthy outcome forthe mother and infant.
KEYWORDS:
Epilepsy, women, pregnancy, anticonvulsants, teratogenesis
Objectives:
On completion of this article the reader will be able to outline the current principles in the management of women withepilepsy during pregnancy.
Accreditation:
The Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.
Credit:
The Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours in category onecredit toward the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actuallyspent in the educational activity.
Disclosure:
Statements have been obtained regarding the author’s relationships with financial supporters of this activity. There is noapparent conflict of interest related to the context of participation of the author of this article.
lepsyare essential to minimize these risks.The reduc-tion of these risks begins with preconceptional plan-ning.Approximately 50% of pregnancies are unplannedin the United States,and because of higher oral contra-ceptive failure for many women with epilepsy,
2–4
their rateof unplanned pregnancies may be even greater.Physi-cians treating women with epilepsy are often not appro-priately knowledgeable about issues of pregnancy and
PREGNANCY IN WOMEN WITH EPILEPSY
 Approximately 1.1 million women with epilepsy are of childbearing age in the United States
1
and give birth toover 20,000 babies each year.The vast majority of thesepregnancies are uncomplicated,but there are increasedobstetric risks and increased adverse neonatal outcomescompared with the general population.Careful planningand management of any pregnancy in a woman with epi-
 
300
SEMINARS IN NEUROLOGY/VOLUME 22,NUMBER 32002
epilepsy,
5,6
and current recommended guidelines
4
regard-ingpreconceptional counseling are often not being fol-lowed in the United States or the United Kingdom.
5,7–9
 The initial visit between the physician and a woman withepilepsy of childbearing age should include a discussionabout family planning.Topics should include effectivebirth control,the importance of planned pregnancies withantiepileptic drug (AED) optimization and folate sup-plementation prior to conception,obstetrical complica-tions,and teratogenicity of AEDs versus the risks of sei-zuresduring pregnancy.The goal is effective control of maternal seizures with the least risk to the fetus.
SEIZURES DURING PREGNANCY
 The effect of pregnancy on seizure frequency is variableand unpredictable between patients.According to re-cent studies,approximately 20 to 33% of patients havean increase in their seizures,7 to 25% a decrease inseizures,and 50 to 83% no significant change.
10–12
Un-fortunately,which route an individual’s course will takeis impossible to know and cannot be predicted on thebasis of factors such as age,ethnic origin,number of pregnancies,seizure type(s),AED(s),and seizure fre-quency during a previous pregnancy.Pregnancy is associated with several physiologicand psychologic changes that can alter seizure frequency,including changes in sex hormone concentrations,changesin AED metabolism,sleep deprivation,and new stresses.One study demonstrated that sleep deprivation or non-compliance played a clear role in up to 70% of women with an increase in seizures during pregnancy,
13
 yetthese two factors are largely modifiable.It is importantto inquire about both sleep patterns and compliance inpregnant patients with epilepsy.Sleep deprivation can bedue to physical discomforts,movements of the fetus,andnocturia.Marital and financial stress and personal doubtsand concerns can contribute to sleep deprivation as wellas cause a more direct increase in likelihood of seizureoccurrence.Noncompliance with medications is commonduring pregnancy and is in large part due to the strongmessage that any drugs during pregnancy are harmful tothe fetus.Teratogenic effects of AEDs are well described,but risks to the fetus are often exaggerated or misrepre-sented.Proper education about the risks of AEDs ver-sus the risks of seizures can be very helpful in ensuringcompliance during pregnancy.During pregnancy,the risk of seizures to the fetusis important and should be discussed thoroughly withthe patient and other family members.Generalized tonic-clonic seizures (GTCSs) can cause maternal and fetalhypoxia and acidosis.
1,14
 After a single GTCS,fetal in-tracranial hemorrhages,miscarriages,and stillbirths havebeen reported.
15
Status epilepticus is an uncommon com-plicationof pregnancy,but when it does occur it carriesa high maternal and fetal mortality rate.In one series of 29 cases,there were 9 maternal deaths and 14 infantdeaths.
16
 A single brief tonic-clonic seizure has beenshown to cause depression of the fetal heart rate formore than 20 minutes,
17
and longer or repetitive tonic-clonic seizures are incrementally more hazardous to thefetus as well as the mother.It is not as clear what the effects of nonconvulsiveseizures are on the developing fetus.One study demon-strated that maternal seizures of all types in the first tri-mester were associated with a higher malformation rateof 12.3% compared with a malformation rate of 4% forinfants of epileptic mothers not exposed to seizures dur-ing the first trimester.
18
No significant differences inmalformation rates have been observed between off-spring of women with different types of epilepsy.
18,19
Inone case report,a complex partial seizure during labor was associated with a strong,prolonged uterine contrac-tion with fetal heart rate deceleration for 3.5 minutes.
20
Many types of seizures can cause trauma,which can re-sult in ruptured fetal membranes with an increased risk of infection,premature labor,and even fetal death.
21
 Abruptio placentae occurs after 1 to 5% of minor and20 to 50% of major blunt injuries.
22
Restrictions fromdriving and climbing heights should be reinforced witheach patient with special emphasis on the risk to thefetus of a seemingly minor injury.
ANTIEPILEPTIC DRUG MANAGEMENT
Management of AEDs during pregnancy can be com-plex.Plasma AED concentrations decrease significantly during pregnancy despite steady or increasing doses andtend to rise again postpartum.
12,23–25
 A similar but evenexaggerated effect is seen with lamotrigine (LTG).
23,24,26
 The changes in AED levels during pregnancy can vary  widely and are not predictable for the individual on thebasis of reported group changes or total levels only formoderately to highly protein-bound AEDs.Althoughthe ratio of free to bound drug increases during preg-nancy,the amount of free AED still usually declines.
1,12
 The optimal approach to monitoring AED levels duringpregnancyis one that measures free levels of any AEDthat is highly or moderately protein bound.
4
 Total levelsare sufficient for AEDs that are minimally proteinbound.The ideal AED (free) level needs to be estab-lished for each individual patient prior to conception andshould be the level at which seizure control is the bestpossible for that patient without debilitating side effects.Levels should be obtained at least at baseline prior toconception,repeated at the beginning of each trimester,and obtained again in the last 4 weeks of pregnancy.
4
Some authors recommend monthly monitoring,giventhe possibility of rapid and unpredictable decreases in AED levels in an individual patient.
12,23,27
 The frequency 
 
PREGNANCY IN THE WOMAN WITH EPILEPSY/
PENNELL
301
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.
21
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.
OBSTETRICAL COMPLICATIONS
 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.
1
 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.
28
TERATOGENESIS
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.
1,29–31
 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.
32
Intrauterine growth retardation results in low birth weight (<2500 g) in 7 to 10% of infants born to women with epilepsy 
1,29
and is even more prevalent in infantsexposed to polytherapy.
33
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
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.
34
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.
21,34
Many of the craniofacial anomalies areoutgrown by age 5 years.
Major Malformations
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%
4,15,30,34,35
Major malformations (Table1) associated with AEDsinclude congenital heart disease,cleft lip/palate,andneural tube defects.
21,34
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.
36
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.
37,38
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%1.52%Cleft lip/palate0.15%1.4%Neural tube defect0.1%12% (VPA)0.5–1% (CBZ)
CBZ, carbamazepine; VPA, valproate.

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