Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes
Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society
C. L. Harden, MD,
K. J. Meador, MD,
P. B. Pennell, MD,
W. A. Hauser, MD,
G. S. Gronseth, MD,
J. A. French, MD,
S. Wiebe, MD,
D. Thurman, MD, MPH,
B. S. Koppel, MD,
P. W. Kaplan, MB, FRCP,
J. N. Robinson, MD,
J. Hopp, MD,
T. Y. Ting, MD,
B. Gidal, PharmD,
C. A. Hovinga, PharmD,
A. N. Wilner, MD,
B. Vazquez, MD,
L. Holmes, MD,
A. Krumholz, MD,
R. Finnell, PhD,
D. Hirtz, MD and
C. Le Guen
Authors’ affiliations are listed at the end of the article.
From the University of Miami (C.L.H.), Miami, FL; Emory University (K.J.M., P.B.P.), Atlanta, GA; Columbia University (W.A.H.), New York, NY; Kansas University Medical Center (G.S.G.), Kansas City; New York University School of Medicine (J.A.F.), New York; University of Calgary (S.W.), Alberta, Canada; Centers for Disease Control and Prevention (D.T.), Atlanta, GA; New York Medical College (B.S.K.), New York; Johns Hopkins University (P.W.K.), Baltimore, MD; Harvard Medical School (J.N.R., L.H.), Boston, MA; University of Maryland (J.H., T.Y.T., A.K.), Baltimore; University of Wisconsin–Madison School of Pharmacy (B.G.); University of Tennessee Health Science Center (C.A.H.), Memphis; private practice (A.N.W.), Newport, RI; New York University (B.V.), New York; Texas A&M University Health Science Center (R.F.), Houston; NINDS (D.H.), Bethesda, MD; and University of Pennsylvania (C.L.), Philadelphia.
Address correspondence and reprint requests to the American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116 guidelines{at}aan.com
Objective: To reassess the evidence for management issues relatedto the care of women with epilepsy (WWE) during pregnancy.
Methods: Systematic review of relevant articles published betweenJanuary 1985 and June 2007.
Results: It is highly probable that intrauterine first-trimestervalproate (VPA) exposure has higher risk of major congenitalmalformations (MCMs) compared to carbamazepine and possiblecompared to phenytoin or lamotrigine. Compared to untreatedWWE, it is probable that VPA as part of polytherapy and possiblethat VPA as monotherapy contribute to the development of MCMs.It is probable that antiepileptic drug (AED) polytherapy ascompared to monotherapy regimens contributes to the developmentof MCMs and to reduced cognitive outcomes. For monotherapy,intrauterine exposure to VPA probably reduces cognitive outcomes.Further, monotherapy exposure to phenytoin or phenobarbitalpossibly reduces cognitive outcomes. Neonates of WWE takingAEDs probably have an increased risk of being small for gestationalage and possibly have an increased risk of a 1-minute Apgarscore of <7.
Recommendations: If possible, avoidance of valproate (VPA) andantiepileptic drug (AED) polytherapy during the first trimesterof pregnancy should be considered to decrease the risk of majorcongenital malformations (Level B). If possible, avoidance ofVPA and AED polytherapy throughout pregnancy should be consideredto prevent reduced cognitive outcomes (Level B). If possible,avoidance of phenytoin and phenobarbital during pregnancy maybe considered to prevent reduced cognitive outcomes (Level C).Pregnancy risk stratification should reflect that the offspringof women with epilepsy taking AEDs are probably at increasedrisk for being small for gestational age (Level B) and possiblyat increased risk of 1-minute Apgar scores of <7 (Level C).
Abbreviations:AAN = Academy of Neurology; AED = antiepileptic drug; CBZ = carbamazepine; CI = confidence interval; LTG = lamotrigine; MCM = major congenital malformation; OR = odds ratio; PB = phenobarbital; PHT = phenytoin; RR = relative risk; SGA = small for gestational age; VPA = valproate; WWE = women with epilepsy.
Recent estimates of the US population1 and the prevalence ofepilepsy2 indicate that approximately one-half million womenwith epilepsy (WWE) are of childbearing age. It has also beenestimated that three to five births per thousand will be toWWE.3 Epilepsy is defined by the presence of recurrent, unprovokedseizures, and the treatment is typically a daily, long-termantiepileptic drug (AED) regimen. The majority of people withepilepsy have well-controlled seizures, are otherwise healthy,and therefore expect to participate fully in life experiences,including childbearing.
This parameter summarizes evidence for three important issuesregarding the clinical management of WWE who are pregnant orplan pregnancy:
What is the risk of major congenital malformations (MCMs) associatedwith intrauterine exposure to AEDs in neonates born to WWE?
What is the risk of adverse long-term cognitive outcomes inchildren born to WWE?
What is the risk of death, low birthweight,and low Apgar scoresin neonates born to WWE?
Major congenital malformations.
Fifty-two relevant articles were identified by the literaturesearch. Articles were classified for risk of bias using AmericanAcademy of Neurology (AAN) criteria for classification of evidencefor causality (appendix e-4A on the Neurology® Web siteat www.neurology.org). Studies rated Class III or higher thatcontributed to conclusions are summarized in tables e-1 throughe-5.
MCMs were defined as structural abnormalities with surgical,medical, or cosmetic importance.5 Minor malformations such asfacial dysmorphism were not considered in the statistical analysis.For the purpose of this parameter, the presence of MCMs wasconsidered an objective outcome. To attain a Class I or II rating,the study must have accounted for confounding by maternal ageand socioeconomic status.
The contribution of maternal epilepsy to the risk of MCMs isnot specifically considered herein, since the evidence is unclearand the risk, if any, appears small.6 However, it cannot bestated that the risk imparted by maternal epilepsy is zero.Therefore, we addressed the question regarding risk of MCMsdue to AEDs taken during the first trimester by including onlystudies where WWE not taking AEDs served as comparators. Weacknowledge that the severity of the maternal epilepsy in termsof seizure type and frequency cannot be completely matched betweencomparator groups and may contribute to the difference in outcomesin the two groups. Women without epilepsy who were taking AEDsfor other reasons were not included.
For the subsequent questions, the evaluation is focused on therisks of AEDs compared to each other, or findings specific toan individual AED such as a dose-malformation relationship.Therefore, three studies used in answering these questions7-9include the offspring of mothers who took AEDs for various indications.
Do AEDs taken during the first trimester of pregnancy increase the risk of MCMs in the offspring of WWE compared to the offspring of WWE not on AEDs?AEDs in general.
One Class I study10 showed no increased risk of MCMs in theoffspring of WWE taking AEDs compared to the offspring of WWEnot taking AEDs (relative risk [RR] 1.19, confidence interval[CI] 0.59–2.40). However, the study was insufficientlysensitive to exclude a substantially increased risk. Two ClassII studies (odds ratio [OR] 3.92, CI 1.29–11.90,5 andOR 1.70, CI 1.07–2.68)11 found increased risks of MCMswith maternal AED exposure compared to untreated WWE.
Valproate.
One Class II study11 demonstrated increased risk of MCMs inthe offspring of WWE using valproate (VPA) in monotherapy (OR4.18, CI 2.31–7.57) or polytherapy (OR 3.54, CI 1.42–8.11).One Class I study10 also showed the risk of MCMs with polytherapyincluding VPA was increased compared to untreated WWE (RR 2.52,CI 1.17–5.44).
Carbamazepine.
One Class I study10 found no increased risk of MCMs in the offspringof WWE taking carbamazepine (CBZ) (RR 0.63, CI 0.28–1.41).
Lamotrigine.
One Class I study10 observed no increased risk of MCMs in theoffspring of WWE taking lamotrigine (LTG) (RR 0.92, CI 0.41–2.05)but was insufficiently sensitive to exclude a substantiallyincreased risk.
The absolute risk of MCMs in the largest Class I study10 withat least 80 outcomes per AED is as follows: CBZ (n = 900) 2.2%(CI 1.4–3.4), VPA (n = 715) 6.2% (CI 4.6–8.8), LTG(n = 647) 3.2% (CI 2.1–4.9), phenytoin (PHT) (n = 82)3.7% (CI 1.3–10.2).
Conclusions
AEDs taken during the first trimester probably increase therisk of MCMs in the offspring of WWE (two adequately sensitiveClass II studies) but it cannot be determined if the increasedrisk is imparted from all AEDs or from only one or some AEDs.
VPA monotherapy during the first trimester possibly increasesthe risk of MCMs in the offspring of WWE (one Class II study).
VPA used in polytherapy probably increases the risk of MCMsin the offspring of WWE (one Class I study).
CBZ probablydoes not substantially increase the risk of MCMsin the offspringof WWE (one Class I study).
There is insufficient evidenceto determine if LTG (one inadequatelysensitive Class I study)or other specific AEDs (no Class IIIor better evidence) increasethe risk of MCMs in the offspringof WWE.
Recommendations
Although there is evidence that AEDs taken during the firsttrimester probably increase the risk of MCMs in the offspringof WWE, it cannot be determined if the increased risk is impartedfrom all AEDs or from only one or some AEDs. Therefore, no recommendationis made from this conclusion.
If possible, avoidance of theuse of VPA as part of polytherapyduring the first trimesterof pregnancy should be consideredto decrease the risk of MCMs(Level B).
If possible, avoidance of the use of VPA monotherapyduringthe first trimester of pregnancy may be considered todecreasethe risk of MCMs (Level C).
Is exposure to a specific AED during the first trimester of pregnancy associated with an increased risk of MCMs compared to exposure to other AEDs?
Two Class I studies (OR 2.97, CI 1.65–5.35,10 and OR 2.51,CI 1.43–4.86)7 revealed that VPA monotherapy is associatedwith a greater risk for MCMs than CBZ monotherapy.
One Class I study10 and one Class II study11 showed that VPAas part of polytherapy was associated with greater risk thanpolytherapy without VPA (OR 2.49, CI 1.31–4.70,10 andOR 1.97, CI 0.58–6.6611).
One Class II study12 showed that VPA is associated with a greaterrisk than PHT (OR 9.06, CI 1.13–72.14).
We performed comparisons for three of the four Class III studies,using primary data from the articles.13–15 All significantcomparisons between AEDs are reported herein. In two Class IIIstudies,13,14 VPA was associated with increased risk when individuallycompared to CBZ (RR 4.34, CI 1.79–10.5313 and RR 3.83,CI 1.41–10.39)14 and LTG (RR 5.58, CI 2.06–15.0913and RR 17.04, CI 2.27–128.05).14 The third Class III study15showed VPA was associated with greater risk than phenobarbital(PB) (RR 5.66, CI 1.19–26.88).
All four Class III studies showed VPA was associated with greaterrisk than all other monotherapies combined. We compared VPAto CBZ, LTG, and PHT in two studies and found increased riskin both (RR 5.6, CI 2.42–12.92,13 and RR 4.59, CI 2.07–10.18).14In the third Class III study,15 we compared VPA to PB, CBZ,PHT, and primidone and found increased risk (RR 3.25, CI 1.27–8.33).In the fourth Class III study, we found increased risk of VPAcompared to three undisclosed AEDs (OR 4.0, CI 2.1–7.4).16
Conclusions
It is highly probable that taking VPA monotherapy during thefirst trimester of pregnancy contributes to the developmentof MCMs in the offspring of WWE compared to taking CBZ (twoClass I studies).
VPA as part of polytherapy in the firsttrimester of pregnancyprobably contributes to the developmentof MCMs in the offspringof WWE compared to polytherapy thatdoes not include VPA (oneClass I study).
Taking VPA duringthe first trimester of pregnancy possiblycontributes to thedevelopment of MCMs in the offspring of WWEcompared to takingPHT (one Class II study).
Taking VPA during the first trimesterof pregnancy possiblycontributes to the development of MCMsin the offspring of WWEcompared to taking LTG (two Class IIIstudies).
Recommendations
To reduce the risk of MCMs, the use of VPA during the firsttrimester of pregnancy should be avoided, if possible, comparedto the use of CBZ (Level A).
To reduce the risk of MCMs, avoidanceof the use of polytherapywith VPA during the first trimesterof pregnancy, if possible,should be considered, compared topolytherapy without VPA (LevelB).
To reduce the risk of MCMs,avoidance of the use of VPA duringthe first trimester of pregnancy,if possible, may be considered,compared to the use of PHT orLTG (Level C).
Is the risk of MCMs greater for AED polytherapy compared to AED monotherapy when taken during the first trimester of pregnancy?
One Class I study10 showed a moderately increased risk of MCMswith polytherapy vs monotherapy (RR 1.62, CI 1.14–2.31).Three Class II studies (OR 1.76, CI 0.94–3.3111; OR 2.00,CI 0.80–3.745; and OR 1.46, CI 0.83–2.56)12 demonstratedno increased risk with polytherapy. However, these studies wereinsufficiently sensitive to exclude a substantially increasedrisk.
Conclusion.
Polytherapy probably contributes to the development of MCMsin the offspring of WWE as compared to monotherapy (one ClassI study).
Recommendation.
To reduce the risk of MCMs, avoidance of the use of AED polytherapyduring the first trimester of pregnancy, if possible, comparedto monotherapy should be considered (Level B).
Is there a relationship between AED dose and the risk of MCMs in the offspring of WWE?
All studies evaluated AED dose in the first trimester and MCMs.In one Class I study,10 a relationship between AED dose andrisk of MCMs was reported for LTG but not VPA. Using the CochranArmitage method,17 we found a significant dose relationshipwith VPA (exact tests one-sided p = 0.02, two-sided p = 0.04)and with LTG (exact tests one-sided p = 0.01, two-sided p =0.02), but not with CBZ (exact tests one-sided p = 0.19, two-sidedp = 0.31). Two Class II studies11,12 and six Class III studies13–15,18–20also found a relationship between VPA dose and MCMs. The VPAdose above which MCMs were significantly more likely to occurwas not consistent, but was approximately 1,000 mg daily infive studies.12,13,18–20
Conclusion.
There is probably a relationship between the dose of VPA andLTG and the risk of development of MCMs in the offspring ofWWE (one Class I study).
Recommendation.
Limiting the dosage of VPA or LTG during the first trimester,if possible, should be considered to lessen the risk of MCMs(Level B).
Are there specific MCMs associated with specific AEDs?
One Class I study10 showed increased risk of neural tube defectsand facial clefts with VPA (RR 5.32, CI 1.38–20.50 forneural tube defects and RR 4.18, CI 1.55–11.25 for facialclefts). One Class II study8 showed increased risk for cleftpalate with PHT and posterior cleft palate with CBZ. AnotherClass II study12 showed increased risk of neural tube defectsand hypospadias with VPA. Two Class III studies showed increasedrisk of spina bifida with VPA,9,21 and one showed increasedrisk of hypospadias.9 Two Class III studies9,15 showed increasedrisk of cardiac malformations associated with PB.
Conclusions
PHT exposure in utero possibly contributes to the risk of cleftpalate (one Class II study).
CBZ exposure in utero possiblycontributes to the risk of posteriorcleft palate (one ClassII study).
VPA exposure in utero probably contributes to neuraltube defectsand facial clefts (one Class I study) and possiblycontributesto hypospadias (one Class II study).
PB exposurein utero possibly contributes to cardiac malformations(twoClass III studies).
Recommendations
Avoidance of the use of VPA, if possible, should be consideredto reduce the risk of neural tube defects and facial clefts(Level B) and may be considered to reduce the risk of hypospadias(Level C).
Avoidance of PHT, CBZ, and PB, if possible, maybe consideredto reduce the risk of specific MCMs: cleft palatefor PHT use,posterior cleft palate for CBZ use, and cardiacmalformationsfor PB use (Level C).
Cognitive teratogenesis.
Thirteen relevant articles were identified by the literaturesearch (table e-6). These were rated for risk of bias usingthe AAN causality evidence classification scheme (appendix e-4A).
The outcome measure was an assessment of the child’s IQat age 2 years or older. Because maternal IQ has an importantinfluence on child IQ,22 studies were downgraded if they didnot control for maternal IQ. Unlike the analysis for MCM risk,the cognitive risk related to AED exposure was not confinedto the first trimester, since risk due to exposure may be presentthroughout pregnancy, as suggested by the literature.23
Is cognitive outcome reduced in children of WWE who are not exposed to AEDs in utero?
Two Class II studies24,25 observed that cognition is not reducedin children of WWE unexposed to AEDs. One was a blinded observationalstudy24 comparing the IQ of 64 children of WWE not taking AEDswith 121 controls. No important differences in IQ were found.The other study25 showed no difference in the IQ of 57 childrenof untreated WWE and 57 control children matched for age, race,and socioeconomic status.
Conclusion.
Cognition is probably not reduced in children of WWE who arenot exposed to AEDs in utero (two Class II studies).
Recommendation.
Counseling of WWE who are contemplating pregnancy should reflectthat there is probably no increased risk of reduced cognitionin the offspring of WWE not taking AEDs (Level B).
Is cognition reduced in children of WWE exposed to AEDs in utero?AEDs in general.
Two Class II studies26,27 and one Class III study28 showed reducedcognition in the children of WWE on AEDs. One Class II study29and one Class III study30 showed no reduction. The outcome measuresfor the studies included IQ testing, development quotient testing,or an assessment of developmental milestones. Differences acrossstudies are likely due to variance in design and inadequatecontrol for confounding factors.
Carbamazepine.
Two Class II studies24,31 and three Class III studies30,32,33showed CBZ does not increase the risk of poor cognitive outcomescompared to unexposed controls.
Valproate.
Two Class II studies24,31 showed VPA poses an increased riskof poor cognitive outcomes compared to unexposed controls.
Phenytoin.
One Class II study34 and two Class III studies30,33 showed PHTposes an increased risk for poor cognitive outcomes comparedto unexposed controls.
Phenobarbital.
Two Class III cohorts (analyzed separately in a single report)of adult men exposed in utero to PB found reduced cognitiveabilities compared to normative populations.23
Conclusions
There is insufficient evidence to determine if the childrenof WWE on AEDs in general are at increased risk for reducedcognition (conflicting Class II studies).
CBZ probably doesnot increase poor cognitive outcomes comparedto unexposed controls(two Class II studies).
VPA is probably associated with poorcognitive outcomes comparedto unexposed controls (two ClassII studies).
PHT is possibly associated with poor cognitiveoutcomes comparedto unexposed controls (one Class II and twoClass III studies).
PB is possibly associated with poor cognitiveoutcomes in maleoffspring of WWE compared to unexposed controls(two Class IIIstudies).
Recommendations
CBZ exposure probably does not produce cognitive impairmentin offspring of WWE (Level B).
Avoiding VPA in WWE duringpregnancy, if possible, should beconsidered to reduce the riskof poor cognitive outcomes (LevelB).
Avoiding PHT in WWEduring pregnancy, if possible, may be consideredto reduce therisk of poor cognitive outcomes (Level C).
Avoiding PB inWWE during pregnancy, if possible, may be consideredto reducethe risk of poor cognitive outcomes (Level C).
Does AED polytherapy exposure during pregnancy pose an increased risk for poor cognitive outcome compared to monotherapy?
Three Class II studies24,26,35 showed that cognitive outcomesare reduced in children exposed to AED polytherapy comparedto monotherapy. Outcome assessments included IQ, verbal IQ,and the Columbia Mental Maturity Scale.
Conclusion.
Cognitive outcomes are probably reduced in children exposedto AED polytherapy as compared to monotherapy in utero (threeClass II studies).
Recommendation.
Monotherapy should be considered in place of polytherapy, ifpossible, for WWE who take AEDs during pregnancy to reduce therisk of poor cognitive outcomes (Level B).
Is exposure to a specific AED in utero associated with poor cognitive outcomes compared to other AEDs?Valproate.
Two Class II studies24,31 demonstrated reduced cognitive outcomesin children exposed to VPA during pregnancy compared to childrenexposed to CBZ. In one of the studies, the risk was also greaterthan that of PHT.31
Other AEDs.
There was no evidence rated Class III or higher regarding otherAEDs.
Conclusions
Cognitive outcomes are probably reduced in children exposedto VPA during pregnancy compared to CBZ (two Class II studies).
Cognitive outcomes are possibly reduced in children exposedto VPA during pregnancy compared to PHT (one Class II study).
Recommendations
For WWE who are pregnant, avoidance of VPA, if possible, shouldbe considered compared to CBZ to reduce the risk of poor cognitiveoutcomes (Level B).
For WWE who are pregnant, avoidance ofVPA, if possible, maybe considered compared to PHT to reducethe risk of poor cognitiveoutcomes (Level C).
Adverse perinatal outcomes.
Thirteen relevant articles were identified by the literaturesearch (table e-7). Articles were rated for risk of bias usingthe AAN prognostic classification of evidence scheme (appendixe-4B).
The outcomes evaluated included 1) small for gestational age(SGA), defined as birthweight below the 10th percentile forthe study population when adjusted for gestational age and gender;2) perinatal death; and 3) Apgar scores.
Is there an increased risk of SGA outcomes in neonates born to WWE?
Two Class II studies36,37 showed increased risk of SGA for offspringof WWE taking AEDs. In one Class II study, pregnancies to WWEtaking AEDs had more than twice the risk of SGA outcomes (n= 87) (OR 2.3, CI 1.3–4.0).36 Pregnancies to WWE not takingAEDs did not show a significantly increased risk of SGA (OR1.6, CI 0.9–2.6). However, the study was insufficientlysensitive to exclude a substantially increased risk.
Another Class II study37 observed twice the risk of SGA in pregnanciesof WWE taking AEDs compared to controls (n = 127) (OR 2.16,CI 1.34–3.47, absolute risk 17.3%). The authors foundno increased risk for SGA in the offspring of WWE not takingAEDs.
Conclusion.
Neonates of WWE taking AEDs probably have an increased riskof SGA of about twice the expected rate (two Class II studies).
Recommendation.
Pregnancy risk stratification should reflect that the offspringof WWE taking AEDs during pregnancy probably have an increasedrisk of SGA. Further, AED use in WWE during pregnancy shouldbe considered in the differential diagnosis of SGA in theiroffspring (Level B).
Is there an increased risk of perinatal death in neonates born to WWE?
Two Class II38,39 studies observed no increased risk of perinataldeath (OR 0.57, CI 0.18–1.77).39 The studies were insufficientlysensitive to exclude a moderately increased risk.
Conclusion.
There is probably no substantially increased risk of perinataldeath in neonates born to WWE (two Class II studies).
Recommendation.
Pregnancy risk stratification should reflect that neonates bornto WWE probably do not have a substantially increased risk ofperinatal death (Level B).
Are Apgar scores lower in neonates born to WWE?
One Class II study37 showed increased risk of 1-minute Apgarscores of <7 for WWE taking AEDs (n = 127) (OR 2.29, CI 1.29–4.05,absolute risk 11.0%). Further, this study showed increased rateof neonatal intensive care unit admission for neonates bornto WWE taking AEDs. These two outcomes were not increased forthe offspring of WWE not taking AEDs. Two Class III studies40,e1showed lowered Apgar scores compared to controls and three ClassIII studies38,39,e2 did not. None of these Class III studiesreported point estimates of comparative risks.
Conclusion.
Neonates of WWE taking AEDs possibly have an increased riskof 1-minute Apgar scores of <7 of about twice the expectedrate (one Class II study).
Recommendation.
Pregnancy risk stratification should reflect that the offspringof WWE taking AEDs during pregnancy possibly have an increasedrisk of 1-minute Apgar scores of <7. Further, AED use inWWE during pregnancy may be considered in the differential diagnosisof a 1-minute Apgar score of <7 in their offspring (LevelC).
Other perinatal outcomes such as respiratory distress, intrauterinegrowth retardation, and neonatal intensive care unit admissiondid not have adequate data to make conclusions.
This parameter focuses on the pregnancy-related risks of AEDs.However, it does not evaluate the risks of not taking AEDs duringpregnancy. The seizure-prevention benefits of taking AEDs areclear for the nonpregnant patient and these same benefits applyfor the pregnant patient and extend to the protection of thefetus from maternal seizures. Although many of the recommendationsin this parameter suggest minimizing AED exposure during pregnancy,for most WWE, discontinuing AEDs is not a reasonable or safeoption. Although the risks of seizures during pregnancy havenot been systematically studied, discontinuing AEDs may exposethe mother and fetus to physical injury from accidents arisingfrom partial or generalized seizures. Decision pathways to assistin deciding when to discontinue AEDs are available.e3
Based upon the evidence reviewed, it seems reasonable to switchWWE of childbearing potential to a less teratogenic regimenwhen possible. The use of VPA is a particular dilemma. WhileVPA is an effective AED,e4 it emerges as the AED with the greatestnumber of data showing an association with risk from in uteroexposure. If the change from VPA to another AED is planned,it seems prudent to do this well before pregnancy to make surethe new treatment adequately prevents seizures. Changing toanother AED during pregnancy poses risk of allergy, other seriousadverse reactions, and polytherapy exposure. Once a patientis pregnant, changing from VPA several weeks into gestationwill not avoid the risk of MCMs, since this phenomenon occursvery early in pregnancy. This may also apply to cognitive teratogenesis,since the timing of exposure related to this adverse outcomeis unknown.
For many AEDs, in particular the newer AEDs, there were toofew patients in the studies to make conclusions, and the teratogenicityof these drugs is unknown.
The finding that some MCMs occur more frequently with specificAED exposure needs to be viewed in context. MCMs seen more frequentlywith VPA, such as neural tube defects, can also be present withexposure to other AEDs, demonstrating that this is not an AED-specificMCM. Like other teratogens, AEDs as a teratogenic category producea pattern of MCMs with overlap among the individual AEDs.
Although this parameter answers some questions, it raises othersthat make this clinical situation even more challenging. Theparameter shows an increased risk of MCMs with VPA exposure,but there is a paucity of specific information about the absoluterisk of most other AEDs. This is particularly true for the newerAEDs, several of which are reasonable alternatives to VPA. Withongoing data submission to AED pregnancy registries, it is hopedthat this information will soon be forthcoming.
The existence of an AED dose-malformation relationship needsto be clarified for all AEDs, with the incorporation of serumlevels as well. Adverse neonatal outcomes and long-term cognitiveoutcomes of children exposed to AEDs in utero for both the olderand newer AEDs need further clarification, as do the short-termand long-term cognitive risks of AED exposure in the neonataland infantile periods through breastfeeding.
In addition, future research should begin to evaluate metabolicsystems for which modification could lower teratogenic risk,such as glutathione reductase, superoxide dismutase, epoxidehydrolase, and other toxin-scavenging mechanisms. Further, theinteractions between AEDs and molecular targets such as histonedeacetylase and peroxisome proliferator-activated receptorsmay play a role in teratogenesis. Greater understanding of thesefactors may eventually permit an individualized assessment ofteratogenic risk for WWE taking AEDs.e5
The authors report the following conflicts of interest: Dr.Harden has served on the scientific advisory board of Cyberonics,GlaxoSmithKline, UCB Pharma, Valeant, and SK Pharmaceuticalsand on the speakers’ bureau of GlaxoSmithKline, Pfizer,UCB Pharma, and Abbott. She serves as an editor of EpilepsyCurrents and receives publishing royalties from Elsevier. Dr.Harden has received research funding from Forest, UCB Pharma,Ortho McNeil, and NIH/NINDS. Dr. Harden sees women with epilepsyin her office practice. Dr. Meador serves as a journal editorfor Neurology, Journal of Clinical Neurophysiology, Cognitiveand Behavioral Neurology, Epilepsy & Behavior, EpilepsyCurrents, and Epilepsy.com. He has received research fundingfrom NIH/NINDS, GlaxoSmithKline, Eisai, Marius, Myriad, Neuropace,SAM Technology, and UCB Pharma. Dr. Meador estimates that 30–40%of his clinical effort is spent on EEGs and the clinical careof patients with epilepsy. Dr. Pennell has served on the ExpertPanel for the Keppra Pregnancy Registry sponsored by UCB Pharma.She has received funding for travel from the Northeast RegionalEpilepsy Group for speaking at their 2008 Epilepsy Symposium,by the UK Research Council for speaking at the Epilepsy ResearchUK International Expert Workshop, by UCB Pharma for attendingthe Executive Panel meeting for the Pregnancy Registry, by theAmerican Epilepsy Society for attending the Board of Directors’Meeting, by the Epilepsy Foundation for attending the Boardof Directors’ and orientation meetings, by the Long IslandJewish Hospital for lecturing at Neurology Grand Rounds, byDuke University for lecturing at Neurology Grand Rounds, byBrigham and Women’s Hospital for lecturing at the EpilepsyResearch Conference, by the Milken foundation for attendingPregnancy Registry meetings, and by Massachusetts General Hospitalfor speaking at the Annual Teratogens Course. She has receivedhonoraria from Journal Watch Neurology for a contributing article,paid for by Massachusetts Medical Society, NEJM, for reviewfor the Lancet Neurology, the Northeast Regional Epilepsy groupfor speaking at 2008 Epilepsy Symposium, North Shore Long IslandJewish Health system, Duke University, University of Maryland,the Massachusetts General Hospital for speaking at the postgraduatecourse in Human Teratogens, and the AAN for speaking and directingannual courses. Dr. Pennell has served as a contributing editorfor Epilepsy Currents and is on the editorial board of Epilepsia.Dr. Pennell has received research support from UCB Pharma, MarinusPharmaceuticals, NIH, NINDS, NIMH, CDC, and Emory UniversityResearch Council. Dr. Hauser has served on the scientific advisoryboard of Ovation and Valeant. He has served on the editorialboard of Acta Neurologica Scandinavia, Neuroepidemiology, andEpilepsy Research. He has received honoraria from Cornell UniversitySymposium on epilepsy and acted as a consultant to Pfizer. Dr.Hauser has received research support from AAMC/CDC, NIH/NINDS,FAA, Mayo Clinic, and Hotchkiss Neurological Institute, andhas given expert testimony in his role as an FAA consultant.Dr. Gronseth serves as an editor of Neurology Now and on thespeakers’ bureau of Boehringer-Ingelheim. He receivescompensation from the AAN for consulting work. Dr. French hasserved on the scientific advisory board of UCB Pharma, Johnsonand Johnson, Eisai, Novartis, Valeant, Icagen, Intranasal, Sepracor,and Marinus. She has received funding for travel to presentfindings or give lectures from UCB Pharma, Kyowa, Eisai, Johnsonand Johnson, Valeant, and GlaxoSmithKline. She has served asan associate editor for Epilepsy Currents and supplement editorfor Epileptic Disorders. Dr. French is the president of theEpilepsy Study Consortium, which receives money from multiplepharmaceutical companies (including GlaxoSmithKline, UCB Pharma,Johnson and Johnson, Cyberonics, Schwarz Pharma, Ortho McNeil,Eisai, Jazz Pharmaceuticals, Ovation Pharmaceuticals, Endo Pharmaceuticals,Bial Pharmaceuticals, Neurovista, Valeant Pharmaceuticals, Icagen,Supernus, Intranasal, SK Pharmaceuticals, Taro Pharmaceuticals,Neurotherapeutics, Sepracor, and Novartis) and she consultson behalf of the consortium. Dr. French has received researchfunding from Johnson and Johnson, Eisai, UCB Pharma, SK Pharmaceuticals,Valeant, Pfizer, NIH, and Epilepsy Research Foundation. Dr.Wiebe serves on the editorial board of Neurology, Epilepsia,Epilepsy & Behavior, and Canadian Journal of NeurologicalSciences. Dr. Thurman is an employee of the CDC. Dr. Koppelreports no disclosures. Dr. Kaplan has served on the speakers’bureau of UCB Pharma, GSK, and Ortho McNeil. He serves as anassociate editor for Neurophysiologie Clinique, Journal of ClinicalNeurophysiology, and Epilepsia. He receives royalties from DemosPublications for the books Neurological Disease in Women, EpilepsyA to Z, Imitators of Epilepsy, and Nonconvulsive Status Epilepticus.He has received speaker honoraria from Medical College of SouthCarolina, Duke University, and Medical College of Virginia,has received research funding from NIH, Schwarz, Ortho McNeil,and Pfizer, and has acted as a consultant for Schering-Ploughand Infinite Biological Technologies. Dr. Robinson reports nodisclosures. Dr. Hopp receives royalties from UpToDate.com electronicmedical journal. She has been on the speakers’ bureauof UCB Pharma and GlaxoSmithKline. Dr. Hopp has given testimonyin a medico-legal case. Dr. Ting served on the scientific advisoryboard of UCB Pharma and has received honoraria from the EpilepsyFoundation of America. Dr. Gidal has served on the scientificadvisory board for GlaxoSmithKline, UCB Pharma, and Abbott Labsand served as an editor for Epilepsy & Behavior, The Annalsof Pharmacotherapy, and Pharmacist’s Letter. Dr. Gidalhas received research support from UCB Pharma. Dr. Hovinga estimatesless than 10% of his clinical effort is spent on pharmacologyconsults. Dr. Wilner has served on the scientific advisory boardof and received funding for travel from GlaxoSmithKline. Hereceives royalties from Demos Publications for Epilepsy: 199Answers and Epilepsy in Clinical Practice. He receives boardof directors compensation from GlaxoSmithKline. Dr. Vazquezhas served on the scientific advisory board of Eisai, UCB, GSK,and Ortho McNeil. She has received honoraria from UCB, GSK,Ortho McNeil, and Eisai. Dr. Vazquez has served on a speakers’bureau for Eisai, GSK, Ortho McNeil, UCB, and Novartis. Dr.Holmes receives research support from Abbott Labs, Eisai, Novartis,Ortho McNeil, and Pfizer. Dr. Krumholz has served on the Departmentof Transportation Expert Panel on Commercial Drivers and Epilepsyand has served on the editorial board of The Neurologist andClinical EEG and Neuroscience. He has received honoraria fromthe Robert Wood Johnson Medical School for grand rounds. Dr.Finnell has served on the scientific advisory board of the NEADstudy at Emory University, the University of Houston Centerfor Life Sciences Technology, the NIH, and the NIEHS NationalAdvisory Environmental Health Sciences Council. He has receivedfunding for travel from Fundacion BBVA, NIEHS National AdvisoryEnvironmental Health Sciences Council, IKMC Steering Committee,European Epilepsy Meeting, NIH, and AES. Dr. Finnell has servedas a journal editor for Birth Defects Research Part A and holdsa patent on folate receptor autoantibody assay. He has receivedhonoraria from McGill University-Montreal Neurological Instituteand has received research funding from the Centers for DiseaseControl and Prevention for the National Birth Defects PreventionStudy and the Methodist Hospital Research Institute. Dr. Finnellhas given expert testimony, prepared affadavits, and acted asa witness regarding legal proceedings related to the topic ofthis manuscript. Dr. Hirtz reports no disclosures. Ms. Le Guenreports no disclosures.
This statement is provided as an educational service of theAmerican Academy of Neurology. It is based on an assessmentof current scientific and clinical information. It is not intendedto include all possible proper methods of care for a particularneurologic problem or all legitimate criteria for choosing touse a specific procedure. Neither is it intended to excludeany reasonable alternative methodologies. The AAN recognizesthat specific patient care decisions are the prerogative ofthe patient and the physician caring for the patient, basedon all of the circumstances involved. The clinical context sectionis made available in order to place the evidence-based guideline(s)into perspective with current practice habits and challenges.No formal practice recommendations should be inferred. The findingsand conclusions in the report are those of the authors and donot necessarily represent the official position of the Centersfor Disease Control and Prevention.
The Mission Statements of the Quality Standards Subcommittee(QSS) and Therapeutics and Technology Assessment (TTA) Subcommittee,Conflict of Interest Statement, QSS members, TTA members, AANclassification of evidence, Classification of recommendations(appendices e-1 through e-5), as well as references e1 throughe5 and tables e-1 through e-7, are available on the Neurology®Web site at www.neurology.org.
Approved by the Quality Standards Subcommittee April 15, 2008;by the Therapeutics and Technology Assessment Subcommittee December17, 2007; by the Practice Committee January 25, 2009; and bythe AAN Board of Directors March 25, 2009.
Supported by The Milken Family Foundation.
Disclosure: Author disclosures are provided at the end of thearticle.
Received February 2, 2009. Accepted in final form March 23,2009.
United States Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, Bridged-Race Population Estimates, United States. July 1st resident population by state, county, age, sex, bridged-race, and Hispanic origin on CDC WONDER On-line Database. Available at: http://wonder.cdc.gov. Accessed June 2008.
Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. How common are the "common" neurologic disorders? Neurology 2007;68:326–337.[Abstract/Free Full Text]
Yerby MS. Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology 2000;55:S21–S31.[Medline]
Harden CL, Hopp J, Ting TY, et al. Practice Parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:126–132.[Abstract/Free Full Text]
Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132–1138.[Abstract/Free Full Text]
Fried S, Kozer E, Nulman I, Einarson TR, Koren G. Malformation rates in children of women with untreated epilepsy. Drug Safety 2004;27:197–202.[Medline]
Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004;93:1774–1776.
Puho EH, Szunyogh M, Metneki J, Czeizel AE. Drug treatment during pregnancy and isolated orofacial clefts in Hungary. Cleft Palate Craniofac J 2007;4:194–202.
Arpino C, Brescianini S, Robert E, et al. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure (MADRE). Epilepsia 2000;41:1436–1443.[Medline]
Morrow J, Russell A, Guthrie E, et al. Malformations risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193–198.[Abstract/Free Full Text]
Artama M, Auvinen A, Raudaskoski T, Isojarvi I, Isojarvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 2005;64:1874–1878.[Abstract/Free Full Text]
Samrén EB, van Duijn CM, Christiaens GCML, Hofman A, Lindhout E. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999;46:739–746.[Medline]
Vajda FJE, Hitchcock A, Graham J, et al. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Eur J Neurol 2006;13:645–654.[Medline]
Meador KJ, Baker GA, Finnell RH, et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006;67:407–412.[Abstract/Free Full Text]
Canger R, Battino D, Canevini MP, et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999;40:1231–1236.[Medline]
Wyszynski WF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005;64:961–965.[Abstract/Free Full Text]
Agresti A. Categorical Data Analysis (Wiley Series in Probability and Statistics),
Mawer G, Clayton-Smith J, Coyle H, Kini U. Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate. Seizure 2002;11:512–518.[Medline]
Omtzigt JGC, Los FJ, Grobbee DE, et al. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992;42 (suppl 5):119–125.[Medline]
Samrén EB, van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997;38:981–990.[Medline]
Bertollini R, Mastoiacovo P, Segni G. Maternal epilepsy and birth defects: a case-control study in the Italian Multicenter Registry of Birth Defects (IPIMC). Eur J Epidemiol 1985;1:67–72.[Medline]
Sattler JM. Assessment of Children revised/updated.
Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995;274:1518–1525.[Abstract/Free Full Text]
Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004;62:28–32.[Abstract/Free Full Text]
Holmes LB, Rosenberger PB, Harvey EA, Khoshbin S, Ryan L. Intelligence and physical features of children of women with epilepsy. Teratology 2000;61:196–202.[Medline]
Koch S, Titze K, Zimmermann RB, Schröder M, Lehmkuhl U, Rauh H. Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents. Epilepsia 1999;40:1237–1243.[Medline]
Oyen N, Vollset SE, Eide MG, Bjerkedal T, Skjærven R. Maternal epilepsy and offspring’s adult intelligence: a population-based study from Norway. Epilepsia 2007;48:1731–1738.[Medline]
Hirano T, Fujioka K, Okada M, Iwasa H, Kaneko S. Physical and psychomotor development in the offspring born to mothers with epilepsy. Epilepsia 2004;45(suppl 8):53–57.[Medline]
Gaily E, Kantola-Sorsa E, Granström ML. Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol 1990;32:403–414.[Medline]
Wide K, Henning E, Tomson T, Winbladh B. Psychomotor development in preschool children exposed to antiepileptic drugs in utero. Acta Paediatr 2002;91:409–414.[Medline]
Adab N, Kini U, Vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75:1575–1583.[Abstract/Free Full Text]
Eriksson K, Viinikainen K, Mönkkönen A, et al. Children exposed to valproate in utero: population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy Res 2005;65:189–200.[Medline]
Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994;271:767–770.[Abstract/Free Full Text]
Vanoverloop D, Schnell RR, Harvey EA, Holmes LB. The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotoxicol Teratol 1992;14:329–335.[Medline]
Lösche G, Steinhausen HC, Koch S, Helge H. The psychological development of children of epileptic parents: II: the differential impact of intrauterine exposure to anticonvulsant drugs and further influential factors. Acta Paediatr 1994;83:961–966.[Medline]
Hvas CL, Henriksen TB, Ostergaard JR, Dam M. Epilepsy and pregnancy: effect of antiepileptic drugs and lifestyle on birth weight. Br J Obstet Gynaecol 2000;107:896–902.
Viinikainen K, Heinonen S, Eriksson K, Kalviainan R. Community-based, prospective, controlled study of obstetric and neonatal outcome of 179 pregnancies in women with epilepsy. Epilepsia 2006;47:186–192.[Medline]
Hiilesmaa VK, Bardy A, Teramo K. Obstetric outcome in women with epilepsy. Am J Obstet Gynecol 1985;152:499–504.[Medline]
Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. Epilepsy and pregnancy: an obstetric perspective. Am J Obstet Gynecol 2004;190:371–379.[Medline]
Laskowska M, Leszczyriska-Gorzelak B, Oleszczuk J. Pregnancy in women with epilepsy. Gynecol Obstet Invest 2001;51:99–102.[Medline]
Related Articles
Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society
C. L. Harden, J. Hopp, T. Y. Ting, P. B. Pennell, J. A. French, W. A. Hauser, S. Wiebe, G. S. Gronseth, D. Thurman, K. J. Meador, B. S. Koppel, P. W. Kaplan, J. N. Robinson, B. Gidal, C. A. Hovinga, A. N. Wilner, B. Vazquez, L. Holmes, A. Krumholz, R. Finnell, and C. Le Guen
Neurology 2009 73: 126-132.
[Abstract][Full Text][PDF]
Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society
C. L. Harden, P. B. Pennell, B. S. Koppel, C. A. Hovinga, B. Gidal, K. J. Meador, J. Hopp, T. Y. Ting, W. A. Hauser, D. Thurman, P. W. Kaplan, J. N. Robinson, J. A. French, S. Wiebe, A. N. Wilner, B. Vazquez, L. Holmes, A. Krumholz, R. Finnell, P. O. Shafer, and C. Le Guen
Neurology 2009 73: 142-149.
[Abstract][Full Text][PDF]
Top.
Abstract.
DESCRIPTION OF THE ANALYTIC...
