© 2009 American Academy of Neurology Practice Parameter Update: Management issues for women with epilepsy—focus on pregnancy (an evidence-based review)

© 2009 American Academy of Neurology Practice Parameter Update: Management issues for women with epilepsy—focus on pregnancy (an evidence-based review) Report of the Quality Standards Subcommittee and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society C. L. Harden, MD; P. B. Pennell, MD; K. J. Meador, MD, FAAN; W. A. Hauser, MD, FAAN; G. S. Gronseth, MD, FAAN; J. A. French, MD, FAAN; S. Wiebe, MD; D. Thurman, MD, MPH; B. S. Koppel, MD, FAAN; J. Hopp, MD; T. Y. Ting, MD; C. A. Hovinga, PharmD; B. Gidal, PharmD; P. W. Kaplan, MB, FRCP, FAAN; J. N. Robinson, MD; A. N. Wilner, MD, FACP, FAAN; B. Vazquez, MD; L. Holmes, MD; A. Krumholz, MD, FAAN; R. Finnell, PhD; P. O. Shafer, RN, MN; D. Hirtz, MD; C. Le Guen

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© 2009 American Academy of Neurology Presentation Objectives To review the evidence on management of women with epilepsy (WWE) who are pregnant or plan pregnancy -Risks of obstetrical complications, change in seizure frequency, teratogenesis, poor perinatal outcomes, breastfeeding, and change in blood levels -Use of vitamin K and folic acid To present evidence-based recommendations

© 2009 American Academy of Neurology Background Recent estimates of the U.S. population 1 and the prevalence of epilepsy 2 indicate that approximately one- half million WWE are of childbearing age. It has also been estimated that 3 to 5 births per thousand will be to WWE. 3 Epilepsy is defined by the presence of recurrent, unprovoked seizures, and the treatment is typically a daily, long-term antiepileptic drug (AED) regimen. The majority of people with epilepsy have well-controlled seizures, are otherwise healthy, and therefore expect to participate fully in life experiences, including childbearing.

© 2009 American Academy of Neurology Gaps in Care There is a perceived need to analyze the evidence, if any, for AEDs that have been widely prescribed over the decade since 1998. Evidence was sought for maintaining seizure control during pregnancy compared to seizure control before conception. The evidence for low incidence of poor obstetrical outcomes was not previously known before this parameter update.

© 2009 American Academy of Neurology Clinical Questions The first step in developing guidelines is to clearly formulate questions to be answered. Questions address areas of controversy, confusion, or variation in practice. Questions must be answerable with data from the literature. Answering the question must have the potential to improve care/patient outcomes.

© 2009 American Academy of Neurology AAN Classification of Evidence All studies rated Class I, II, III, or IV Five different classification systems: –Therapeutic Randomization, control, blinding –Diagnostic Comparison to gold standard –Prognostic –Screening –Causation

© 2009 American Academy of Neurology AAN Level of Recommendations A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. Note that recommendations can be positive or negative.

© 2009 American Academy of Neurology AAN Level of Recommendations: Causality A = Risk factor is a highly probable contributor to the development of disease or outcome. Recommendation: Risk factor should be avoided or reduced, if possible. (Level A rating requires two or more consistent Class I studies all showing an effect size (R.R.) ≥2 with lower confidence limits >1. In addition, either (1) a causal inference is coherent with known biologic mechanisms and related scientific evidence or (2) findings clearly demonstrate that higher doses of exposure increase likelihood of disease or outcome.) B = Risk factor is a probable contributor to the development of disease or outcome. Recommendation: Risk factor avoidance or reduction (if possible) should be considered. (Level B rating requires at least one Class I study fulfilling other criteria above, OR two or more consistent Class II studies, showing an effect size (R.R. or O.R.) ≥1.5 with lower confidence limits >1.)

© 2009 American Academy of Neurology AAN Level of Recommendations: Causality C = Risk factor is a possible contributor to the development of disease or outcome. Recommendation: Risk factor avoidance or reduction (if possible) may be considered. (Level C rating requires 1 Class II or 2 or more Class III studies, showing effect estimate(s) with consistent significant departure(s) from null value.) U = A causal relationship between the risk factor and disease or outcome is unproven or unsupported. Recommendation: None. (Evidence not meeting criteria for Class I – Class III.) Note that recommendations can be positive or negative.

© 2009 American Academy of Neurology Translating Class to Recommendations A = Requires at least two consistent Class I studies.* B = Requires at least one Class I study or two consistent Class II studies. C = Requires at least one Class II study or two consistent Class III studies. U = Studies not meeting criteria for Class I through Class III.

© 2009 American Academy of Neurology Translating Class to Recommendations *In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

© 2009 American Academy of Neurology Clinical Questions 1. Do WWE have an increased risk of pregnancy-related complications? 2. Do WWE have an increased risk of epilepsy-related complications during pregnancy? 3.Do AEDs taken during the first trimester of pregnancy increase the risk of major congenital malformations (MCMs) in the offspring of WWE compared to the offspring of WWE not on AEDs? 4.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?

© 2009 American Academy of Neurology Clinical Questions 5. Is the risk of MCMs greater for AED polytherapy compared to AED monotherapy when taken during the first trimester of pregnancy? 6.Is there a relationship between AED dose and the risk of MCMs in the offspring of WWE? 7.Are there specific MCMs associated with specific AEDs? 8.Is cognitive outcome reduced in children of WWE who are not exposed to AEDs in utero? 9.Is cognition reduced in children of WWE exposed to AEDs in utero?

© 2009 American Academy of Neurology Clinical Questions 10.Does AED polytherapy exposure during pregnancy pose an increased risk for poor cognitive outcome compared to monotherapy? 11. Is exposure to a specific AED in utero associated with poor cognitive outcomes compared to other AEDs? 12. Is there an increased risk of small for gestational age (SGA) outcomes in neonates born to WWE? 13. Is there an increased risk of perinatal death in neonates born to WWE? 14. Are Apgar scores lower in neonates born to WWE? 15. Does preconceptional folic acid supplementation reduce the risk of birth defects in neonates of WWE taking AEDs?

© 2009 American Academy of Neurology Clinical Questions 16. What is the risk of hemorrhagic disease in neonates born to WWE taking AEDs? 17. Does prenatal vitamin K supplementation reduce the risk of hemorrhagic complications in the newborns of WWE taking AEDs? 18. Do maternally ingested AEDs cross the placenta or penetrate into breast milk? 19. Does indirect exposure to maternally ingested AEDs lead to symptomatic effects in the newborn? 20. For each of the AEDs, does pregnancy cause a change in the levels of the medication or clearance of the medication?

© 2009 American Academy of Neurology Methods OVID MEDLINE, MEDLINE in Process, Current Contents, Biological Abstracts, and BIOSIS –1985 to June 2007 (with manual searches through February 2008) –Relevant, fully published, peer-reviewed articles

© 2009 American Academy of Neurology Methods Search terms –seizures/epilepsy, catamenial epilepsy, anticonvulsants, antiepileptic drugs –pregnancy, pregnancy registry, breastfeeding, oral contraceptives, polycystic ovary syndrome, fertility –teratogenesis, birth defects, cognitive outcome, vitamin K, folate/folic acid –hormone replacement therapy, menopause, perimenopause

© 2009 American Academy of Neurology Methods Four panelists reviewed each article for inclusion. Risk of bias was determined using the classification of evidence for each study (Classes I–IV). Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed.

© 2009 American Academy of Neurology Literature Review 285 articles 876 abstracts Inclusion criteria: - Relevant to the clinical questions - Limited to human subjects - Bibliographies, meta- analyses, and articles identified by panel members Exclusion criteria: - Articles relevant to eclampsia rather than seizures due to epilepsy or basic mechanisms such as teratogenesis or placental AED metabolism

© 2009 American Academy of Neurology Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations. Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician. Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report. AAN Classification of Evidence for Screening

© 2009 American Academy of Neurology AAN Classification of Evidence for Causality Class I: Prospective cohort study design that satisfies these criteria: (a) groups studied are representative of population of interest (‘broad spectrum’); (b) risk factors and outcomes are clearly defined with validated or generally accepted criteria, and measured independently or objectively; (c) comparison groups are matched for known possible confounding risk factors, or the effects of such confounders are controlled in the study analysis; AND (d) measures of association are expressed (or can be calculated) as rate ratios, risk ratios, relative risks (R.R.) or population attributable risks with confidence intervals. Class II: Retrospective cohort or case-control study designs that satisfy criteria (a), (b), and (c) above, in which (d) the measure of association may also be expressed (or can be calculated) as an odds ratio (O.R.) with confidence intervals. Class III: Other cohort or case-control study designs in which groups studied represent a narrow spectrum of the population of interest, or the measure of association does not include an R.R. or O.R. but does include an aggregate measure such as a correlation or group mean with standard deviation or p-value. Criterion (b) above must still be satisfied. Obvious confounding is not evident.

© 2009 American Academy of Neurology AAN Classification of Evidence for Causality Class IV: Studies not meeting criteria for Class I, II, or III. Specifically, studies that are non-comparative, unrepresentative of the population of interest, with major biases or confounding, lacking useful measures of effect, or lacking measures of effect estimate stability. Notes: In addition to the criteria above, any causal inference requires that exposure to the risk factor precede the development of the outcome. In addition, there may be need to allow for an induction period. In translating evidence, a requirement of two or more studies implies that such studies should not include the same subjects. Exploratory studies involving multiple comparisons of a variety of exposures and outcomes may be rated lower if it is evident that the study was designed without an a priori hypothesis or focus upon the specific exposure and outcome of interest. Randomized clinical trials (RCTs) are equivalent to prospective cohort studies in which the risk of confounding has been minimized. Evidence from such studies may be considered Class I, provided it satisfies criteria (a), (b), and (d) above. Note, however, that it is preferable to apply the AAN criteria for therapeutic studies when classifying evidence pertaining to the experimental (treatment) variables of an RCT.

© 2009 American Academy of Neurology AAN Classification of Evidence for Prognosis Class I: Evidence provided by a prospective study of a broad spectrum of persons who may be at risk for developing the outcome (e.g. target disease, work status). The study measures the predictive ability using an independent gold standard for case definition. The predictor is measured in an evaluation that is masked to clinical presentation and the outcome is measured in an evaluation that is masked to the presence of the predictor. All patients have the predictor and outcome variables measured. Class II: Evidence provided by a prospective study of a narrow spectrum of persons at risk for having the condition, or by a retrospective study of a broad spectrum of persons with the condition compared to a broad spectrum of controls. The study measures the prognostic accuracy of the risk factor using an acceptable independent gold standard for case definition. The risk factor is measured in an evaluation that is masked to the outcome.

© 2009 American Academy of Neurology AAN Classification of Evidence for Prognosis Class III: Evidence provided by a retrospective study where either the persons with the condition or the controls are of a narrow spectrum. The study measures the predictive ability using an acceptable independent gold standard for case definition. The outcome, if not objective, is determined by someone other than the person who measured the predictor. Class IV: Any design where the predictor is not applied in an independent evaluation OR evidence provided by expert opinion or case series without controls.

© 2009 American Academy of Neurology AAN Classification of Evidence for Therapeutic Intervention Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required**: a. concealed allocation, b. primary outcome(s) clearly defined, c. exclusion/inclusion criteria clearly defined, d. adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias. e. For non inferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required***: 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority. 2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment. (e.g. for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). 3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. 4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

© 2009 American Academy of Neurology AAN Classification of Evidence for Therapeutic Intervention Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement. Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.

© 2009 American Academy of Neurology AAN Classification of Evidence for Therapeutic Intervention **Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. ***Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

© 2009 American Academy of Neurology Conclusions –Based on evidence from one Class I and one Class II study, it is probable that WWE taking AEDs do not have a substantially increased risk of Cesarean delivery. Because of the lack of statistical precision in the Class I and Class II studies and the evidence from multiple Class III studies, a moderately increased risk of Cesarean delivery is possible. –There is insufficient evidence to support or refute an increased risk of pre-eclampsia in WWE taking AEDs. –Based on results from two conflicting Class II studies, there is insufficient evidence to support or refute an increased risk of pregnancy-induced hypertension in WWE.

© 2009 American Academy of Neurology Conclusions, cont. –Based on evidence from one Class I study, it is probable that WWE taking AEDs do not have a moderately increased risk of premature contractions and premature labor and delivery during pregnancy. However, based on evidence from one Class II study, it is possible that WWE who smoke do have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy compared to women without epilepsy who smoke. –Based on evidence from one Class I and one Class III study, it is probable that WWE taking AEDs do not have a substantially increased risk of late pregnancy-related bleeding complications. However, because of a lack of statistical precision in this study, a moderately increased risk cannot be excluded. –Data are inadequate to support or refute an increased risk of spontaneous abortion in WWE.

© 2009 American Academy of Neurology Recommendations Counseling of WWE who are pregnant or are contemplating pregnancy should reflect that: –there is probably no substantially increased risk (greater than 2 times expected) of Cesarean delivery for WWE taking AEDs (Level B). However, there is possibly a moderately increased risk (up to 1.5 times expected) of Cesarean delivery for WWE taking AEDs (Level C). –there is probably no substantially increased risk (greater than 2 times expected) of late pregnancy bleeding for WWE taking AEDs (Level B). –there is probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery for WWE taking AEDs (Level B).

© 2009 American Academy of Neurology Recommendations, cont. Counseling of WWE who are pregnant or are contemplating pregnancy should reflect that: –there is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke (Level C). –there is insufficient evidence to support or refute an increased risk of pre-eclampsia, pregnancy-related hypertension, or spontaneous abortion (Level U).

© 2009 American Academy of Neurology Conclusions –There is insufficient evidence to determine the change in seizure frequency in pregnant WWE. –There is insufficient evidence to support or refute an increased risk of status epilepticus in pregnant WWE. –Two Class II articles show the rate of remaining seizure free during pregnancy if WWE are seizure free for at least 9 months to 1 year prior to pregnancy is probably 84 ̶ 92%.

© 2009 American Academy of Neurology Recommendations Counseling of WWE who are pregnant or are contemplating pregnancy should reflect that: –seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84 ̶ 92%) of remaining seizure free during pregnancy (Level B). –there is insufficient evidence to support or refute an increased risk of a change in seizure frequency or status epilepticus (Level U).

© 2009 American Academy of Neurology Clinical Context –Some of the most important findings of this practice parameter are what they do not demonstrate. There was no conclusive evidence of an increased risk of many obstetrical complications often discussed as associated with WWE during pregnancy. This raises the possibility that there is no true difference in the rates of obstetrical complications in WWE compared to the general population. –Further, the findings do not suggest high rates of seizure increase or status epilepticus during pregnancy or an increased risk of seizure relapse during pregnancy for WWE who are seizure free. The data available to determine how seizure-free WWE fare during pregnancy indicate it is likely that they will remain seizure free, providing practitioners with another reason to strive for seizure freedom in their patients planning pregnancy.

© 2009 American Academy of Neurology Clinical Context ̶ It is hoped that this information will herald a new outlook about how high (or low) the actual risk is for health complications in WWE who become pregnant, and may serve to decrease the anxiety and perhaps the stigma produced by this clinical situation for both patient and practitioner.

© 2009 American Academy of Neurology Analysis of Evidence Question 3: 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?

© 2009 American Academy of Neurology Conclusions –AEDs taken during the first trimester probably increase the risk of MCMs in the offspring of WWE (two adequately sensitive Class II studies) but it cannot be determined if the increased risk is imparted from all AEDs or from only one or some AEDs. –Valproate (VPA) monotherapy during the first trimester possibly increases the risk of MCMs in the offspring of WWE (one Class II study). –VPA used in polytherapy probably increases the risk of MCMs in the offspring of WWE (one Class I study). –Carbamazepine (CBZ) probably does not substantially increase the risk of MCMs in the offspring of WWE (one Class I study). –There is insufficient evidence to determine if lamotrigine (LTG) (one inadequately sensitive Class I study) or other specific AEDs (no Class III or better evidence) increase the risk of MCMs in the offspring of WWE. –

© 2009 American Academy of Neurology Recommendations –Although there is evidence that AEDs taken during the first trimester probably increase the risk of MCMs in the offspring of WWE, it cannot be determined if the increased risk is imparted from all AEDs or from only one or some AEDs. Therefore, no recommendation is made from this conclusion (Level U). –If possible, avoidance of the use of VPA as part of polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs (Level B). –If possible, avoidance of the use of VPA monotherapy during the first trimester of pregnancy may be considered to decrease the risk of MCMs (Level C).

© 2009 American Academy of Neurology Analysis of Evidence Question 4: 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?

© 2009 American Academy of Neurology Conclusions –It is highly probable that taking VPA monotherapy during the first trimester of pregnancy contributes to the development of MCMs in the offspring of WWE compared to taking CBZ (two Class I studies). –VPA as part of polytherapy in the first trimester of pregnancy probably contributes to the development of MCMs in the offspring of WWE compared to polytherapy that does not include VPA (one Class I and one Class II study). –Taking VPA during the first trimester of pregnancy possibly contributes to the development of MCMs in the offspring of WWE compared to taking phenytoin (PHT) (one Class II study). –Taking VPA during the first trimester of pregnancy possibly contributes to the development of MCMs in the offspring of WWE compared to taking lamotrigine (LTG) (one Class II study).

© 2009 American Academy of Neurology Recommendations –To reduce the risk of MCMs, the use of VPA during the first trimester of pregnancy should be avoided, if possible, compared to the use of CBZ (Level A). –To reduce the risk of MCMs, avoidance of the use of polytherapy with VPA during the first trimester of pregnancy, if possible, should be considered, compared to polytherapy without VPA (Level B). –To reduce the risk of MCMs, avoidance of the use of VPA during the first trimester of pregnancy, if possible, may be considered, compared to the use of PHT or LTG (Level C).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Polytherapy probably contributes to the development of MCMs in the offspring of WWE as compared to monotherapy. Recommendation: –To reduce the risk of MCMs, avoidance of the use of AED polytherapy during the first trimester of pregnancy, if possible, compared to monotherapy should be considered (Level B).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –There is probably a relationship between the dose of VPA and LTG and the risk of development of MCMs in the offspring of WWE (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).

© 2009 American Academy of Neurology Conclusions Conclusions: –PHT exposure in utero possibly contributes to the risk of cleft palate (one Class II study). –CBZ exposure in utero possibly contributes to the risk of posterior cleft palate (one Class II study). –VPA exposure in utero probably contributes to neural tube defects and facial clefts (one Class I study) and possibly contributes to hypospadias (one Class II study). –Phenobarbital (PB) exposure in utero possibly contributes to cardiac malformations (two Class III studies).

© 2009 American Academy of Neurology Recommendations –Avoidance of the use of VPA, if possible, should be considered to 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, may be considered to reduce the risk of specific MCMs: cleft palate for PHT use, posterior cleft palate for CBZ use, and cardiac malformations for PB use (Level C).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Cognition is probably not reduced in children of WWE who are not exposed to AEDs in utero (two Class II studies). Recommendation: –Counseling of WWE who are contemplating pregnancy should reflect that there is probably no increased risk of reduced cognition in the offspring of WWE not taking AEDs (Level B).

© 2009 American Academy of Neurology Conclusions –There is insufficient evidence to determine if the children of WWE on AEDs in general are at increased risk for reduced cognition (conflicting Class II studies). –CBZ probably does not increase poor cognitive outcomes compared to unexposed controls (two Class II studies). –VPA is probably associated with poor cognitive outcomes compared to unexposed controls (two Class II studies). –PHT is possibly associated with poor cognitive outcomes compared to unexposed controls (one Class II and two Class III studies). –PB is possibly associated with poor cognitive outcomes in male offspring of WWE compared to unexposed controls (two Class III studies).

© 2009 American Academy of Neurology Recommendations Recommendations: –Avoiding VPA in WWE during pregnancy, if possible, should be considered to reduce the risk of poor cognitive outcomes (Level B). –Avoiding PHT in WWE during pregnancy, if possible, may be considered to reduce the risk of poor cognitive outcomes (Level C). –Avoiding PB in WWE during pregnancy, if possible, may be considered to reduce the risk of poor cognitive outcomes (Level C).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Cognitive outcomes are probably reduced in children exposed to AED polytherapy as compared to monotherapy in utero (three Class II studies). Recommendation: –Monotherapy should be considered in place of polytherapy, if possible, for WWE who take AEDs during pregnancy, to reduce the risk of poor cognitive outcomes (Level B).

© 2009 American Academy of Neurology Conclusions/Recommendations Conclusions: –Cognitive outcomes are probably reduced in children exposed to VPA during pregnancy compared to CBZ (two Class II studies). –Cognitive outcomes are possibly reduced in children exposed to VPA during pregnancy compared to PHT (one Class II study). Recommendations: –For WWE who are pregnant, avoidance of VPA, if possible, should be considered, compared to CBZ to reduce the risk of poor cognitive outcomes (Level B). –For WWE who are pregnant, avoidance of VPA, if possible, may be considered compared to PHT to reduce the risk of poor cognitive outcomes (Level C).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Neonates of WWE taking AEDs probably have an increased risk of SGA of about twice the expected rate (two Class II studies). Recommendation: –Pregnancy risk stratification should reflect that the offspring of WWE taking AEDs during pregnancy probably have an increased risk of SGA. Further, AED use in WWE during pregnancy should be considered in the differential diagnosis of SGA in their offspring (Level B).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –There is probably no substantially increased risk of perinatal death in neonates born to WWE (two Class II studies). Recommendation: –Pregnancy risk stratification should reflect that neonates born to WWE probably do not have a substantially increased risk of perinatal death (Level B).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Neonates of WWE taking AEDs possibly have an increased risk of 1-minute Apgar scores of <7 of about twice the expected rate (one Class II study). Recommendation: –Pregnancy risk stratification should reflect that the offspring of WWE taking AEDs during pregnancy possibly have an increased risk of 1-minute Apgar scores of <7. Further, AED use in WWE during pregnancy may be considered in the differential diagnosis of a 1-minute Apgar score of <7 in their offspring (Level C).

© 2009 American Academy of Neurology Clinical Context –This parameter focuses on the pregnancy-related risks of AEDs. However, it does not evaluate the risks of not taking AEDs during pregnancy. The seizure-prevention benefits of taking AEDs are clear for the nonpregnant patient and these same benefits apply for the pregnant patient and extend to the protection of the fetus from maternal seizures. Although many of the recommendations in this parameter suggest minimizing AED exposure during pregnancy, for most WWE, discontinuing AEDs is not a reasonable or safe option. Although the risks of seizures during pregnancy have not been systematically studied, discontinuing AEDs may expose the mother and fetus to physical injury from accidents arising from partial or generalized seizures. Decision pathways to assist in deciding when to discontinue AEDs are available. 4

© 2009 American Academy of Neurology Clinical Context –Based upon the evidence reviewed, it seems reasonable to switch WWE of childbearing potential to a less teratogenic regimen when possible. The use of VPA is a particular dilemma. While VPA is an effective AED, 5 it emerges as the AED with the greatest number of data showing an association with risk from in-utero exposure. If the change from VPA to another AED is planned, it seems prudent to do this well before pregnancy to make sure the new treatment adequately prevents seizures. Changing to another AED during pregnancy poses risk of allergy, other serious adverse reactions, and polytherapy exposure. Once a patient is pregnant, changing from VPA several weeks into gestation will not avoid the risk of MCMs, since this phenomenon occurs very early in pregnancy. This may also apply to cognitive teratogenesis, since the timing of exposure related to this adverse outcome is unknown.

© 2009 American Academy of Neurology Clinical Context –For many AEDs, in particular the newer AEDs, there were too few patients in the studies to make conclusions, and the teratogenicity of these drugs is unknown. –The finding that some MCMs occur more frequently with specific AED exposure needs to be viewed in context. MCMs seen more frequently with VPA, such as neural tube defects, can also be present with exposure to other AEDs, demonstrating that this is not an AED-specific MCM. Like other teratogens, AEDs as a teratogenic category produce a pattern of MCMs with overlap amongst the individual AEDs.

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –The risk of MCMs in the offspring of WWE is possibly decreased by folic acid supplementation (two adequately sensitive Class III studies). Recommendation: –Preconceptional folic acid supplementation in WWE may be considered to reduce the risk of MCMs (Level C).

© 2009 American Academy of Neurology Clinical Context –Folic acid supplementation is generally recommended to reduce the risk of MCMs during pregnancy, 6 and although the data are insufficient to show that it is effective in WWE, there is no evidence of harm and no reason to suspect that it would not be effective in this group. Therefore, the strength of this evidence should not impact the current folic acid supplementation recommendation that all women of childbearing potential, with or without epilepsy, be supplemented with at least 0.4 mg of folic acid daily prior to conception and during pregnancy. 7 There was insufficient published information to address the dosing of folic acid and whether higher doses offer greater protective benefit to WWE taking AEDs.

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –There is insufficient evidence to determine if the risk of neonatal hemorrhagic complications in the newborns of WWE taking AEDs is substantially increased (one inadequately sensitive Class II study). Recommendation: –Counseling of WWE who are pregnant or are contemplating pregnancy should reflect that there is insufficient evidence to support or refute an increased risk of hemorrhagic complications in the newborns of WWE taking AEDs (Level U).

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –Evidence is inadequate to determine if prenatal vitamin K supplementation in WWE reduces neonatal hemorrhagic complications. Recommendation: –There is insufficient evidence to support or refute a benefit of prenatal vitamin K supplementation for reducing the risk of hemorrhagic complications in the newborns of WWE (Level U).

© 2009 American Academy of Neurology Conclusions –PB, primidone (PRM), PHT, CBZ, levetiracetam (LVT), and VPA probably cross the placenta in potentially clinically important amounts (one Class I and supporting Class II studies or two or more Class II studies). –Gabapentin (GBP), LTG, oxcarbazepine (OXC), and topiramate (TPM) possibly cross the placenta in potentially clinically important amounts (at least one Class II study for each). –There are insufficient data to determine if ethosuximide (ESM) crosses the placenta in clinically important amounts (one Class III study showing significant penetration).

© 2009 American Academy of Neurology Conclusions, cont. –PRM and LVT probably penetrate into breast milk in potentially clinically important amounts (one Class I study and a supporting Class II study or two Class II studies). –GBP, LTG, and TPM possibly penetrate into breast milk in potentially clinically important amounts (one Class II study each). –VPA, PB, PHT, and CBZ probably do not penetrate into breast milk in potentially clinically important amounts (one Class I study and a supporting Class II study or two Class II studies). –There are insufficient data to determine if ESM penetrates breast milk in clinically important amounts (one Class III study showing significant transfer).

© 2009 American Academy of Neurology Recommendations –The fact that PB, PRM, PHT, CBZ, LVT, VPA, GBP, LTG, OXC and TPM cross the placenta may be factored into the clinical decision regarding the necessity of AED treatment for a woman with epilepsy (Level B for PB, PRM, PHT, CBZ, LVT, and VPA and Level C for GBP, LTG, OXC, and TPM). –VPA, PB, PHT, and CBZ may be considered as not transferring into breast milk to as great an extent as PRM, LVT, GBP, LTG, and TPM (Level B when compared to PRM and LVT and Level C when compared to GBP, LTG and TPM).

© 2009 American Academy of Neurology Clinical Context –Because of small sample size, there was no way to analyze the potential contribution of other clinical factors, such as AED polytherapy, on the passive transfer of AEDs to newborns of WWE.

© 2009 American Academy of Neurology Conclusion/Recommendation Conclusion: –There is no evidence to determine if indirect exposure to maternally ingested AEDs has symptomatic effects on the newborns of WWE. Recommendation: –No recommendation is made (Level U).

© 2009 American Academy of Neurology Clinical Context –Certainly many of the AEDs cross through the placenta or into breast milk in measurable concentrations, with some meaningful differences in AEDs, particularly for breast milk transfer. The clinical consequences for the newborn of ingesting AEDs via breast milk remain sorely underexplored and will continue to produce anxiety in WWE bearing children and all who care for these clinical dyads.

© 2009 American Academy of Neurology Conclusions –Pregnancy probably causes an increase in the clearance and a decrease in the level of LTG during pregnancy. The decrease in LTG level is associated with an increase in seizure frequency (one Class I and two Class II studies). –Pregnancy probably causes a small decrease in concentration of CBZ (9% in second trimester and 12% in third trimester) (one Class I study). –Pregnancy probably causes an increase in the clearance and a decrease in the level of PHT during pregnancy (one Class I study). –Pregnancy possibly causes a decrease in the level of the active OXC metabolite, monohydroxy derivative (MHD) (two Class III studies).

© 2009 American Academy of Neurology Conclusions, cont. –Pregnancy possibly causes a decrease in the level of LVT (one Class II study). –Evidence for a change in clearance or level of PB, VPA, PRM, and ESM during pregnancy is inadequate to reach a conclusion.

© 2009 American Academy of Neurology Recommendations –Monitoring of LTG, CBZ, and PHT levels during pregnancy should be considered (Level B). –Monitoring of LVT and OXC (as MHD) levels during pregnancy may be considered (Level C). –There is insufficient evidence to support or refute a change in PB, VPA, PRM, or ESM levels related to pregnancy (Level U), and this lack of evidence should not discourage monitoring levels of these AEDs during pregnancy.

© 2009 American Academy of Neurology Clinical Context –The studies reviewed provide some evidence supporting active monitoring of AED levels during pregnancy. This is especially true for LTG where changes in LTG levels were associated with increases in seizure frequency. It seems reasonable to individualize this monitoring for each patient with the aim of maintaining a level near the preconceptional level, presumably at which the woman with epilepsy was doing well with seizure control. However, the studies reviewed fall short of determining that adoption of an active AED monitoring program would result in improved seizure control during pregnancy.

© 2009 American Academy of Neurology Clinical Context –Unfortunately, the studies reviewed provided no clear data on the timing of the return to the prepregnancy pharmacokinetic state after pregnancy. One study 9 demonstrated that following an empiric postpartum taper schedule of LTG reduced the occurrence of postpartum toxicity, but more systematic information is needed regarding the pharmacokinetic alterations in AED metabolism postpartum for all AEDs in order to determine the management of AED dosing in the postpartum period.

© 2009 American Academy of Neurology Future Research –Stronger evidence is needed to determine if there are increased risks of pre-eclampsia, pregnancy-induced hypertension, and spontaneous abortion for WWE. These risks should be evaluated in large, prospective, studies using well-matched control groups. The effect of specific AEDs on obstetrical outcomes also remains unexplored and deserves further study. The existing databases for evaluating the outcomes of pregnancies exposed to AEDs could potentially provide a source for such information. Further evaluation for the risks of seizure increase during pregnancy should be done, using prospective baseline information when possible. This type of analysis would help to reveal more information about the causes of seizure increase during pregnancy, which may be more complicated than AED noncompliance, decreased levels due to pregnancy metabolism, or lack of sleep. For example, the effect of the

© 2009 American Academy of Neurology Future Research hormonal changes during pregnancy on seizure frequency could be evaluated in a careful, prospective study. –Although this parameter answers some questions, it raises others that make this clinical situation even more challenging. The parameter shows an increased risk of MCMs with VPA exposure, but there is a paucity of specific information about the absolute risk of most other AEDs. This is particularly true for the newer AEDs, several of which are reasonable alternatives to VPA. With ongoing data submission to AED pregnancy registries, it is hoped that this information will soon be forthcoming. –The existence of an AED dose-malformation relationship needs to be clarified for all AEDs, with the incorporation of serum levels as well. Adverse neonatal outcomes and long-term cognitive

© 2009 American Academy of Neurology Future Research outcomes of children exposed to AEDs in utero for both the older and newer AEDs need further clarification, as do the short-term and long-term cognitive risks of AED exposure in the neonatal and infantile periods through breastfeeding. –In addition, future research should begin to evaluate metabolic systems for which modification could lower teratogenic risk, such as glutathione reductase, superoxide dismutase, epoxide hydrolase, and other toxin-scavenging mechanisms. Further, the interactions between AEDs and molecular targets such as histone deacetylase and peroxisome proliferator-activated receptors may play a role in teratogenesis. Greater understanding of these factors may eventually permit an individualized assessment of teratogenic risk for WWE taking AEDs. 10

© 2009 American Academy of Neurology Future Research –The issue of whether preconceptional folic acid supplementation for WWE, particularly at high doses, provides additional benefit in preventing MCMs needs to be clarified. Similarly, the risk of hemorrhagic disease of the newborn in neonates born to WWE taking AEDs and whether late-pregnancy vitamin K supplementation could be beneficial need to be determined. Studies of some commonly used AEDs were so limited that no recommendations could be made regarding these specific medications, such as zonisamide or TPM.

© 2009 American Academy of Neurology Future Research –Although many of the AEDs were shown to cross the placenta or enter breast milk, studies were limited in duration and did not systematically evaluate neonatal symptoms; more defined study on acute and prolonged outcomes in exposed neonates needs to be performed. This is particularly true for more subtle side effects, such as cognition and general healthy neonatal development. Information about how AED levels change during pregnancy based on individual metabolic capacity, as well as neonatal metabolism of AEDs consumed through breast milk, is needed in order to guide dosing and clinical monitoring of both mother and infant.

© 2009 American Academy of Neurology Acknowledgments The authors thank Andres M. Kanner, MD; Alison M. Pack, MD; and Carmel Armon, MD, FAAN, for their participation in the campaign to raise awareness about the guidelines and for their contributions to the development of summary versions of the guidelines.

© 2009 American Academy of Neurology References 1.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. http://wonder.cdc.gov. http://wonder.cdc.gov. 2.Hirtz D, Thurman DJ, Gwinn-Hardy K, et al., How common are the “common” neurologic disorders? Neurology 2007;68:326-337. 3.Yerby MS. Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology 2000;55:S21-31. 4.Chadwick D. Starting and stopping treatment for seizures and epilepsy. Epilepsia 2006;47(Suppl 1):58-61. 5.Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369(9566):970-971.

© 2009 American Academy of Neurology References 6.Czeizel AE, Dobó M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2004;70(11):853-861. 7.Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morbidity and Mortality Weekly Report 1992; September 11/41(RR-14):001. 8.American Academy of Pediatrics Vitamin K Ad Hoc Task Force: Controversies concerning vitamin K and the newborn. Pediatrics. 1993 May;91(5):1001-1003. 9.Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology 2008;70:2130-2136. 10.Sankar R. Teratogenicity of antiepileptic drugs: role of drug metabolism and pharmacogenomics. Acta Neurol Scand 2007;117:65-71. For a complete list of references, please access the full guidelines at www.aan.com/guidelines www.aan.com/guidelines

© 2009 American Academy of Neurology Practice Parameter Update: Management issues for women with epilepsy—focus on pregnancy (an evidence-based review)

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© 2009 American Academy of Neurology Practice Parameter Update: Management issues for women with epilepsy—focus on pregnancy (an evidence-based review)

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