Presentation Objectives

1. 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 Practice Parameter Update: Management issues for women with epilepsy—focus on pregnancy (an evidence-based review)

2. If you have questions, comments, or feedback regarding this slide presentation, or would like to modify the contents for presentation in a lecture, please contact guidelines@aan.com

3. 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

4. Overview • Background • Gaps in care • AAN guideline process • Analysis of evidence, conclusions, recommendations • Recommendations for future research

5. Background • Recent estimates of the U.S. population1 and the prevalence of epilepsy2 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.

6. 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.

7. AAN Guideline Process • Clinical Question • Evidence • Conclusions • Recommendations

8. 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.

9. Literature Search/Review Complete Search Review abstracts Review full text Select articles Relevant Rigorous, Comprehensive, Transparent

10. 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

11. 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.

12. 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.)

13. 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.

14. 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.

15. 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).

16. Applying This Processto the Issue We will now turn our attention to the guidelines.

17. 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? • 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? • 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?

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

19. Clinical Questions • 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?

20. 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?

21. 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

22. 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

23. 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.

24. 876abstracts 285 articles Literature Review • 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

25. 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 interventionof 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 Evidencefor Screening

26. AAN Classification of Evidencefor 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.

27. AAN Classification of Evidencefor 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.

28. AAN Classification of Evidencefor 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.

29. AAN Classification of Evidencefor 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.

30. AAN Classification of Evidencefor 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.

31. AAN Classification of Evidencefor 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.

32. AAN Classification of Evidencefor 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).

33. Analysis of Evidence Question 1: Do WWE have an increased risk of pregnancy-related complications?

34. 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.

35. 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.

36. 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).

37. 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).

38. Analysis of Evidence Question 2: Do WWE have an increased risk of epilepsy-related complications during pregnancy?

39. 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%.

40. 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).

41. 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.

42. 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.

43. 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?

44. 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.

45. 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).

46. 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?

47. 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).

48. 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).

49. Analysis of Evidence Question 5: Is the risk of MCMs greater for AED polytherapy compared to AED monotherapy when taken during the first trimester of pregnancy?

50. 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).