confidential draft: not to be or disseminated draft: not to be published, cited, or disseminated 5 1...

CONFIDENTIAL DRAFT: NOT TO BE PUBLISHED, CITED, OR DISSEMINATED

1

1

Protocol for proposed Updated Practice Guideline Project: Management Issues for Women 2

with Epilepsy 3

Proposal of the Guideline Development, Dissemination, and Implementation Subcommittee of 4

the American Academy of Neurology, in full collaboration with the American Epilepsy Society 5

and the Society for Maternal Fetal Medicine 6

7

Authors (Listed alphabetically; final order to be determined later in the guideline 8

development process) 9

Diane K. Donley, MD1; Elizabeth Dueweke2, Jacqueline French, MD3, Elizabeth Gerard, MD4; 10

David Gloss, MD, MPH&TM5; Wendy R. Miller, PhD, RN, CCRN2; Sarah Osmundson, MD6; 11

Allison Pack7; Brandy Parker-McFadden8; Maryam Oskoui, MD, MSc9; Kaitlyn Parratt, MD10; 12

Page Pennell, MD11; George Saade, MD12; Kelly Sullivan, PhD13; Sanjeev V. Thomas, MD14; 13

Shannon Sparling Abdul-Wahab15; Torbjorn Tomson, MD16 14

1. Northern Michigan Neurology, Traverse City, MI 15

2. Epilepsy Foundation 16

3. New York University, New York, NY 17

4. Northwestern University, Chicago, IL 18

5. Charleston Area Medical Center, Charleston, West Virginia 19

6. Vanderbilt University, Nashville, TN 20

7. Columbia University, New York, NY 21

8. My Epilepsy Story 22


2

9. Department of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, 1

Quebec 2

10. Royal Prince Alfred Hospital, Camperdown, NSW, Australia 3

11. Brigham and Women’s Hospital, Boston, MA 4

12. University of Texas Medical Branch, Galveston, TX 5

13. Georgia Southern University, Statesboro, GA 6

14. Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India 7

15. Epilepsy Foundation of Greater Los Angeles, Los Angeles, CA 8

16. Karolinska Institutet, Stockholm, Sweden 9

10

11

Correspondence to 12

American Academy of Neurology: 13

[email protected] 14

15

Approved by the AAN Guideline Development, Dissemination, and Implementation 16

Subcommittee on July 21, 2018. All comments submitted during the 30-day public comment 17

period in which this protocol is posted will be reviewed and addressed by the author panel 18

members. Although all comments will be considered, author panel members will not specifically 19

respond to individual comments online. 20

21


3

STUDY FUNDING 1

This practice guideline protocol was developed with financial support from the American 2

Academy of Neurology (AAN). Authors who serve as AAN subcommittee members (DKD, AP, 3

KS), or as methodologists (MO), or who are AAN staff members (SM) were reimbursed by the 4

AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were 5

reviewed. 6

7

DISCLOSURES 8

D. K. Donley has no disclosures. 9

E. Dueweke serves as a member of the Infantile Spasms Network, is employed as 10

Communications Manager at the Epilepsy Foundation, and has received reimbursement for travel 11

to attend the AES Pipeline Conference in December 2016 and the Child Neurology Foundation 12

Infantile Spasms Conference in August 2017. 13

J. French receives compensation for consulting work on behalf of the Epilepsy Study Consortium 14

for Acadia, Acorda, Adamas, Alexza, Anavex, Axcella Health, Biogen, BioPharm Solutions, 15

Cavion, Cerecor, Cerebral Therapeutics, Concert Pharmaceuticals, Covance, CuroNZ, Eisai, 16

Empatica, Engage, Georgia Regents University, Glaxo Smith-Kline, GW Pharma, J&J 17

Pharmaceuticals, Marinus, MonosolRx, Monteris, Nestle-Health Science, Neurelis, Novartis, 18

Otsuka, Ovid, Pfizer, Pfizer-Neusentis, Sage Therapeutics, Shire, SK Life Sciences, Sunovion, 19

Takeda, UCB Inc., Upsher Smith, Ultragenyx, Xenon Pharmaceuticals, Xeris, Zogenix and 20

Zynerba; serves on scientific advisory boards for Anavex Life Science Corp (biopharmaceutical 21

company), Ovid Pharmaceuticals, Sage Therapeutics, Blackfynn; receives travel reimbursement 22


4

from Upsher Smith, Ultragenyx, Marinus, Pfizer, SK, GW Pharma, UCB, Takeda,Ovid, Sage 1

Therapeutics, Neurelis, Biogen, CuroNZ, Engage, Marinus, Novartis, Otsuka, SK Life Sciences, 2

Sunovion, Takeda, Zogenix, Zynderba; receives research support from Acorda, Alexza, Biogen, 3

Eisai Medical Research, Alexza, Engage, LCGH, Neurelis, Lundbeck, Ovid, Pfizer, SK Life 4

Sciences, Sunovion, Takeda, and UCB; receives New York University salary support from the 5

Epilepsy Foundation; and serves on editorial boards for Lancet Neurology, Neurology Today and 6

receives research support from NINDS 7

8

E. Gerard has received funding from SAGE pharmaceuticals for serving as a site principal 9

investigator (PI) for a multicenter clinical trial, has received government funding from the 10

National Institute of Neurological Disorders and Stroke (NINDS) for serving as a PI for a 11

multicenter clinical trial (MONEAD U01 NS038455), has received an Northwestern Memorial 12

Hospital internal grant for research on an Eleanor Wood-Prince Grants Initiative project, has 13

received reimbursement for travel for an academic conference/lecture series from UCB-China, 14

and has received honoraria from UCB-China and from Continuum. 15

D. Gloss has no disclosures. 16

W. R. Miller has received research support from Indiana University School of Nursing as part of 17

the Ethel Clarke Fellowship for serving as a PI for Patient Preferences for Delivery of a Web-18

Based Epilepsy Self-Management Intervention, has received research support from Indiana 19

University Networks Institute for serving as a co-PI (no effort) for the study Sudden Unexpected 20

Death in Epilepsy: Identifying Risk Factors with Social Media Mining, and receives research 21


5

support from the National Institute of Health (NIH)/NINDS for serving as a core investigator 1

(P30 investigator) for the development of a brain safety lab. 2

S. Osmundson has received funding from the NIH for the study 2K12HD043483-17 Building 3

Interdisciplinary Research Careers in Women’s Health. 4

A. Pack serves on editorial board for the journal Epilepsy Currents, receives royalties from 5

UpToDate, and receives funding from the NIH for serving as coinvestigator and site PI for the 6

Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, 7

and funding from Bayer for serving as a co-investigator on a study on women with epilepsy 8

initiating a progestin IUD. 9

B. Parker-McFadden serves as Executive Director for My Epilepsy Story (since 2012) and 10

receives consultation fees, serves as a member of the ELC Group (since 2013) (no compensation 11

received), serves as a Patient-Centered Outcomes Research Institute (PCORI) Ambassador (no 12

compensation received), and has received compensation from PCORI for grand rounds and 13

receives travel reimbursement from PCORI for attending meetings. 14

K. Parratt receives funding from Zynerba for serving as a subinvestigator for the study 15

Cannabidiol ZYNN2-CL-04 and ZYNN2-CL-04 for Partial Onset Seizures, receives funding 16

from SK Life Science for serving as a subinvestigator for the study Cenobamate YKP3089C021 17

for Partial Onset Seizures, has received funding from Eisai Inc. for the study Perampanel E2007-18

G00-335 for Partial Onset Seizures, has received funding from Marinus Pharmaceuticals for the 19

study Ganaxolone 10420603 for Partial Onset Seizures, has received honoraria from Esai for a 20

dinner meeting lecture. 21


6

P. Pennell serves as Clinical Associate Editor for the journal Epilepsy Currents; has received 1

reimbursement for travel from the NIH, American Epilepsy Society, and various medical schools 2

to deliver grand rounds on research scenarios; has received honorarium from the AAN, AES, and 3

multiple medical schools; has a spouse who receives research funding from Department of 4

Defense, National Science Foundation, NIM, and University of California Davis, and research 5

support from Advanced Energy Consortium; has received funding from Epilepsy and Harvard 6

Catalyst; has received funding for serving as a PI from the Milken Family Foundation, Epilepsy 7

Therapy Project, and Epilepsy Foundation for the study Women with Epilepsy: Pregnancy 8

Outcomes and Deliveries; has received funding from the NIH/NINDS and the National Institute 9

of Child Health and Human Development for serving as one of the two Principal Investigators 10

for the MONEAD study, funded by NIH (NINDS and NICHD). 11

G. Saade has served on scientific advisory boards for Sage Therapeutics and GestVision; has 12

received research support from Sera Prognostics; receives research support from the NIH for 13

studies related to chronic hypertension and pregnancy, human placenta evaluation, pregnancy 14

and cardiovascular health, and from NICHD for clinical obstetrics issues; serves on the editorial 15

board for the journal American Journal of Perinatology; has received honoraria for speaking 16

engagements at multiple universities; and has given expert testimony, prepared an affidavit, and 17

acted as a witness for legal proceedings regarding preeclampsia. 18

K. Sullivan has no disclosures. 19

S. V. Thomas serves as a PI of a pregnancy registry in India that has generated clinical data 20

pertaining to the use of antiepileptic drugs during pregnancy, has received honorarium for BMJ 21

Masterclasses on epilepsy, has received research grants from the Indian Government. 22


7

S. Sparling Abdul-Wahab has no disclosures. 1

T. Tomson serves as the Associate Editor of the journal Epileptic Disorders; receives funding 2

from UCB, GSK, Eisai, Bial, Jazz, Sanofi, Janssen-Cilag, Novartis (for serving as a PI in the 3

EURAP study and the International Antiepileptic Drugs and Pregnancy Registry); has received 4

honoraria, which was allocated to his department, for lectures at symposia from Livanova, UCB, 5

Eisai, and Sandoz; has received funding from GSK for serving as a PI for a study on sudden 6

unexpected death in epilepsy; has received research funding from Stockholm County Council; 7

and has received research funding from the Europen Union, Nordforsk, and Citizens United for 8

Research in Epilepsy. 9

10

ACKNOWLEDGMENTS 11

The authors acknowledge Cynthia L. Harden, MD for drafting the protocol and clinical 12

questions. Although Dr. Harden had no conflicts of interest at the time the project was initiated 13

in March 2018, she accepted a new employment position with Xenon Pharmaceuticals in 14

September 2018. Because Dr. Harden is now employed by a company in industry, she is 15

ineligible to continue to serve on the guideline development panel, per the AAN clinical practice 16

guideline development process manual.1 17

18

DESCRIPTION OF AAN DOCUMENT TYPES 19

This protocol is the planning document for one of four AAN document types: focused systematic 20

review, comprehensive systematic review, practice advisory (based on a systematic review), or 21


8

practice guideline (based on a systematic review). The term guideline is the general term that 1

refers to all AAN evidence-based documents. Because it is for planning purposes only, this 2

protocol document is not a substitute for the complete systematic review or guideline. 3

4

GUIDELINE PROJECT PROTOCOL 5

6

Guideline project development plan 7

This proposed project will be developed in accordance with the processes described in the 2017 8

edition of the AAN clinical practice guideline development process manual.1 The developers of 9

this guideline project intend to develop a practice guideline based on a systematic review that 10

updates three guidelines published in 2009: 11

1. “Practice Parameter update: Management issues for women with epilepsy—Focus on 12

pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes”2 13


pregnancy (an evidence-based review): Obstetrical complications and change in seizure 15

frequency”3 16


pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and 18

breastfeeding”4 19


9

This protocol will be posted for public comment. Patient representatives will be included on the 1

panel. Monthly check-in calls with the author panel will be held to assess and ensure progress of 2

the guideline. 3

4

Guideline project timeline 5

Following is the tentative timeline for development of this practice guideline based on a 6

systematic review: 7

8

Panel formation: April 2018 9

Drafting of protocol: April 2018 to June 2018 10

Approval of protocol by the AAN Guideline Development, Dissemination, and Implementation 11

Subcommittee (GDDI): July 2018 12

Protocol posted for public comment: October 2018 to November 2018 13

Literature search: October 2018 14

Panel review of abstracts: October 2018 to March 2019 15

Review of full articles, data extraction, and development of evidence tables: March 2019 to 16

September 2019 17

Systematic review draft submitted to AAN GDDI, AES Guidelines & Assessment Committee 18

(GAC), and SMFM Publications Committee (PC): October 2019 19


10

Development of recommendations based on systematic review and other pillars (principles, 1

strong related evidence from other conditions, inferences): September to December 2019 2

Submission of draft practice guideline to AAN GDDI, AES GAC, and SMFM PC for review 3

and approval for public comment: January 2020 4

Posting of practice guideline for public comment: February 2020 5

Submission of practice guideline to AAN GDDI for review and approval of final document 6

(Neurology will conduct preliminary review concurrently; when approved by GDDI, the AAN 7

Practice Committee also will review): April 2020 8

Submission to Neurology: May to July 2020 9

GDDI Leadership and AAN Practice Committee, AES Council on Clinical Activities (CCA), 10

and SMFM PC : July 2020 11

Submission to Neurology for final peer-review: August 2020 12

Submission to AAN GDDI, AES, SMFM Board of Directors for final approval: October 2020 13

14

Composition of the author panel 15

In September 2017, the AAN GDDI recruited a multidisciplinary panel consisting of 15 AAN 16

clinician members, AES and SMFM representatives, and patient representatives to develop this 17

practice guideline project protocol. The panel included content experts (EG, SO, KP, PP, GS, 18

SVT, and TT ), a methodology expert (MO), AAN GDDI members (DKD, JF, DG, KS, and AP), 19

AES physician representatives (DG, PP), an SMFM physician representative (SO, GS), and four 20

patient advocates/representatives (ED, WRM, BPM, SSAW). The all panel members were 21


11

required to submit online disclosure forms and copies of their curriculum vitae (CV). The panel 1

leadership, consisting of the lead developer at the time of panel formation and the (CH), the 2

AAN methodologist at the time of panel formation (DG), and the AAN staff person (SM), 3

reviewed the disclosure forms and CVs for financial and intellectual conflicts of interest (COI). 4

These documents were screened specifically to exclude both those individuals with a clear 5

financial conflict and those whose profession and intellectual bias would diminish the credibility 6

of the review in the eyes of the intended users. In accordance with AAN policy, the lead 7

developer (AP) has no COI. Three of the 15 guideline developers (EG, KP, and TT) were 8

determined to have COI, but each COI was judged to be not significant enough to preclude these 9

developers from authorship. The developers determined to have COI (EG, KP, and TT) will not 10

be permitted to review or rate the evidence. These individuals will be consulted in an advisory 11

capacity to help with the validation of the key questions, the scope of the literature search, and 12

the identification of seminal articles to validate the literature search. Because the panel majority 13

is free of conflicts of interest, the entire panel may vote on the guideline recommendations, with 14

those panel members free of conflicts of interest leading the recommendation development 15

process. The lead developer recommended the final panel membership to the AAN GDDI 16

leadership, who reviewed the list of members and the panel leaders’ disclosure forms, and 17

provided final approval. This panel will be solely responsible for the final decisions about the 18

design, analysis, and reporting of the proposed systematic review and proposed subsequent 19

practice guideline, which will then be submitted for approval to the AAN Guideline 20

Development, Dissemination and Implementation Subcommittee (GDDI), AES Guidelines & 21

Assessment Committee (“GAC”) and SMFM Publications Committee (PC). 22

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Introduction to proposed project topic 1

In 1998, the AAN practice parameter “Management issues for women with epilepsy (summary 2

statement) Report of the Quality Standard Subcommittee of the American Academy of 3

Neurology”5 was published. This publication included management issues related to pregnancy 4

for women with epilepsy but also included management issues not related to pregnancy (e.g., 5

catamenial seizure exacerbation). 6

In 2009, the 1998 practice parameter was updated. The 2009 update was done according to the 7

2004 AAN guideline development process6 and did not include any of the authors from the 1998 8

practice parameter. The 2009 update resulted in three guidelines, all of which focused on specific 9

pregnancy-related management issues for women with epilepsy: 10


pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes”2 12


pregnancy (an evidence-based review): Obstetrical complications and change in seizure 14

frequency”3 15


pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and 17

breastfeeding”4 18

During the 9 years following the 2009 update, multiple publications regarding the management 19

of women with epilepsy during pregnancy have been published, with several papers addressing 20

catamenial seizure management, the interactions of antiepileptic drugs (AEDs) with hormonal 21


13

birth control, pregnancy rates, and risks for menopausal women with epilepsy. Many of these 1

publications provide outcome information not available in the 2009 update. 2

For example, risks associated with exposure to AEDs through breast milk was addressed in the 3

2009 guidelines by evaluating the level of medication in breast milk, without clinical outcomes 4

available. However, now reports that address later clinical and cognitive outcomes in the child 5

from exposure to AEDs through breast milk are available. 6

We propose to update the 2009 guidelines because of the availability of many reports with low 7

systematic bias that address pregnancy outcomes. However, we also propose to include in the 8

update management issues outside of pregnancy to address other life epochs that present 9

concerns specific to women with epilepsy, such as contraception, catamenial seizure occurrence, 10

pregnancy rates, perimenopause and menopause, and the use of hormone therapy. 11

Updates to the 2009 guidelines will occur throughout a series of guidelines, each focusing on a 12

specific group of management issues for women with epilepsy. This first guideline update will 13

focus on birth defects related to the use of AEDs and drug-level changes related to pregnancy. 14

15

Rationale for this practice guideline 16

The purpose of this practice guideline based on a systematic review is to systematically assess all 17

high-quality studies regarding the management of women with epilepsy, including pregnancy 18

outcomes. The systematic review will then be used to develop recommendations regarding 19

management of women with epilepsy and their reproductive lives. 20


14

During the past 9 years there have been multiple publications regarding the issues for 1

management of women with epilepsy, including some Class II studies documenting the 2

mitigating factors for cognitive outcome and risks for infants born to mothers with epilepsy who 3

take AEDs (the NEAD studies), including the clinical and teratogenic risks of breastfeeding. The 4

new data, while limited in scope for pregnancy because this area will be an update from 2009, 5

will greatly expand the usefulness of the guidelines for neurologists and the care extenders they 6

supervise because it will address other important, day-to-day management considerations for 7

providing care to women with epilepsy. 8

9

Clinical questions 10

The included study populations for AED structural teratogenesis will be confined to those with at 11

least 369 exposures per drug. Comparisons will be across different AED exposures and across 12

doses within an AED exposure. Comparisons to the population of women with epilepsy not 13

taking AEDs will not be done because of the small sample size as well as likely heterogeneity of 14

disease in this group. The final recommendations developed may include counseling statements 15

that are derived from principles of care rather than directly from the systematic review. The 16

systematic review for this practice guideline addresses the following causation-type clinical 17

questions (see 2017 process manual1 for evidence rating scheme for causation studies): 18

1. For women with epilepsy who are pregnant, what are the relative risks of major congenital 19

malformations across specific AEDs in the exposed offspring? (Types of studies from which evidence 20

would be considered to answer this question: prospective observational, retrospective observational 21

[may be included since outcomes are objective]) 22

23


15

2. For women with epilepsy who are pregnant, what are the relative risks of cognitive teratogenesis 1

across specific AEDs in the exposed offspring? (Types of studies from which evidence would be 2

considered to answer this question: prospective observational) 3

4

3. For women with epilepsy who are pregnant, what are the risks of taking AEDs (all AEDs evaluated 5

individually) at higher doses versus lower doses for major congenital malformations in the exposed 6

offspring? (Types of studies from which evidence would be considered to answer this question: 7

prospective observational, retrospective observational-may be included since outcomes are objective) 8

9

4. For women with epilepsy who are pregnant, what are the risks of taking AEDs evaluated 10

individually) at higher doses versus lower doses for cognitive teratogenesis in the exposed offspring? 11

(Types of studies from which evidence would be considered to answer this question: prospective 12

observational) 13

14

5. For women with epilepsy who are pregnant, what are the risks of AEDs used as polytherapy versus 15

monotherapy for major congenital malformations in the exposed offspring? (Types of studies from 16

which evidence would be considered to answer this question: prospective observational, retrospective 17

observational-may be included since outcomes are objective) 18

19

6. For women with epilepsy who are pregnant, what are the risks of taking AEDs as polytherapy versus 20

monotherapy for cognitive teratogenesis in the exposed offspring? (Types of studies from which 21

evidence would be considered to answer this question: prospective observational) 22

23


16

7. For women with epilepsy who are pregnant, does having seizures during pregnancy versus being 1

seizure free during pregnancy have adverse effects on fetal outcome (Types of adverse effects would 2

include cognitive problems, small for gestational age, preterm delivery)? (Types of studies from 3

which evidence would be considered to answer this question: prospective observational) 4

5

8. For women with epilepsy taking AEDs: 6

A. Do the AEDs serum levels change during pregnancy compared with prepregnancy serum 7

levels? (Types of studies from which evidence would be considered to answer this question: 8

prospective observational) 9

B. Is a decrease in serum levels of AEDs associated with seizure occurrence? (Types of studies 10

from which evidence would be considered to answer this question: prospective observational) 11

C. Does dose adjustment produce adverse AED effects (e.g., dizziness, clumsiness, diplopia) in 12

pregnant women? (Types of studies from which evidence would be considered to answer this 13

question: prospective observational) 14

15

9. For pregnant women with epilepsy who take folic acid, versus women with epilepsy who do not take 16

folic acid: 17

A. Are the pregnancy outcomes different for women with epilepsy who take folic acid? 18

B. At what doses of folic acid do these differences emerge? 19

(Types of studies from which evidence would be considered to answer this question: prospective 20

observational) 21

22

10. For women with epilepsy, is seizure frequency different in those who are pregnant versus those who 23

are not pregnant? (Types of studies from which evidence would be considered to answer this 24

question: prospective observational) 25


17

1

Question Population Intervention Comparison Outcome1 women with

epilepsy who are pregnant

Specific AEDs No AEDs Major congenital malformations

2 women with epilepsy who are pregnant

Specific AEDs No AEDs Cognitive teratogenesis


AEDs at high dose

AEDs at low dose

Major congenital malformation


AEDs at high dose

AEDs at low dose

Cognitive teratogenesis


AEDs used as polytherapy

AEDs used as monotherapy

Major congenital malformations


AEDs used as polytherapy

AEDs used as monotherapy

Cognitive teratogenesis


Having seizures during pregnancy

Being seizure free during pregnancy

Fetal outcome: cognitive, SGA, preterm birth

8A Women with epilepsy taking AEDs

Being pregnant Before being pregnant

Serum AED levels

8B Women with epilepsy who are pregnant

Decrease in serum AED level

Unchanged serum AED level from prepregnancy

Seizure occurrence

8C Women with epilepsy who are pregnant

AED dose adjustment

Maintaining same AED dose

Adverse events in mother

9A Women with epilepsy

Folic acid Not taking folic acid

Pregnancy outcomes

9B Women with epilepsy

High dose folic acid

Low does folic acid

Pregnancy outcomes

10 Women with epilepsy

Being pregnant Not being pregnant

Seizure frequency

2

Abbreviation: AED = antiepileptic drug 3


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Rationale for the clinical questions 1

The clinical questions encompass the questions and findings of the 2009 guidelines and build on 2

literature available since then. 3

4

Consideration of patient preferences 5

Patient preferences will be solicited from at least two women with epilepsy included on the 6

author panel. 7

8

Relevant special populations and multiple morbidities 9

Considerations for women with epilepsy and other neurologic disabilities, such as stroke and 10

cerebral palsy, and data regarding races affected will be included. 11

12

Rationale for special populations and multiple morbidities 13

Epilepsy often occurs in the setting of additional neurologic disabilities. Practitioners struggle 14

with management of additional neurologic disabilities in women with epilepsy, especially those 15

who are also pregnant. 16


19

Plan to address special populations and multiple morbidities in the practice guideline 1

The literature will be searched for studies that primarily address women with epilepsy, and the 2

studies that are returned from the search will be reviewed for participants with morbidities in 3

addition to epilepsy, who will be addressed as a subset. 4

5

Study screening and selection criteria: inclusion and exclusion criteria for article selection 6

Types of participants 7

Women with epilepsy 8

Types of intervention 9

Causation Questions: AEDs, pregnancy, folic acid 10

Treatment Questions: AEDs 11

12

Comparison groups 13

Women with epilepsy who are not receiving AEDs or other interventions previously noted. For 14

the evaluation of seizure change during pregnancy, nonpregnant women with epilepsy. For the 15

evaluation of age at menopause and for pregnancy rates, women without epilepsy. 16

17

Types of outcome measures 18

Major congenital malformations, autism, cognitive disabilities, learning disabilities, dose of 19

AEDs, specific AEDs, seizure increase, miscarriage, small for gestational age, small head 20


20

circumference, bleeding during pregnancy, early labor, hemorrhagic disease of the newborn, 1

folic acid dose, serum levels of AEDs. 2

3

Literature search strategy 4

Inclusion and exclusion criteria 5

Inclusion Criteria: 6

General: 7

o Human studies 8

o Dates: June 2007 to present (June 2007 was the cut off of the previous guideline) 9

o Languages: all languages 10

o Study types: randomized controlled trials, prospective cohort studies, 11

retrospective cohort studies, case-control studies. 12

Population: Women with epilepsy—all available cohorts will be evaluated individually as 13

we have confirmation that there is less than 20% overlap in subjects across all 14

international registries as per email from Torbjorn Tomson on July 30, 2018, that stated 15

“For the latest analysis of eight monotherapies we had the following ‘overlap’ with other 16

registries. 3% of our pregnancies were from the UK-Ireland Register and the EURAP 17

included pregnancies also accounted for 3% of all UK-Ireland pregnancies; AUS 18

contributed 6% of the EURAP pregnancies and these accounted for 20% of all 19

pregnancies in the Australian registry; Finally Kerala contributed 3% of the EURAP 20

pregnancies and these represented 11% of the Kerala pregnancies. I agree that ideally we 21


21

don’t want to count the same pregnancy twice, but as you can see the contribution to 1

EURAP from the other registries reporting independently is minor.” 2

o Female patients aged 18 years or older, with 90% of those included to be aged 18 3

years or older or patients of child bearing potential 4

o For questions 8a-c and 10, studies with 20 patients or more. 5

o For questions 1 through 7 and 9a-b, studies with 369 patients or more. The 6

rationale for this number is listed as follows: 7

Assuming that 4% of the subjects in the population have the factor of 8

interest, the study would require a sample size of 369 for estimating7 the 9

expected proportion with 2% absolute precision and 95% confidence. In 10

other words, if you select a random sample of 369 from a population and 11

determine that 4% of subjects have the factor of interest, you would be 12

95% confident that between 2% and 6% of subjects in the population have 13

the factor of interest. 14

o Meta-analyses will be applied if deemed appropriate. 15

Outcomes: clinical-pathologic correlation (etiologic diagnosis) 16

Exclusion Criteria: 17

General: 18

o Animal studies 19

o Study types: case studies, reviews, meta-analyses 20

Population 21

o Studies with more than 10% of patients younger than 18 years 22


22

o Studies with fewer than 369 pregnancy outcomes 1

Outcomes: those not listed above 2

Terms and databases to be used in the literature search 3

Keywords 4

a) Key Text words and Index words for the condition or closely related conditions, if 5

appropriate (linked by the word "OR"): 6

b) Key text words for identification of special populations and relevant comorbidities 7

(linked by the word "OR"): 8

c) Key Text words and Index words for the intervention (linked by the word "OR"): 9

Databases to search: Medline, Cochrane. EMBASE, CINAHL, DARE 10

11


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DISCLAIMER 1

Clinical practice guidelines, practice advisories, systematic reviews and other guidance published 2

by the American Academy of Neurology and its affiliates are assessments of current scientific 3

and clinical information provided as an educational service. The information: 1) should not be 4

considered inclusive of all proper treatments, methods of care, or as a statement of the standard 5

of care; 2) is not continually updated and may not reflect the most recent evidence (new evidence 6

may emerge between the time information is developed and when it is published or read); 3) 7

addresses only the question(s) specifically identified; 4) does not mandate any particular course 8

of medical care; and 5) is not intended to substitute for the independent professional judgment of 9

the treating provider, as the information does not account for individual variation among 10

patients. In all cases, the selected course of action should be considered by the treating provider 11

in the context of treating the individual patient. Use of the information is voluntary. AAN 12

provides this information on an “as is” basis, and makes no warranty, expressed or implied, 13

regarding the information. AAN specifically disclaims any warranties of merchantability or 14

fitness for a particular use or purpose. AAN assumes no responsibility for any injury or damage 15

to persons or property arising out of or related to any use of this information or for any errors or 16

omissions. 17

18

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CONFLICT OF INTEREST 1

The American Academy of Neurology (AAN) is committed to producing independent, critical, 2

and trustworthy clinical practice guidelines (CPGs). Significant efforts are made to minimize the 3

potential for conflicts of interest to influence the recommendations of this CPG. Management 4

and disclosure of guideline developer relationships is conducted in compliance with the 2017 5

AAN process manual section titled, “Implementing the AAN Conflict of Interest Policy for 6

Guidelines and Case Definitions,” which can be viewed at www.aan.com.1 7

8

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