North American Commission Symposium Controversies in the ... · this activity is based on the best available evidence. Unapproved Use Disclosure ... residents, general physicians,

North American Commission Symposium Controversies in the Management of Epilepsy

During Pregnancy

Symposium Co-Chairs:

Sheryl Haut, M.D.

And

Page Pennell, M.D

Saturday, December 3, 2016 Convention Center – General Assembly

5:30 – 7:30 p.m.

Accreditation The American Epilepsy Society is accreditedby the Accreditation Council for ContinuingMedical Education (ACCME) to providecontinuing medical education for physicians.

AMA Credit Designation StatementThe American Epilepsy Society designates this live activity for amaximum of 29.50 AMA PRA Category 1 Credits™. Physiciansshould claim only the credit commensurate with the extent oftheir participation in the activity.

International Credits: The American Medical Association hasdetermined that non-U.S. licensed physicians who participate inthis CME activity are eligible for a maximum of 29.50 AMA PRACategory 1 Credits™.

Physician Assistants: AAPA accepts certificates of participationfor educational activities certified for AMA PRA Category 1Credits™ from organizations accredited by ACCME or arecognized state medical society. Physician assistants mayreceive a maximum of 29.50 hours of Category 1 credit forcompleting this program.

Continuing Education for Nurses andPharmacists

Jointly provided by AKH, Inc.,Advancing Knowledge in Healthcare,and the American Epilepsy Society.

Nurses:Advancing Knowledge in Healthcare is accredited as aprovider of continuing nursing education by the AmericanNurses Credentialing Center’s Commission on Accreditation.This activity is awarded 29.50 contact hours.

Pharmacists:Advancing Knowledge inHealthcare is accredited by the AccreditationCouncil for Pharmacy Education as a provider ofcontinuing pharmacy education.

Select portions of this Annual Meeting are approved forpharmacy CE credit. Specific hours of credit for approvedpresentations and the Universal Activity Numbers assigned tothose presentations are found elsewhere in the programmaterials. Criteria for success: credit is based on documentedprogram attendance and online completion of a programevaluation/assessment.

If you have any questions about this CE activity relative tonursing and/or pharmacy CE, please contact AKH Inc [email protected].

The American Board of Psychiatry and Neurology has reviewedthe 70th Annual Meeting — American Epilepsy Society and hasapproved this program as part of a comprehensive epilpesyprogram, which is mandated by the ABMS as a necessarycomponent of maintenance of certification.

Claiming CME Credit and CME CertificatesAttendees who registered in the following categories may claimCME or CE for the meeting: physician, health care provider,trainee, one-day and two-day. Meeting registration includescredit claiming: there is no separate fee to claim CME/CE.

Attendees will receive an emailed notification to access theonline evaluation and credit claim system.

The evaluation and credit claim system will remain openthrough Tuesday, February 28, 2017. Evaluations and creditclaims must be completed by this date in order to record andreceive your CME/CE certificate.

Attendance Certificate/International AttendeesA meeting attendance certificate will be available at theregistration desk for international meeting attendees onTuesday, December 6.

Resolution of Conflicts of InterestIt is the policy of the American Epilepsy Society to ensurebalance, independence, objectivity and scientific rigor. Allpersons involved in the selection, development andpresentation of content are required to disclose any real orapparent conflicts of interest. In accordance with the ACCMEStandards for Commercial Support of CME, AES implementedthe mechanism of prospective peer review of this CME activity,to identify and resolve any conflicts. Additionally, the content ofthis activity is based on the best available evidence.

Unapproved Use DisclosureAES requires CME authors to disclose to learners whenproducts or procedures being discussed are off-label,unlabeled, experimental and/or investigational (not FDAapproved); and any limitations on the information that ispresented, such as data that are preliminary or that representongoing research, interim analyses and/or unsupportedopinion. This information is intended solely for continuingmedical education and is not intended to promote off-label useof these medications. If you have questions, contact themedical affairs department of the manufacturer for the mostrecent prescribing information. Information aboutpharmaceutical agents/devices that is outside of U.S. Food andDrug Administration approved labeling may be contained inthis activity.

DisclaimerThis CME activity is for educational purposes only and does notconstitute the opinion or endorsement of, or promotion by, theAmerican Epilepsy Society. Reasonable efforts have been takento present educational subject matter in a balanced, unbiasedfashion and in compliance with regulatory requirements.However, each activity participant must always use his or herown personal and professional judgment when consideringfurther application of this information, particularly as it mayrelate to patient diagnostic or treatment decisions including,without limitation, FDA-approved uses and any off-label,investigational and/or experimental uses.

EDUCATION CREDITS

American Epilepsy Society | www.AESnet.org | Houston, Texas 70th Annual Meeting | 6th Biennial North American Regional Epilepsy Congress 23

OVERVIEW Management of women with epilepsy during child-bearing years requires complex decision-making, with the goal of optimal maternal seizure control balanced against potential fetal risks of in utero anti-epileptic drug exposure. An abundance of data is now available to differentiate risks between some AEDs with regard to both structural teratogenecity and neurodevelopmental consequences. However, evidence is still lacking regarding many of the AEDs overall, and details of how best to dose AEDs during critical time windows to optimize maternal and fetal outcomes is an area of active research. Peripartum is a particularly vulnerable time for seizure worsening; data is now available to support the benefits of breastfeeding in women with epilepsy on AEDs but sleep disruption can worsen seizures in many. This session will provide the latest data available regarding these issues, as well as delve into some of the more contemporary controversies including when use of valproate is justifiable in this special patient population, dosing strategies, and when therapeutic drug monitoring should be used and alternative strategies when it is not available. LEARNING OBJECTIVES Following participation in this symposium, learners should be able to: • List the antiepileptic drugs (AED) that carry relatively higher teratogenic risk (structural and

neurodevelopmental). • Review and discuss how each AED does or does not increase the teratogenic risk. • Describe gestational pharmacokinetic principles and restate how to adjust medications during pregnancy

to maintain seizure control, as well as in the postpartum period. • Delineate approaches for counseling women regarding strategies to lower seizure risk during the

peripartum period. • Recognize and describe the neurodevelopmental risks of children born to women with epilepsy, with

specific • considerations of contributory factors that include family history, vitamin use, AED type and dose, and

maternal seizure control as well as other obstetric and neonatal complications. • Identify the neurocognitive profiles to monitor during early child development.

TARGET AUDIENCE Basic: Those new to epilepsy treatment or whose background in the specialty is limited, e.g., students, residents, general physicians, general neurologists and neurosurgeons, other professionals in epilepsy care, administrators. Intermediate: Epilepsy fellows, epileptologists, epilepsy neurosurgeons, and other providers with experience in epilepsy care (e.g., advanced practice nurses, nurses, physician assistants), neuropsychologists, psychiatrists, basic and translational researchers. PROGRAM Co-Chairs: Sheryl Haut, M.D., and Page B. Pennell, M.D. Introduction Sheryl Haut, M.D. The Valproate Controversy: The Worldwide Perspective Torbjorn Tomson, M.D. Pre-pregnancy Planning: AED Choice and Pregnancy Outcomes Kimford J. Meador, M.D.

Management of Epilepsy During Pregnancy and Postpartum: AED Dosing Strategies Page B. Pennell, M.D. Postpartum Management: Risk of Seizures and Safety, Newborn Care and Nursing Sanjeev Thomas, M.D. Panel Discussion All Faculty Education Credit 2.0 CME Credits Nurses may claim up to 2.0 contact hours for this session.

Pharmacy Credit Pharmacists: AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 2.0 contact hours (0.2 CEUs). UAN 0077-9999-16-087-L01-P. Initial Release Date: 12/3/16.

FACULTY/PLANNER DISCLOSURES It is the policy of the AES to make disclosures of financial relationships of faculty, planners and staff involved in the development of educational content transparent to learners. All faculty participating in continuing medical education activities are expected to disclose to the program audience (1) any real or apparent conflict(s) of interest related to the content of their presentation and (2) discussions of unlabeled or unapproved uses of drugs or medical devices. AES carefully reviews reported conflicts of interest (COI) and resolves those conflicts by having an independent reviewer from the Council on Education validate the content of all presentations for fair balance, scientific objectivity, and the absence of commercial bias. The American Epilepsy Society adheres to the ACCME’s Essential Areas and Elements regarding industry support of continuing medical education; disclosure by faculty of commercial relationships, if any, and discussions of unlabeled or unapproved uses will be made. FACULTY / PLANNER BIO AND DISCLOSURES Sheryl Haut, MD, Chair Professor Albert Einstein College of Medicine Dr. Sheryl Haut is Professor of Clinical Neurology and Director of the Adult Epilepsy Program at Montefiore-Einstein. Dr. Haut has a Masters of Clinical Research with Distinction from Albert Einstein College of Medicine. Her research interests focus on seizure clustering; seizure prediction and pre-emption; and alternative therapies for epilepsy. She is one of the first investigators to run a clinical trial of stress management for epilepsy, using smartphone diaries. Dr. Haut is the current Chair of the North American Commission of the International League Against Epilepsy, and is active nationally in the American Epilepsy Society, and the American Academy of Neurology, serving on committees of both organizations. Dr. Haut discloses receiving support for Consulting Fees (e.g., advisory boards): Acorda, Siga Page B. Pennell, MD, Chair and Faculty Professor Brigham and Women's Hospital, Harvard Medical School Page B. Pennell, MD is Professor of Neurology at Harvard Medical School and Director of Research for the Division of Epilepsy at Brigham and Women’s Hospital, with a secondary appointment in the Division of

Women’s Health. She is an adult epileptologists and a clinician investigator with a focus on sex-specific outcomes in epilepsy. Dr. Pennell’s clinical studies focus on the effects of hormones and neurosteroids on seizure provocation, pharmacokinetic changes of AEDs with differing reproductive phases, and maternal and fetal outcomes during pregnancy in women with epilepsy, with an emphasis on balancing maternal seizure control against the teratogenic risks of in utero anti-epileptic drug exposure, including potential effects on fetal brain development. Dr. Pennell discloses she has no financial relationships to disclose relevant to this activity. Kimford J. Meador, MD, Faculty Professor Stanford University School of Medicine Dr. Meador is Professor of Neurology & Neurosciences at Stanford University, and Clinical Director, Stanford Comprehensive Epilepsy Center. He graduated from Georgia Institute of Technology, MD from Medical College of Georgia, internship U. Virginia, Public Health Corps service, neurology residency Medical College of Georgia, and Behavioral Neurology fellowship U. Florida. He was faculty at Medical College of Georgia where he was Charbonnier Professor of Neurology, then Chair of Neurology Georgetown U., Melvin Greer Neurology Professor U. Florida and Director of Epilepsy Program & of Clinical Alzheimer Research Program, and Professor of Neurology & Pediatrics and Director Epilepsy & Clinical Neurocience Research Emory University (2008-2013) . Dr. Meador has authored > 350 peer-reviewed publications. Dr. Meador discloses receiving support for Other Financial or Material Support: Epilepsy Study Consortium; Provide consultant expertise to the Epilepsy Consortium for companies. Monies go to Dr. Meador's university.: Epilepsy Study Consortium Sanjeev V. Thomas, MD, DM, Faculty Professor of Neurology Sree Chitra Tirunal Institute for Medical Sciences Dr. Sanjeev V. Thomas, MD, DNB, DM, FAMS, FIAN, FANA; Professor of Neurology & Head of R. Madhavan Nayar Centre for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, India. President Elect, Indian Epilepsy Society, Member, ILAE Task force for treatment guidelines, Member, Editorial Board Epilepsy Research Journal and International Journal of Epilepsy, PI Kerala Registry of Epilepsy and Pregnancy, Member Central Committee of the International Registry of antiepileptic drugs and Pregnancy (EURAP). Past Secretary, Indian Academy of Neurology, Past Editor, Annals of Indian Academy of Neurology (2006 - 2011), Fulbright Visiting Lecturer Fellowship (2011) to Ohio State University, Columbus OH. Dr. Thomas discloses receiving support for Honoraria: BMJ Masterclass India Torbjörn Tomson, MD, PhD, Faculty Professor Karolinska Instiitutet Torbjörn Tomson, MD, PhD, is professor of neurology the Department of Clinical Neuroscience Karolinska Institute, and consultant neurologist at the Karolinska University Hospital, Stockholm, Sweden. His main research interests are pregnancy outcomes and mortality in epilepsy and particularly SUDEP. He is chair of EURAP, the International Antiepileptic drugs and pregnancy registry. He is presently member of the ILAE Commission on European Affairs and chair of the ILAE Publication Task Force. He is FRCP Edinburgh, Honorary

professor at Hanoi Medical University and received in 2013 the America Epilepsy Society Research Recognition Award for Clinical Science. He has published more than 200 original articles and reviews in the field of epilepsy. Dr. Tomson discloses he has no financial relationships to disclose relevant to this activity. CME REVIEWERS Rohit Das, MD, MPH, Reviewer Rohit R Das MD MPH is Associate Professor of Neurology and Neurotherapeutics (Epilepsy Division) UT Southwestern Medical School Dallas Texas and Fellow in Patient Safety, Roudebush VA Medical Center, United States Department of Veterans Affairs, Indianapolis IN and Competency Director in Systems Based Practice Indiana University School of Medicine Indianapolis IN Dr. Das discloses receiving support for Honoraria: LivaNova PHARMACY/NURSE PLANNERS Gigi Smith, PhD, RN, CPNP-PC: No financial relationships to disclose relevant to this activity. Dorothy Duffy, PharmD: No financial relationships to disclose relevant to this activity. AKH STAFF / AES STAFF AKH staff and planners: No financial relationships to disclose relevant to this activity. AES staff and planners: No financial relationships to disclose relevant to this activity. CLAIMING CREDIT: PHYSICIANS

Attendees who registered in the following categories may claim CME or CE for the meeting: physician, health care provider, trainee, one-day and two-day. Meeting registration includes credit claiming: there is no separate fee to claim CME/CE. Attendees will receive an emailed notification to access the online evaluation and credit claim system. The evaluation and credit claim system will remain open through Tuesday, February 28, 2017. Evaluations and credit claims must be completed by this date in order to record and receive your CME/CE certificate. Physicians can claim CME credit online at https://cme.experientevent.com/AES151/ This Link is NOT Mobile-friendly! You must access it from a laptop, desktop or tablet. How to Claim CME Credit To claim CME credits online, please follow the on-screen instructions at the above url. Log in using your last name and zip code, OR your last name and country if you’re not from the United States. All CME credits must be claimed by February 28, 2017. Questions? Contact Experient Customer Service at: 800-974-9769 or [email protected]

NURSING & PHARMACY

PLEASE NOTE: Providing your NABP e-profile # is required. The National Association of Boards of Pharmacy (NABP) requires that all pharmacists and pharmacy technicians seeking CE credit have an ID number issued by NABP. Pharmacy CE providers, such as AKH Inc., Advancing Knowledge in Healthcare, are required to submit participant completion information

directly to NABP with your ID number and birth information to include month and date (not year) as a validation to this ID number. If you do not have an ID number (this is not your license #), go to: www.MyCPEmonitor.net

Nursing and Pharmacy credit (per session) is based on attendance as well as completion of an online evaluation form available at:

WWW.AKHCME.COM/2015AES

THIS MUST BE DONE BY JANUARY 15, 2017 TO RECEIVE YOUR CE CREDIT. We cannot submit credit to NABP after this date. If you have any questions, please contact AKH at [email protected].

DISCLAIMER Opinions expressed with regard to unapproved uses of products are solely those of the faculty and are not endorsed by the American Epilepsy Society or any manufacturers of pharmaceuticals.

11/20/2016

1

The Valproate Controversy:The Worldwide Perspective

Torbjörn TomsonDepartment of Clinical Neuroscience

Karolinska Institutet, Stockholm, Sweden

Disclosure

Eisai, UCB Honorarium to my department for Ad Board  participation

GSK Grant for SUDEP studyGSK, Eisai; UCB,  Grants for EURAP Novartis, Bial Pregnancy Registry 

BMJ Educational Honorarium for lectures

1

Learning Objectives

• To understand the spectrum of teratogenic risks with fetal exposure to valproate (VPA)

• To understand risk factors for adverse pregnancy outcomes with valproate

• To have insight in changing patterns of valproate prescribing to women of childbearing potential

2

• Dalens B, Raynaud EJ, Gaulme J. 

• Teratogenicity of valproic acid. J Pediatr 1980; 97: 332–33.

• Gomez MR. Possible teratogenicity of valproic acid. J Pediatr 1981; 98: 508–09.

• Lindhout D, Schmidt D. In‐utero exposure to valproate and neural tubedefects. Lancet 1986; 1: 1392–93.

• Robert E, Guibaud P. Maternal valproic acid and congenital neural tubedefects. Lancet 1982; 2: 937.

• DiLiberti JH, Farndon PA, Dennis NR, Curry CJ. The fetal valproatesyndrome. Am J Med Genet 1984; 19: 473–81.

First observations suggesting clinical teratogenicity ofVPA >35 years ago

3

Valproate monotherapy associated with broad rangeof major congenital malformations (MCM) Pooled data from 32 studies 

52

21 24 26

51

714

20

28

2

11

2

9

0

35

61 59

31

56

1 10 0

2

0

6

3

carbamazepine

(7308)

lamotrigine

(7100)

barbiturates

(852)

phenytoin

(1218)

Cardiac

Neural tube defects

Cleft palate and cleft lip

Hypospadia

valproate

(4270)

levetiracetam

(754)

topiramate

(470)

0%

2%

4%

Tomson et al Lancet Neurol 2015 

4NAAPR

(n=10

33)

EURAP

(n=14

02)

UK (n =

165

7)

NAAPR (n

=1441

)

EURAP

(n=12

80)

UK (n

=2098

)

NAAPR (n

=323)

EURAP

(n =

1010

)

UK (n=12

20)

NAAPR (n

=199)

EURAP

(n=21

7)

NAAPR (n

=416)

EURAP

(n =

103)

UK (n=82

)0%

5%

10%

15%

20%

rate

of m

alfo

rmat

ions

(%),

95%

CI

lamotrigine

phenobarbital

carbamazepine

phenytoin

valproate

Overall MCM risks higher with valproateMonotherapy data from pregnancy registries

Tomson et al., Lancet Neurol 2011, Tomson et al., Neurology 2015, Hernandez‐Diaz et al., Neurology 2012, Campbell et al., JNNP 2014 5

11/20/2016

2

Figure 1: Risk of major malformations by average valproate dose (mg) during the first trimester .

0 6 12 18 24 30 36

VPA<700

Figure 3: Major congenital malformation rate by drug dose.

UK Ireland Campbell et al JNNP 2014

MC

M r

ate

(%

)

Valproate

12

10

6

0

2

4

8

Carbamazepine Lamotrigine

VPA<600

Figure 2: Risk of major malformations. Figure 4: Cumulative rates of occurrence of pregnancies with malformations below various thresholds of daily valproate doses.

AUS Vajda et al, J clin Neurosci 2014NAPPR Hermandez-Diaz Neurology 2012

EURAP Tomson et al Lancet Neurol 2011

0 5 10 15 20 25 30 35

Lamotrigine

1-500

501-999

1000-1500

Percent

Va

lpro

ate

do

se (

mg

)

% M

alfo

rme

d o

ffs

pri

ng

0

20

15

10

5

01000 2000 3000

Upper limit of dose (mg/day)

Monotherapy cases

All cases

VPA<500

Tomson T. et al. Lancet Neurol. 2011; 10, 609-617 Campbell E et al. J. Neurol. Neurosurg. Psychiatry 2014; 85(9), 1029-1034

Hernandez-Diaz S. et al. Neurology 2012; 78(2), 1692-1699 Vajda FJE. J. Clin. Neuroscience. 2014. 21; 716-721 Upper limit of VPAdose (mg/day)

Percent of MCMs (95% CI)

The MCM risk with VPA depends on the dose

6

Outcome of previous pregnancy a risk factor

• Women with epilepsy on AEDs with major malformation in previous pregnancy had 35.7% risk of major malformation in next pregnancy if on same AED (vs 3% if not)

• Higher rates with VPA: 57.2% vs. 7.0%, respectively

Vajda et al., Epilepsia 2013

7

Adding one other AED to valproate has no major impact on MCM risk

Treatment VPA <700 mg/day

VPA 700‐1500 mg/day

VPA >1500 mg/day

P*

VPA mono 5.9% 11.0% 24.0% p<0.0001

VPA+LTG 7.0% 6.8% 31.0% p=0.0034

VPA+Other 5.4% 11.2% 19.2% p=0.0270

Total 6.0% 10.7% 23.8% p<0.0001

Tomson et al., Neurology 2015;85:866‐72

9

Valproate can affect cognitive development

Meador et al., NEJM 2009

Meador et al., Lancet Neurol 2013

Neurodevelopmental Effects of Antiepileptic Drugs, NEAD Study309 mother/child pairs from 25 centers in US & UK

Prospective study of cognitive outcomes after fetal exposure to monotherapy with carbamazepine, lamotrigine, phenytoin or valproate

10

NEAD: Outcome at 6 years and dose‐dependency

Meador et al., Lancet Neurol 2013

CBZ LTG PHT VPA

Completers, n 61 74 40 49

Mean IQ (95% CI)

106(103‐109)

108(105‐111)

109(105‐113)

98(95‐102)

Dose CBZ LTG PHT VPA

Low 107 106 108 104

High 106 109 106 94

Median DoseCBZ 800 mgLTG 500 mgPHT 400 mgVPA 1000 mg

11

Valproate Exposure and Risk of Autism, Autism Spectrum Disorder (ASD), and ADHD

Population‐based Danish register studyASD 4.4% (95% CI, 2.6%‐7.5%) (HR  3.0)Autism 2.5% (95% CI, 1.3%‐4.8%) (HR = 4.9)

Christensen et al JAMA 2013

Small prospective study reporting increased scores in Childhood Autism Rating Scale at 6‐8 years if exposed to VPA polytherapy (n=15)

Data from prospective NEAD study at 6 yearsChildren exposed to valproate had ‐Greater risk of diagnosis of ADHD‐Lower General Adaptive Composite scores

Wood et al., Epilepsia 2015

Cohen et al., Epilepsy & Behav 2013

13

11/20/2016

3

Use of VPA has changed over time internationallyEURAP: The International Antiepileptic Drugs and Pregnancy Registry

0

5

10

15

20

25

30

35

40

45

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Proportion (%) of pregnancies with valproic acid

monotherapy

polytherapy

15

0.0

5.0

10.0

15.0

20.0

25.0

30.02000‐2010

2011‐2014

Change in VPA use over time by country in EURAP Proportion (%) of monotherapy pregnancies with valproate

16

Regulators and Guidelines on Valproate use

Doctors in the EU are now advised not to prescribe valproate for epilepsy or bipolar disorder in pregnant women, in women who can become pregnant or in girls unless other treatment are ineffective or not tolerated.

November 2014

June 2013

With regard to valproate use in pregnant women withepilepsy or bipolar disorders, valproate productsshould only be prescribed if other medications are not effective in treating the condition or are otherwiseunacceptable.With regard to women of childbearing age who arenot pregnant, valproate should not be taken for anycondition unless the drug is essential to the management of the woman’s medical condition.

Valproate should not be used in female children, in femaleadolescents, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated

February 2016

17

Tool Kit with Checklists endorsed by UK‐MHRA*

*Medicines and Healthcare Products Regulatory Agency 18

Concerns from the epilepsy community

Treatment alternatives are few for generalized idiopathic/geneticepilepsies

Efficacy of alternatives may not be comparable to VPA, and/or teratogenic risks significant, or not yet fully assessed

Unlike men, women and girls with epilepsy risk to be denied the mosteffective treatment

The risks with uncontrolled seizures may be neglected

Women may be encourged to rapid discontinuation or switch from VPA, even during pregnancy

With potentially serious consequences for them and for the fetus

With lack of evidence for reduction in teratogenic risks

19

Withdrawal or switch from VPA during pregnancyassociated with poorer seizure control

1st trimester Entire pregnancy

Tomson et al Epilepsia 2016

Stable VPA  n=1588Withdrawn VPA  n=93Switched from VPA n=38

20

11/20/2016

4

Task Force appointed by ILAE CEA and EAN

Clinician has responsibility to actively inform about risk with fetal exposure to valproate

The choice of treatment is a shared decision between clinician and fully informed patient

Wherever possible, valproate should be avoided in the treatment of girls and women of childbearing potential

Epilepsia 2015;56:1006‐19

CEA, Commission on European Affairs; EAN, European Academy of Neurology 21

ILAE CEA/EAN  Use of VPA in situations where VPA may be considered mostappropriate AED for seizure/epilepsy type

In newly diagnosed:VPA may be considered when the epilepsy, or concurrent

disabilites, are so severe that pregnancy is extremely unlikely

Patient established on VPA, not considering pregnancy:VPA can be continued for those whose seizures were only

controlled after failing other appropriate alternatives, and for whom risks of withdrawal are not acceptable

VPA can be continued in IGE, when, after careful information, patient and clinician agree that benefits of remaining outweighrisks of withdrawal or switch

Women who wish to continue on VPA, but are willing to accept risks with dose reduction, should aim for doses not exceeding500‐600 mg/day

Epilepsia 2015;56:1006‐19 22

ILAE CEA/EAN  Use of VPA in situations where VPA may be considered mostappropriate AED for seizure/epilepsy type

Patient established on VPA considering future pregnancy:Treatment should be reassessed and changes carefully considered

for every women considering pregnancy

Withdrawal or switch should be considered if likelihood of relapseis acceptable to patient

Treatment changes should be completed and evaluated, and lowest effective dose established, before conception

Women already on VPA while pregnantSwitch to other treatment generally not recommended during

pregnancy in patient with good seizure control

Withdrawal of VPA in a pregnant woman should only be initiatedif the risk of doing so is acceptable to the patient 

Epilepsia 2015;56:1006‐19 23

Impact on Clinical Care and Practice

• Girls and women on valproate should be carefully informed about the teratogenic risks, treatment be reassessed and alternatives considered

• Whenever possible valproate should be avoided in girls and women of childbearing potential

• If valproate is deemed to be necessary aim at lowest effective dose, preferably not exceeding 500‐600 mg/day

24

#AES2016

11/28/2016

1

Pre‐Pregnancy Planning: AED Choice and 

Pregnancy Outcomes

Kimford J. Meador, MD

Department of Neurology & Clinical Neuroscience

Stanford University, Palo Alto, California, USA

DisclosuresGrants:NIH/NINDS 2U01‐NS038455. Meador (Multi‐PI). “Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs.”*NIH/NINDS 3 U01 NS038455. Meador (Multi‐PI). “Metabolomic Indicators of Risk in the MONEAD Cohort.”NIH/NINDS R01NS088748. Drane (PI). “Dissecting the Cognitive Roles of Hippocampus & Other Temporal Lobe Structures.” Role: Co‐I. NIH 1 R01 NS076665. Marino (PI) "Characterizing and Predicting Drug Effects on Cognition." Role: Consultant.Sunovion Pharma. Meador (PI). “Cognitive and Behavioral Effects of EslicarbazepineAcetate and Carbamazepine in Healthy Adults.” Consultant (No direct personal income): 

Epilepsy Consortium (funds paid to my university)* for Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher Smith Laboratories, UCB Pharma and VivusPharmaceuticals .

Other: Clinical income: EEG procedures and patient care*

*Items with asterisk involve income > $10,000 for recent years.

Learning Objectives

• Understand present state of knowledge on the anatomical and behavioral teratogenetic effects of antiepileptic drugs.

• Understand factors to address in an adequate informed consent of women with epilepsy related to pregnancy issues.

When should pre‐pregnancy planning be done?

• Before pregnancy!

• Since half of pregnancies are not plan, waiting until a woman is planning a pregnancy is inadequate.

• Informed consent of issues related to pregnancy should be done when a Rx for an antiepileptic drug is written for any woman of childbearing potential.

AEDs & Hormonal Contraceptive Agents

Lower hormone levels• Carbamazepine• Clobazam• Eslicarbazepine• Felbamate• Oxcarbazepine (>1200mg)

• Perampanel• Phenobarbital• Phenytoin• Primidone• Rufinamide• Topiramate (>200mg)

No significant effects• Clonazepam• Ethosuximide• Ezogabine• Gabapentin• Lacosamide• Lamotrigine*• Levetiracetam• Pregabalin• Tiagabine• Valproate**• Vigabatrin• Zonisamide• IUDs

* Estradiol lowers lamotrigine level** Valproate can interact with other drugs but not OCPs

Congenital Malformations

• General Population = 2 ‐ 3%

• Older Studies noted rates in

Infants of Mothers with Epilepsy = 4 – 8%

(Range = 1.25 ‐ 18.6%)

Major Malformations: Heart Defects, Orofacial Clefts, Skeletal, Urological & Neural Tube Defects (Valproate = 1.5%, Carbamazepine < 0.5%)

11/28/2016

2

Major Congenital Malformations% MCMs (# MCM / # Sample)

EURAP NAAPR

Valproate 9.7% (98/1010) 9.3% (30/323)

Phenobarbital 7.4% (16/217) 5.5% (11/199)

Topiramate 6.8% (5/73 ) 4.2% (15/359)

Phenytoin 5.8% (6/103) 2.9% (12/416)

Carbamazepine 5.6% (79/1402) 3.0% (31/1033)

Oxcarbazepine 3.3% (6/184) 2.2% (4/182)

Lamotrigine 2.9% (37/1280) 1.9% (31/1562)

Levetiracetam 1.6% ((2/126) 2.4% (11/450)

Tomson et al, Seizure 2015;28:46–50

EURAP: Dose Dependent Effects on MCMs

Antiepileptic Drug N % Seizure Free % Malformations

Cabamazepine

<400 mg/d 148 64% 3.4%

400 to <1000 mg/d 1047 67% 5.3% *

>1000 mg/d 207 62% 8.7% *

Lamotrigine

<300 mg/d 836 67% 2.0%

>300 mg/d 444 68% 4.5% *

Phenobarbital

<150 mg/d 166 71% 5.4% *

>150 mg/d 51 69% 13.7% *

Valproate

<700 mg/d 431 71% 5.6% *

700 to <1500 mg/d 480 66% 10.4% *

>1500 mg/d 99 61% 24.2% *

Tomson et al., Lancet Neurol 2011;10: 609-17 * More MCMs than LTG<300mg/d

Conclusions: Anatomical Teratogenesis

• Valproate poses special risk.

• Possible dose dependent risks for all AEDs

• Spina Bifida: – Valproate = 12.7 X, Carbamazepine = 2.6 X

• Intermediate Risks: Phenobarb & Topiramate.

• Risks of most AEDs and specific polytherapycombination are uncertain.

• Mechanisms & reasons for individual variance are unknown.

Fetal AED Exposure:Cognitive & Behavioral Effects

• Animal studies demonstrate adverse cognitive & behavioral effects of fetal AED exposure.

• Human studies demonstrate that fetal valproate• lowers FSIQ by 7‐10 points vs. common AEDs• even at low dose (<800mg/d) lowers verbal IQ & increases need for special education

• Increases risk of autism.

Vorhees CV. Environ Health Perspect 1994;102 (Suppl 2):145-53; Meador et al. NEJM 2009;360:1597-605; Meador et al. Lancet Neurology 2013: 12(3):244-52; Christensen et al, JAMA 2013;309(16):1696-1703.

Fetal Levetiracetam & Topiramate: Cognition at 5‐9 years old

No AED TPM LEV VPAN 55 27 42 47

FSIQ 100  100 99 96(SD) (14) (13) (14) (14)

VIQ 102 99 101 94

(SD) (13) (11) (11) (15)

FSIQ = Mean Full Scale IQVIQ = Mean Verbal IQ SD=standard deviation

Bromley et al, Neurology 2016;87:1‐11

AEDs and Apoptosis in Developing Animal Brain

• Widespread neural apoptosis in rats aged 3‐30 days

– Present for clonazepam, diazepam, phenobarb, phenytoin, valproate, & vigabatrin1,2

– Absent for carbamazepine, lamotrigine, levetiracetam, & topiramate monotherapy3‐8

• Reduced expression of neutrophins & extracellular signal proteins2

1. Bittigau et al. Proc Natl Acad Sci U S A. 2002. 2. Bittigau et al. Ann N Y Acad Sci. 2003. Glieret al. Exp Neurology. 2004. 4. Manthey et al. Exp Neurol 2005. 5. Kim et al. JPET 2007. 6. Katz et al, JPEG 2007. 7. Forcelli et al, JPEG 2012. 8. Forcelli et al, Ann Neurol 2012.

11/28/2016

3

Child IQ & Periconceptional FolateF=11.4, p<.0009. Adjusted Mean IQs (95% CIs)

Meador et al. Lancet Neurology 2013: 12(3):244-52

Folate = 108 (106, 111)     No Folate = 102 (98, 104)

Conclusions: Behavioral Teratogenesis

• Valproate poses a special risk for behavioral as well as anatomical teratogenesis.

• Risks for many AEDs and polytherapies are uncertain due to lack of both animal and human data.

• Mechanisms & reasons for individual variance are unknown.

• Neonates may also be at risk.

Clinical Implications• Most children born to WWE are normal.

• WWE of childbearing potential should be taking folate (dose uncertain: 0.4 – 4.0mg/d).

• WWE should receive informed consent outlining risks PRIOR to conception 

(i.e., when the 1st Rx is written).

• Informed consent should include known relative anatomical & behavioral teratogenesis, the unknowns, contraceptive, and pregnancy & postpartum issues.

WWE=Women with epilepsy

Clinical Implications

• Valproate is a poor 1st choice AED for WWE of childbearing potential. If it is used, dose as low as possible.

• Phenobarbital & Topiramate pose intermediate risks.

• Risks for many AEDs uncertain and additional research is needed.

WWE=Women with epilepsy

Further Research Needed To:• Delineate cognitive effects of fetal & neonatal exposure for other AEDs & combinations.

• Establish relations based on AED blood levels.

• Determine AEDs effects on cerebral lateralization.

• Confirm effects of periconceptional folate.

• Determine risks for maternal outcomes.

• Determine reasons for individual variability.

• Determine underlying mechanisms.

MONEAD StudyMaternal Outcomes & Neurodevelopmental Effects of Antiepileptic Drugs

http://www.neadstudy.comFunded by NIH/NINDS #2U01-NS038455

20 sites

11/28/2016

4

MONEAD Study• MATERNAL OUTCOMES:

Risks in WWE during pregnancy • Seizures • OB Complications• Depression (pregnancy & postpartum)

• OUTCOMES in CHILDREN of WWE:• Neurodevelopment Cognitive & behavioral• Neonatal Outcomes • Breastfeeding Effects if WWE taking AED.

• Pharmacokinetics: Relation of AED exposure & outcomes

• Groups expanded: WWE on new AEDs, polytherapy, and no AED, and also 2 control groups (nWWE & pHealthy)

AEDs=Antiepileptic Drugs; WWE=Women with Epilepsy; p=pregnant; n=non‐pregnant

#AES2016

11/28/2016

1

Management of Epilepsy During Pregnancy and Postpartum: AED 

Dosing Strategies

Page B. Pennell, MD

Professor of Neurology

Harvard University, Brigham and Women’s Hospital Boston, MA, USA

DisclosuresResearch Grants contributing to salary support:

NIH/NINDS, NICHD U01‐NS038455. Pennell, Meador (Multi‐PI). “Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs.”

NIH/Common Fund U01 NS038455. Pennell, Meador (Multi‐PI). “Metabolomic Indicators of Risk in the MONEAD Cohort.”

Epilepsy Foundation. Pennell, French, Harden (Multi‐PI). “Women with Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD)”.

Commercial Interests: None.

Travel and/or honoraria: American Epilepsy Society, American Academy of Neurology, Tbilisi State Medical University, Indian Academy of Neurology, University of Maryland, UCSF, UTSW, Columbia University, NYU, International Association of Therapeutic Drug Monitoring and Clinical Toxicology, National Institute of Neurological Sciences, Peru Ministry of Health, and the National Institutes of Health

Learning Objectives

• Delineate how dosing strategies can be implemented prior to conception to lower fetal risk

• Describe gestational and postpartum pharmacokinetic principles, by type of AED 

• State how to adjust medications during pregnancy to maintain seizure control, and how to adjust postpartum to avoid symptomatic toxicity

A Precise Balancing Act: Benefits versus Risks of AEDs during Pregnancy

• Teratogenic effects on offspring significant, with increased risk for major congenital malformations (MCMs) 

• Neurodevelopmental defects common, with lifelong consequences

• Risk for adverse OB and Neonatal outcomes likely higher

• Growing evidence that not only type of AED but amount of AED impacts level of risk

Clinical dilemma of minimizing teratogenic effects of AED exposure while maintaining maternal seizure control

AED dosing strategies prior to conception

• Not only should AED choice be re‐evaluated, but dose as well

• Based on the findings that MCM risk increases with dose at conception, and neurodevelopmental risk increases with dose of some AEDs throughout pregnancy

• Key Questions:

• What is the individualized target concentration?

• Determine this prior to conception, updating annually

• Were any changes made in interacting meds that would allow a dose decrease prior to conception (hormonal contraceptives)?

EURAP: Number of offspring with MCMs for the four monotherapies at 

different doses at conception (mg per day), (rate, 95% CI)

Tomson T, et al. Lancet Neurol 2011;10(7):609-17.

11/28/2016

2

Lamotrigine and Contraceptives

• LTG serum concentration‐lower in EE group 

• No difference in women using progestins only compared to  controls 

Reimers A, et al. Epilepsia 2005;.

• Baseline LTG levels reached at an average of 8.0 (SD 3.69) days after the starts of COCs

• 2/7 women had seizure worsening, correlating with the lower concentrations. Wegner I, Neurology, 2009

• Baseline LTG levels reached at an average of 8.0 (SD 3.69) days after the starts of COCs

• 2/7 women had seizure worsening, correlating with the lower concentrations. Wegner I, Neurology, 2009

Sabers A, et al. Neurology 2003;

Strategies for Glucuronidated AEDs

• Applies to lamotrigine, valproic acid1 and probably oxcarbazepine

• Personal Suggested strategy for LTG (not evidence‐based):

– Establish individualized target concentration while on Estrogen‐containing Contraceptives when seizures are controlled and without side effects

– Stop hormonal contraceptive and decrease LTG daily dose by 50%

– Obtain LTG level two weeks later and adjust further prn 

1Herzog AG, et al. Neurology 2009.

Risk vs. Benefit

• Some data for 1 side of equation: how to improve reproductive safety profile

• But to make an informed decision, the patient also should know other side

– What is the risk of changing AED type and/or AED dose?

• Project title: Consequences of altering antiepileptic drugs for pregnancy planning in women with epilepsy

• P. Emma Voinescu, MD, PhD

• Award: Susan Spencer Clinical Research Training Fellowship

– Funded by AES, EF and American Brain Foundation (AAN)

Risks of Seizures

versus

Risks of Antiepileptic Drugs

Risk of Seizures during Pregnancy

Teramo K, et al. J Perinat Med. 1979;7(1):3‐6; Vinten J, et al. Neurology 2005;64(6):949‐54; Chen YH, et al. Arch Neurol 2009;66(8):979‐84; Macdonald SC, et al. JAMA Neurol 2015.

Generalized Tonic-Clonic Convulsions Maternal & fetal hypoxia & acidosis, fetal brady

Miscarriage & stillbirths

Developmental delay (>5 GTCC in pregnancy)

All seizures:

• Increased OR for LBW, SGA, preterm delivery (1.3-1.6 fold)

• Status epilepticus• 30% maternal mortality; 50% infant mortality

• Maternal Death Risks• Death rate during pregnancy in WWE 10-fold higher (SUDEP)

• 11.5 OR [95% CI, 8.64-15.19]), of death during delivery hospitalization

Seizure Frequency during Pregnancycompared to the first trimester

EURAP Study Group. Neurology. 2006; Battino D, EURAP. Epilepsia 2013. 

0

10

20

30

40

50

60

70

80

Decrease No Change Increase

16% 17%

64%

11/28/2016

3

Seizure frequency change compared to non‐pregnant baseline

Pennell PB, Ngy 2008; Sabers A, Epilepsia 2009; Petrenaite V, Epi Res 2009; Harden CL, Ngy. 2009; Johnson EL, Epi Beh 2014; Wegner I, Epilepsia 2010;  Reisinger TL, et al. Epi Beh 2013; Thomas SV, et al Epilepsia 2012.

• Studies report that 20‐50% (9‐75%) of women have seizure worsening during pregnancy compared to baseline

• Depends on several factors:• Baseline seizure frequency, in prior month or 9‐12 months• Seizure types (Focal > Generalized)• AEDs at beginning of pregnancy (LTG, OXC, Polytherapy)• Use of Therapeutic Drug Monitoring• Patient Adherence• Other factors less known: sleep, stress, neurosteroids• Varies with GA in pregnancy and peripartum (Thomas SV)

Effects of TDM with LTG in Pregnancy

Pirie DAJ, et al. EJOGRB 2014.

Physiological Changes in Pregnancy: Effects on Drug Disposition

Pennell PB, Neurology 2008.

Parameter Consequences

Total body water; xtc fluid Altered drug distribution

Fat stores Elimination of lipid soluble drugs

Cardiac output Hepatic blood flow;   elimination 

Increased RBF;  GFR Renal clearance of unchanged drug

Altered CYP/UGT activity Altered systemic absorption &/or hepatic elimination of 50% of drugs

Maternal albumin  Altered free fraction; increased hepatic extraction 

Drug Clearance

Daily dose (mg/kg/day)

_____________________________

AED concentration (mg/L)

Total and Free LTG Clearance Across Pregnancy

0

1

2

3

4

5

6

Baseline 1st Trimester 2nd Trimester 3rd Trimester

(m

g/k

g)/(m

g/L

)

Mean Total LTG Cl

Mean Free LTG Cl

Pennell PB, et al. Neurology, 2008. Funded by NIH P50 MH68036.

N=305 samples, 53 Pregnancies

Proportion of Patients That Had Worsening of Seizures Above Their Baseline With the Use of TDM

Pennell PB, et al. Neurology, 2008. Funded by NIH P50 MH68036.

Seizure Frequency

0

0.05

0.1

0.15

0.2

0.25

1 2 3 4 5 6 7 8 9 10 PP1 PP2 PP3

M onth

Proportion of patient

Increased seizures, all-types D oubled seizures, all-types

Increased G TC Sz's D oubled G TC Sz's

• Ratio to target concentration of 0.65 predicts increased seizure risk• Empiric taper of LTG over 10 days reduced postpartum toxicity (p<0.05))

Pennell PB, et al. Neurology 2008. Supported by NIH P50 MH68036

11/28/2016

4

Post hoc estimates of LTG CL/F increase during pregnancyMaroon data points: subjects w/ high rate of increase (population I) Blue data points: subjects w/ low rate of increase (population II)

Rolepally Pennell, Birnbaum. Annals of Clin & Translational Neurology 2014.

The GA-associated increase in CL/F displayed a 10-fold higher rate in 77% of the women (0.118 L/h per week) compared to 23% (0.0115 L/h per week).

Major routes of elimination of AEDs

Pennell PB, Neurology 2008.

Cytochrome P450 metabolism*

Phenytoin†

Phenobarbital†

Carbamazepine†

Zonisamide

Glucuronidation*

Valproate†

Lamotrigine

Oxcarbazepine

Renal excretion*

LevetiracetamPregabalinVigabatrinTopiramateLacosamide

* Main route of elimination† Highly protein bound

Pharmacokinetic Changes During Pregnancy

AED Increase in Clearance

Levetiracetam 243%

Lamotrigine 65-230%

Oxcarbazepine 56-163%

Phenobarbital 60%

Phenytoin 19-117%

Free Phenytoin 25%

* Evidence for a change in clearance or levels of VPA, PRM, ESX, CBZ is conflicting or lacking.

Pennell PB, Hovinga C.  Int Rev Neurobiol 2008; Harden CL, et al. Neurology 2009.

CBZ Clearance and Seizure Stability during Pregnancy

Pennell PB, et al. Neurology, 2008. Funded by NIH P50 MH68036.

Findings:

• N=15 pregnancies in 12 WWE

• No significant changes in CBZ clearance during pregnancy, (total and free CBZ & -10,11-epoxide)

• Free Fraction of CBZ increased from 23% at baseline to 32% in the third trimester (p=0.008)

Conclusions:

• No clear relationship between decreased concentrations & increased SzF.

• The increase in free fraction of CBZ may help protect against seizure worsening.

• TDM of CBZ during pregnancy may not be necessary when resources are limited.

Johnson E, Pennell PB, et al. Epilepsy Behav 2014

Clinical impact of Gestational‐induced Changes in Clearance

Pennell PB, et al. Neurology, 2008. Funded by NIH P50 MH68036.

Reisinger TL, Newman M, Loring D, Pennell PB, Meador KJ. Epil & Beh 2013.

Women with epilepsy on a variety of AEDsRisk for seizures deterioration higher in 

a) patients w/ seizures in previous 12 monthsb) focal epilepsy

Seizures worsened signifcantly during the 2nd trimestera) when ABL < 65% from preconception baseline

Reisinger TL, Newman M, Loring D, Pennell PB, Meador KJ. Epil & Beh 2013.

11/28/2016

5

Postpartum AED tapers

• Evidence for empiric taper of LTG over 10 days reduced postpartum toxicity (p<0.05))without seizure worsening• 4/6 non-adherent vs. 3/21 adherent had pp toxicity (p=0.04)

• Subsequent study demonstrated return to LTG baseline clearance over 2‐3 weeks postpartum

• Similar principles can likely be applied to OXC

• Other AEDs less clear:

• CyP450 metabolism change to baseline over 3 mos., based on data with PHT

• Renal excretion returns to baseline over 2‐3 weeks

Ohman, Epilepsia 2004; De Haan, Neurology 2004; Pennell PB, Neurology 2008. Rolepally et al. Annals Clin & Trans Ngy 2014.

MONEAD StudyMATERNAL OUTCOMES:

• Seizures: Change in seizure frequency during pregnancy and early postpartum.

• OB Complications• Depression (pregnancy & postpartum)

OUTCOMES in CHILDREN of WWE:• Neurodevelopment Cognitive & behavioral• Neonatal Outcomes • Breastfeeding Effects if WWE taking AED.

Pharmacokinetics: Relation of AED exposure & outcomes

Relation of Seizure frequency and severity & outcomes

Goal: optimizing balance b/t AED exposure and seizures

Guiding Principles for AED Management in Pregnancy & PP

• Preconception Transition to AED with favorable teratogenic profile

Establish individual target concentration

Lower dose as needed, with adjustment after D/C of EST contraceptives

Use XR formulation and BID dosing if possible

• Pregnancy Monthly AED levels for therapeutic drug monitoring

Adjust dose for seizures, SEs, and to maintain RTC > 0.65 

• Postpartum Adjust dose to (slightly above) pc baseline over 2 weeks – 3 months, depending 

on AED

Educate about clinical signs of medication toxicity

What are strategies when no AED level measurements are available?

#AES2016

11/19/2016

1

Postpartum Management: Risk of Seizures and Safety, Newborn 

Care, & Nursing

Sanjeev V. Thomas MD, DM.Professor of Neurology,

Sree Chitra Tirunal Institute for Medical Sciences

Trivandrum, India

Disclosure

Grants:Department of Biotechnology (SCT/ABS/IAEC‐85/5)Department of social justice, GOK Consultancy Honorarium from British Medical Journal for the BMJ Master class 2016

Learning Objectives

• To understand the postpartum risk of women with epilepsy and their newborns

• To develop strategies to improve safety to the mother and baby in post partum periody p p p

Post partum period

Early phase(0 to 12 hours after delivery)

• PPH• Eclampsia

Subacute phase(Day one to 6 wk )

• Estrogen dominence

• Progesterone

Delayed phase(up to 6 months) 

• Lasts up to 6 months

• Progesterone decline

• Prolactin declines (except in breast feeding)

• Oxytocin and vasopressin decline

• Low FT3 and FT4; • low free cortisol

Post partum hemorrhage

• No class I studies• Class II (3)

• Kaaja 2002,• Choulika 2004

• Class III (3)• Class III (3)• Borthen (2015) studies 

• PPH risk  OR 1.5 (1.3‐1.8)• Increased with VPA, LTG, • operative vag. Delivery

• OR for PPH or HDN were not reduced by Vit K supplementation (Sveberg L, 2015) 

Vitamin K Post natal NICE guidelines 2006 & 14

• All parents should be offered vitamin K prophylaxis for their babies to prevent the rare but serious and sometimes fatal disorder of vitamin K deficiency bleeding. [2006]

• Vitamin K sho ld be administered as a single dose of• Vitamin K should be administered as a single dose of 1 mg intramuscularly as this is the most clinically and cost‐effective method of administration. [2006]

• If parents decline intramuscular vitamin K for their baby, oral vitamin K should be offered as a second‐line option [2006]

https://www.nice.org.uk/guidance/cg37/chapter/1‐Recommendations

11/19/2016

2

Vitamin K supplementationAAN practice parameter 2009

• There is insufficient evidence to support or refute a benefit of prenatal vitamin K supplementation for reducing the risk of post partum hemorrhage or hemorrhagic disease of new born

Oral vitamin K supplementation during last month of pregnancyInjection vitamin K to the newborn

Post partum seizure risk

• EURAP (2013) N=3784– AED added and /or dose increased during TM3 compared to TM1

• CBZ 8.8%

• LTG 35.0%

• PB 27.4%

• VPA 14.6%

• EURAP (2006): N= 1956 – seizures during delivery 3.5%

Seizure frequency during pregnancy Seizure control LTG TDM/ CFM

D.A.J. Pirie et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 172 (2014) 26–31

LEV concentration and clearance in pregnancy Increased seizure risk

Pharmacokinetics

Sleep deprivation

Co medication

LTG dose to be reduced to pre pregnancy range

Blood level monitoring of AEDs and tailor the dose to maintain pre pregnancy levels

11/19/2016

3

Pharmacokinetic characteristics of antiepileptic drugs (Davanzo et al. 2013)

Davanzo et al. Italian Journal of Pediatrics 2013, 39:50. http://www.ijponline.net/content/39/1/50

Breast milk penetration of AEDs (Harden et al 2009)

• PRM significant 1 1• LEV significant 2• GBT significant 1• LTG significant 1• LTG significant 1• TPM significant 1• ETX significant 1• VPA NS 1 1• PB NS  1 1• CBZ NS  2• PHT NS  2

Blood levels of AEDs (dried blood spot)MONEAD study (n=121)

• DBS taken between 6 weeks and 3 months • Blood levels of AEDs (dried blood spot)

• AED <LLoQ(%) levels• Lamotrigine (64) 9.4 2.2ug/ml• Levetiracetam (54) 74 1 2 6 ug/ml• Levetiracetam (54)  74.1 2.6 ug/ml• Carbamazepine (9) 100 ‐• Oxcarbazepine (7) 100 ‐

Breastfeeding and 6 year IQMeador et al 2014.

n= 181CBZ, LTG, PHT, VPA mono

• Drug group VPA 7 – 13 points lower

• Drug dose regr. Coeff ‐0.1Drug dose regr. Coeff 0.1

• Maternal IQ +0.2

• Periconception folate 6 points higher with FA

• Breastfeeding 4 points higher with Breastfeeding

• Verbal index 4 points higher with breastfeeding

Breast feeding Nice guideline

• A supportive environment for breastfeeding

• Starting successful breastfeeding

• Continuing successful breastfeeding

• Assessing successful breastfeeding• Assessing successful breastfeeding

• Expression and storage of breast milk

https://www.nice.org.uk/guidance/cg37/chapter/1‐Recommendations

How to monitor infants who are breast fed

• Monitor for alertness, physical activity• Monitor for any cutaneous eruptions.

11/19/2016

4

AED ‐ OCP interaction

• Absorption – PgP– competitive inhibition

– Progesterone induced PgP expression

• Transport in the bloodTransport in the blood– Sex Hormone binding globulin

• Metabolism ‐ Oxidation P450 egradation

• Elimination Glucuronidation

• Bone mineral density

Seizure increase / decrease while on contraception (Herzog 2015)

3.3 3.2 21 3.7 4.6

‐2.5 ‐4 ‐10.3 ‐14.2 ‐2.5tubal ligation Barrier Hormonal IUD Traditional

Increase Decrease

OR for seiz. Increase while on HCP(Herzog 2015)

Elements that may influence contraceptive choices for WWE

• Safety• Effectiveness• Availability

– Accessibility– Affordability

• Acceptability.• Duration of contraception• Risk behaviour• Physical condition• Metabolic status• Breast feeding• AED therapy

Contraceptive choices while on EIAEDs

• Avoid– COC Pills, patches, rings

– POP pills / depots

• Consider– high estrogen COCP / double dose

d / l– continuous dosing / tricycling

• Parenteral options– Inj. Medroxy progesterone depot

– Hormone eluting intrauterine systems

– Selective Estrogen receptor modifier

• Switch over to NEIAEDs

• Non hormonal methods

• Combinations

Categories for Classifying Hormonal Contraceptives and IUDs

1 =  A condition for which there is no restriction for the use of the contraceptive method. 

2 =  A condition for which the advantages of using the method generally outweigh the theoretical 

kor proven risks. 

3 =  A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 

4 =  A condition that represents an unacceptable health risk if the contraceptive method is used

11/19/2016

5

Medical Eligibility Criteria for contraceptionUSA / UK /  WHO

COCpil/patch/ring POP Inj DMPA implant IUD cu IUCD

Epilepsy NEIAED 1 1 1 1 1 1

EIAED USA 3 3 1 2 1 1

LTG USA 3 1 1 1 1 1

d ( l )PPP<21 d (non lactating) WHO 3

PPP non lactating USA 4 1 1 1

PPP <21d USA 4 1 1 1 1 1

PPP 21 ‐ 42 d + VTE USA 3 1 1 1 1 1

PPP 21‐42 d  WHO 2 ‐ 3

PPP 21 ‐ 42d USA 2 1 1 1 1 1

PPP > 42 d USA 1 1 1 1 1 1

breast feeding USA 2 1 1 1 1 1

<6 wk (breast feeding) WHO 4 3 3

6wk ‐ 6 m (breast feeding) WHO 3

Child care knowledge/practice

Nursing (6)

Growth Dev (4)

Nursing (7)

Growth Dev (2)

CHILD CARE KNOWLEDGE CHILD CARE PRACTICE

(6) (4)

Safety (7)

Stimulation (3)

(7) (2)

Safety(12)

Stimulation (4)

Child care knowledge & Practice comparison of WWE and women without epilepsy

26

28

30

32

20

22

24

26

CRK CRP

WWE

WWoE

Sleep adequacy 

152025303540

cntrlWWE

40

50

60

70

80

90

Accidental dropping of babies

051015

WWE WWoE

Falls 11 4

No falls 77 83

0

10

20

30

OR 2.96 (.096‐9.7)

Managing post partum period

• Provide adequate information

• risk of seizure aggravation

• need for AED monitoring

• Encourage breast feedingg g

• Support facilities

• To ensure adequate rest, sleep

Precautions to prevent accidents

#AES2016