Complications with the use of anticonvulsants in pregnancy
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1.1 MILLION WWE. Mark Yerby M.D., M.P.H.. WOMEN with EPILEPSY HAVE ... AEDs imperative for WWE. Incomplete information hinders effective medical management ...

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Complications with the use of anticonvulsants in pregnancy

Complications with the Use of Anticonvulsants in Pregnancy


Prevalence of epilepsy

PREVALENCE of EPILEPSY

  • 3.2 MILLION AMERICANS

  • 50 % WOMEN

  • 40 % CHILDBEARING AGE

    • 1.1 MILLION WWE


Women with epilepsy have unique problems

WOMEN with EPILEPSY HAVE UNIQUE PROBLEMS

  • SEIZURES EXACERBATED by HORMONES

  • INFERTILITY

  • CONTRACEPTIVE FAILURE

  • COSMETIC EFFECTS

  • HIGH RISK PREGNANCIES


Difficulties associated with aed

Difficulties Associated with AED

  • Metabolism of Hormonal Contraceptives Accelerated by AED

  • Concentration of AED Decline in Pregnancy

  • First Trimester Exposure is Associated with Risk of Malformations

  • Competitive Inhibitors of Vitamin K

  • Transfer to Breast Milk


Clinical dilemma

Clinical Dilemma

  • Drugs generally contraindicated in pregnancy

  • WWE unable to stop AED

    • Increases risk of seizures

      • Injury

      • Miscarriage

      • Developmental delay

    • Loss of Job or Driving Privileges

    • Risk of cognitive decline


Safety of new aed

Safety of New AED ?

  • 8 New AED since 1993 - Little Empirical Data

  • No Malformations in Monotherapy

  • Felbamate: 9+ Pregnancies

  • Gabapentine: 100+ Pregnancies

  • Lamotrigine: 189+ Pregnancies

  • Oxcarbazepine 23 + Pregnancies

  • Topiramate: 5 + Pregnancies

  • Tiagabine: 29 + Pregnancies

  • Trileptal: 12 + Pregnancies

  • Zonisamide 26 + Pregnancies


Hormonal contraceptive failure

Hormonal Contraceptive Failure

  • Enzyme Inducing AED

    • CBZ, DPH, PB, PRM, TOP

    • Increase Clearance of Co-medication

  • O.C. - Norplant - Depo-Provera

    • All have Reported Failures w/ AED


Aed levels decline as pregnancy progresses

AED Levels Decline as Pregnancy Progresses

  • Even in the Face of Constant & Sometimes Increased Dosage

  • Dissociation of Plasma Protein Binding

  • Total Levels Decline for all “older” AED

  • Free Levels do not Decline at the same Rate

  • Different AED Decline at Different Rates

  • Levels Rise in the Post Partum Period


Significance of declining aed 1 4 1 3 of women increase seizures

Falls - Injury

Premature Labor

Miscarriage

Suppression Fetal Heart Rate

Epilepsy in the Child

Abruptio Placenta

Intracranial Hemorrhage

Perinatal Seizures

Infant Mortality

Developmental Delay

Significance of Declining AED1/4 - 1/3 of Women Increase Seizures


Risk of status in pregnancy

Risk of Status in Pregnancy

  • Status fortunately uncommon

  • Abrupt Cessation of AED Increases the Risk

  • 29 reported cases (Teramo & Hiilesmaa 1982)

    • 9 Maternal

    • 14 Fetal Deaths


Adverse pregnancy outcomes

ADVERSE PREGNANCY OUTCOMES

  • DECEASED VIABILITY

    • Increased Fetal Loss & Infant Mortality

  • DECREASED GROWTH

    • Increased Small for Dates

  • NEONATAL COMPLICATIONS

    • Hemorrhage

  • MALDEVELOPMENT

    • Malformations, Anomalies, Developmental Delay


Congenital malformations

Congenital Malformations

  • Reported with all AED

    • RR = 2 - 2.4

    • 4 - 6 %

    • Most Common

      • Oro - Facial Clefts

      • Midline Heart Defects

      • Skeletal Defects


Malformations

Malformations

  • Risk Factors

    • Polytherapy

    • High Plasma Concentrations

  • Mechanisms - Toxic Metabolites

    • Epoxide Metabolites

    • Free Radial Formation


Pharmacokinetics pharmacogenetics teratogenicity

Pharmacokinetics / Pharmacogenetics & Teratogenicity

  • Metabolites of AED are associated with Malformations.

  • Specific AED are metabolized by specific pharmacokinetic pathways.

  • The pharmacogenetics of individual persons dictates the effectiveness of the metabolism .

  • Teratogenicity occurs when genetic factors leading to poor metabolism fail to eliminate toxic intermediaries.


Neural tube defects aed exposure

Neural Tube Defects & AED Exposure

  • Some AED Associated with Increased Risk of Neural Tube Defects

    • Valproic Acid 1 - 2 %

      • (Omtzigt 1992 NTD rate with VPA = 5.4 %)

    • Carbamazepine 0.5 %


Neural tube defects association with valproic acid

Neural Tube Defects Association with Valproic Acid

  • SUPPORTING EVIDENCE

    • Case Series, Case Reports

    • Dose Response Effect, (Omtzigt 1992)

      • Mean dose 1641 mg. with NTD

      • Mean does 941 mg. without NTD

  • PROBLEMS

    • No Controlled Studies

    • Possible Association Primary Epilepsy


Developmental delay

DEVELOPMENTAL DELAY

  • PREVALENCE = 1.2 - 6.2 %

  • RISK FACTORS

    • Low Maternal IQ

    • Polytherapy

    • Poor Maternal Seizure Control


Neonatal hemorrage

NEONATAL HEMORRAGE

  • DESCRIBED with: PB, PRM, PHT, CBZ, ETH

  • FIRST 24 HOURS

  • HIGH MORTALITY

  • AED Competitive Inhibitors Vit. K

  • PREVENTION:

    • Maternal Vit. K 10 mg/ day last Week Pregnancy


Breast feeding

BREAST FEEDING

  • Milk / Plasma Ratio < 1

  • Low Volumes Consumed

  • Milk Concentration Inverse of Protein Binding

  • Exceptions:

    • Lamictal M / P > 1

    • Topiramate M / P < 1

    • ZonisamideM / P = 0.9


Aed kinetics in plasma breast milk

AED Kinetics in Plasma & Breast Milk

  • Breast Milk / PlasmaElimination Half-life (hour)

  • AnticonvulsantConcentration RatioAdultNeonate % Protein Binding

  • Carbamazepine 0.4 - 0.6 8 - 25 8 - 28 75

  • Ethosuximide 0.9 40 - 60 40 < 10

  • Phenobarbital 0.4 - 0.6 75 - 12645 - 500 45

  • Phenytoin 0.2 - 0.4 12 - 5015 - 105 90

  • Primidone 0.7 - 0.9 4 - 12 7 - 60 < 20

  • Valproic Acid 0.01 6 - 18 30 - 60 90


  • Aed kinetics new aed

    AED Kinetics “New AED”

    • Breast Milk / PlasmaElimination Half-life (hour)

  • AnticonvulsantConcentration RatioAdultNeonate % Protein Binding

  • Felbamate?14 -22?24 - 35

  • Gabapentine?5 - 8? 0

  • Lamotrigine0.4 - 0.724? 55

  • Levetiracetam?6- 8? < 10

  • Oxcarbazepine0.58 - 10? 45

  • Tiagabine?4.5 - 13? 95

  • Topiramate< 119 - 23? 15

  • Zonisamide0.950 -60?


  • Pharmacokinetics older aed in pregnancy

    Pharmacokinetics “Older” AED in Pregnancy

    • Percent Decrease

      • Total Level Percent Free Fraction

      • Anticonvulsant by 3rd Trimester Normal Maternal Neonatal

      • Carbamazepine 40% 22% 25% 35%

      • Ethosuximide ? 90% ? ?

      • Phenobarbital 55% 51% 58% 66%

      • Phenytoin 56% 9% 11% 13%

      • Primidone 55% ? ? ?

      • Derived Phenobarbital 70% 75% 80% ?

      • Valproic Acid 50% 9% 15% 19%


    Conclusions

    Conclusions

    • Women with Epilepsy Cannot Safely Stop AED

      • Increased Risk of Seizures

    • AED can Increase Risks

      • Malformations

      • Neonatal hemorrhage

      • ? Developmental Delay

    • Incomplete Information on “Older” Pre 1993 AED

    • Scanty Information on “Newer” Post 1993 AED


    Exclusion of women from clinical trials

    Obstacles to Studies in Women

    Potential effect on fertility

    Potential effect on fetal anatomical development

    Potential effect on cognitive development

    Consequence of Lack of Data

    No safety information

    No knowledge of risks for fetal exposure

    Little opportunity for risk reduction

    Exclusion of Women from Clinical Trials


    Methods for ethical collection of pharmacokinetic data in women with epilepsy

    Methods for Ethical Collection of Pharmacokinetic Data in Women with Epilepsy

    • Well designed informed consent

    • Trials of AED effect on Hormonal Contraceptives and Vitamin K

      • do not require pregnancy

    • Trials of Kinetics in Pregnancy and Breast Milk

      • Study non-human primates

      • Use unplanned pregnancies

      • Indemnify manufacturer and investigator


    Better use of post marketing experience

    Better use of Post Marketing Experience

    • Many women will use AED post market

    • Systematic surveillance projects

      • Target Pharmacies / Prescriptions / Specialists

      • Current Registries used as models

      • Use CDC or CROs for surveillance

      • Determine threshold signal for intervention

      • Regular reporting of cumulative experience


    Summary

    Summary

    • AEDs contribute to risks:

      • infertility, contraceptive failure, adverse pregnancy outcome

    • AEDs imperative for WWE

    • Incomplete information hinders effective medical management

    • Improved premarketing clinical trials and post marketing surveillance

      • Permit selection of safer drugs

      • Clinicians know what to expect in pregnancy


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