# Presentation: 056430

## Complications  with the Use of Anticonvulsants in Pregnancy

## PREVALENCE  of  EPILEPSY

**3.2 MILLION  AMERICANS **
**50 %  WOMEN**
**40 %  CHILDBEARING  AGE**
**     ****1.1  MILLION  WWE**

## WOMEN with EPILEPSY HAVE UNIQUE  PROBLEMS

**SEIZURES  EXACERBATED  by ****	****	****	****HORMONES**
**INFERTILITY**
**CONTRACEPTIVE  FAILURE**
**COSMETIC  EFFECTS**
**HIGH RISK PREGNANCIES**

## 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

**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  ?

**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

** ****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

_**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**

## 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

**DECEASED  VIABILITY**
**Increased  Fetal  Loss & Infant Mortality**
**DECREASED  GROWTH**
**Increased Small for Dates**
**NEONATAL  COMPLICATIONS**
**Hemorrhage**
**MALDEVELOPMENT**
**Malformations, Anomalies, Developmental Delay**

## Congenital  Malformations

**Reported with all AED**
**RR = 2 - 2.4**
**4 - 6 %**
**Most  Common**
**Oro - Facial Clefts**
**Midline  Heart  Defects**
**Skeletal  Defects**

## Malformations

**Risk Factors**
**Polytherapy**
**High Plasma Concentrations**
**Mechanisms - Toxic Metabolites**
**Epoxide  Metabolites**
**Free Radial  Formation**

## 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

**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

**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

**PREVALENCE  =  1.2 - 6.2 %**
**RISK  FACTORS**
**Low  Maternal  IQ**
**Polytherapy**
**Poor Maternal  Seizure  Control**

## 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

**Milk / Plasma  Ratio  < 1**
**Low  Volumes  Consumed**
**Milk  Concentration  Inverse  of  Protein  Binding**
**Exceptions:**
**Lamictal  ****	****	****M / P  > 1**
**Topiramate ****	**** ****	****M / P <  1**
**Zonisamide****	****	****M / P = 0.9**

## AED Kinetics in Plasma & Breast Milk

-         _**Breast Milk / Plasma**_**              **_**Elimination Half-life (hour)**_
_**Anticonvulsant**_**     **_**Concentration Ratio**__**	**__**Adult**_**         **_**Neonate     % 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 - 126****	****45 - 500            45**
**Phenytoin****	****   0.2 - 0.4              ****	****12 - 50****	****15 - 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”

_**Breast Milk / Plasma**_**              **_**Elimination Half-life (hour)**_
_**Anticonvulsant**_**     **_**Concentration Ratio**__**	**__**Adult**_**     **_**Neonate   % Protein Binding**_
**Felbamate****	****?****	****	****14 -22****	****?****	****24 - 35**
**Gabapentine****	****?****	****	****5 - 8****	****?****	****     0**
**Lamotrigine****	****0.4 - 0.7****	****	****24****	****?****	****    55**
**Levetiracetam****	****?****	****	****6- 8****	****?****	****  < 10**
**Oxcarbazepine****	****0.5****	****	****8  - 10****	****?****	****    45**
**Tiagabine****	****?****	****	****4.5 - 13****	****?****	****    95**
**Topiramate****	****< 1****	****	****19 - 23****	****?****	****    15**
**Zonisamide****	****0.9****	****	****50 -60****	****?****	**

## 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

**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**

## 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

**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

**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**