Maternal and Neurodevelopmental Outcomes of in Utero Antiepileptic Drug (AED) Exposure

There is a compelling need for prospective, properly controlled studies in women with
epilepsy (WWE) during pregnancy to improve maternal and child outcomes. The proposed
investigations are pertinent to the National Institute of Neurological Disorders and Stroke
Epilepsy Research Benchmarks and will address multiple gaps in our knowledge noted by the
recent American Academy of Neurology guidelines. This multicenter investigation will employ a
prospective, observational, parallel-group, cohort design with an established research team.

The specific aims are to:

1. Determine if women with epilepsy have increased seizures during pregnancy and delineate
the contributing factors;

2. Determine if C-section rate is increased in women with epilepsy and delineate
contributing factors;

3. Determine if women with epilepsy have an increased risk for depression during pregnancy
and post-partum period and characterize risks factors;

4. Determine the long-term effects of in utero antiepileptic drug exposure on verbal
intellectual abilities and other neurobehavioral outcomes in the children of women with
epilepsy;

5. Determine if small for gestation age and other adverse neonatal outcomes are increased
in children of women with epilepsy;

6. Determine if breastfeeding when taking antiepileptic drugs impairs the child's verbal
intellectual and other cognitive abilities.

An overall goal of the proposed research is to establish the relationship between
antiepileptic drug exposure and outcomes in the mother and child as well as describe and
explain the variability in antiepileptic drug exposure and response.

Anticonvulsant blood levels (ABLs) and area-under-the-concentration-time-curves (AUCs) will
be used as direct measures of drug exposure. The results will enable clinicians to
prospectively calculate individual dosing regimens for the mother in order to optimize dosing
and limit unnecessary drug exposure to the child. In addition, genetic samples will be
collected, which will provide a valuable resource for future pharmacogenetics studies to
further delineate individual variability across patients.

Inclusion Criteria for All Women

- Pregnant women with epilepsy up to 20 weeks gestation, healthy pregnant women without
epilepsy up to 20 weeks gestation, or non-pregnant women with epilepsy.

- Ability to maintain a daily medical diary.

- Language skills in English or Spanish adequate to perform the cognitive tests and
questionnaires.

- Access to a telephone for phone contacts.

- Age 14-45 inclusive.

Inclusion Criteria applicable for pregnant women only. -Ability for follow-up through 6
years after giving birth.

Criteria applicable for non-pregnant women with epilepsy only:

- Minimum of 9 months post live birth, miscarriage, or elective termination.

- Not currently breastfeeding.

Exclusion Criteria for All Women

- Women with an expected IQ<70.

- IV drug use in past year or any of the following since the beginning of pregnancy:
Alcohol abuse, cocaine, or methamphetamine) or sequelae of drug/alcohol abuse.

- History of psychogenic non-epileptic spells.

- History of positive Syphilis test.

- History of HIV positive test.

- Progressive cerebral disease (e.g., multiple sclerosis, progressive brain tumor).

- Presence of other major medical illness (e.g., diabetes, cancer).

- Any medical, psychiatric, or other condition that, in the judgment of the
investigator, is a contraindication to protocol participation or impairs ability to
give informed consent.

- Concurrent participation in an experimental drug trial.

Exclusion criteria applicable for pregnant women only.

- Exposure to known teratogens during pregnancy, excluding AEDs.

- Detection of fetal major congenital malformation prior to enrollment in current
pregnancy.

- History of a known genetic disorder in herself or a primary relative (may contact
MONEAD team with details for possible exception).

- Use of non-licensed midwife as primary source of natal care and/or planning home
delivery or delivery at a stand-alone birth center, independent from a hospital.

Exclusion criteria applicable for all women with epilepsy.

-Planned surgical intervention for epilepsy that would occur during the subject's
participation in the project

Exclusion criteria applicable for pregnant women with epilepsy only. -History of switching
AEDs during pregnancy prior to enrollment. "Switching" AEDs includes changing from no AED
therapy to therapy, discontinuing a current AED therapy, or changing to a different AED
therapy.

Exclusion criteria applicable for non-pregnant women only.

- Diagnosed by a health care professional as perimenopausal or postmenopausal.

- History of switching AEDs within 90 days of enrollment. "Switching" AEDs includes
changing from no AED therapy to therapy, discontinuing a current AED therapy, or
changing to a different AED therapy.

Inclusion Criteria for Study Family Members

- The Father must be the biological father of the child in the study.

- The Maternal Relative must be a full biological relative or half-sibling of the mother
chosen by the following hierarchy:

1. st choice: Sister of closest age to the mother in the trial

2. nd Sister of next closest age

3. rd Brother of closest age

4. th Brother of next closest age

5. th Mother

6. th Father of pregnant mother in the study

7. th Half-Sibling if NO Primary FULL relatives are available.

Exclusion Criteria for Study Family Members

- Any medical, psychiatric, or other condition that, in the judgment of the
investigator, is a contraindication to protocol participation or impairs ability to
give informed consent.