Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)
Condition: Epilepsy; Pregnancy
MeSH terms: Epilepsy
Study type: Observational

Summary: 
      Epilepsy is one of the most common neurological disorders affecting women of childbearing
      age. Poor pregnancy outcomes are increased in these women and their children. The proposed
      studies will increase our knowledge on multiple levels to improve care and reduce adverse
      outcomes in these mothers and children. An overall goal of this study 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.
    

Detailed description: 
      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.

      FACTORS ASSESSED IN MONEAD.

      Maternal factors: IQ, age, education, employment, ethnic group, maternal and family medical
      history including prior pregnancies and psychiatric disorders, socioeconomic status, site,
      periconception and pregnancy folate, concomitant medications, alcohol use, tobacco use, or
      other drug use during pregnancy, unwanted pregnancy, pregnancy complications, medical
      diseases and serious adverse events, McMaster Family Assessment Device (FAD), Block Food
      Frequency, and for WWE: types and frequency of seizures or epilepsy, antiepileptic drug
      dosages & blood levels, and compliance.

      Depression during pregnancy and post-partum as determined by the screening instrument (Beck
      Depression Inventory-II; BDI-II), the EPDS (Edinburgh Postnatal Depression Scale) and
      confirmed by the Structured Clinical Interview for DSM-IV (SCID), Beck Anxiety Inventory
      (BAI), Pittsburgh Sleep Index, and Perceived Stress Scale in mothers, Parental Stress Index,
      and Neurological Disorders Depression Inventory in Epilepsy (NDDI-E).

      Maternal hormones (estradiol, progesterone) and Vit D will be drawn at Visit 1, 2, 3, 4, 5, 6
      and 7. Maternal continine Levels will be collected via urine sample at Visit 3 on all
      non-smoking mothers. If the continine result is positive for tobacco smoke exposure, an LC/MS
      (liquid chromatography/mass spectrometry test.

      Paternal & relative factors: In fathers and a primary maternal relative, the following were
      collected: head circumference, IQ estimates, socioeconomic status, dob, race, ethnicity,
      family history, and medical history. For the father, marital status, total household income,
      employment status. weight, height, and handedness were also collected.

      Adult IQ Assessments:

      Peabody Picture Vocabulary Test (PPVT), Wechsler's Adult Intelligence Scale (WAIS).

      Child factors: enrollment & birth gestational ages, birthweight, breastfeeding, AED levels
      when breastfeeding, physical examinations, childhood medical diseases (including congenital
      malformations), head circumference, weight, serious adverse events, developmental delays, and
      special education. Also, obtained premature delivery, APGARs (1 & 5 minutes), Neonatal
      Intensive Care Unit admissions and all admissions >12hrs, hypoglycemia (<45), need for
      resuscitation, and neonatal death. Child Hgb, Hct, PKU, TSH, and T4 at delivery from med
      records if collected.

      Child Cognitive/Behavioral Assessments:

      Denver II, Behavior Assessment System for Children - Parent (BASCP-2) and Teacher (BASCT-2),
      Behavior Rating Inventory of Executive Functioning Preschool (BRIEFP) and version 2
      (BRIEF-2), Adaptive Behavior Assessment Scale 3 (ABAS-3), Modified Checklist for Autism in
      Toddlers (M-CHAT), Modified Edinburgh Handedness Inventory, Gilliam Autism Rating Scale 3
      (GARS-3), Bayley Scales of Infant and Toddler Development-3 (BSID-III), Differential
      Abilities Scale-II (DAS-II), Preschool Language Scale-5 (PLS-5), Peabody Picture Vocabulary
      Test-4 (PPVT-4), Beery-Buktenica Developmental Test of Visual-Motor Integration-6 (VMI-6),
      Torrance Test of Creative Thinking- Figural (TTCT-F), NEuroPSYchological Assessment 2nd
      edition (NEPSY2), Expressive One Word Picture Vocabulary Test-4 (EOWPVT4), Wechsler's
      Intelligence Scale for Children 5 (WISC5) Coding subtest, Children's Memory Scale (CMS),
      Lafayette Grooved Pegboard (GPB), Wide Range Achievement Test 5th edition (WRAT5), and Social
      Responsiveness Scale 2

      Verbal intellectual ability at age 6 years is the ultimate primary outcome. It is determined
      by Verbal Index which is average of Word Definitions and Verbal Similarities subtests from
      the Differential Ability Scales-2nd ed. (DAS-II),50 -School Age Level, Expressive One-Word
      Picture Vocabulary Test-4,51 the Phonological Processing, Comprehension of Instructions and
      Sentence Repetition subscales from the NEPSY-2 57 and the Peabody Picture Vocabulary Test-4th
      ed. (PPVT-4).52 Children will not reach age 6 in this initial grant period, so primary
      outcome at age 2 will be the Language Scale from the Bayley Scales of Infant & Toddler
      Development-III.

      Cerebral Lateralization will be assessed as verbal minus non-verbal difference scores and
      proportion of dextrals in PWWE vs. HPW and in their children as assessed by the Edinburgh
      Handedness Inventory.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects will be recruited by the investigators from their clinic populations and
        advertisements.
      
Biospecimen description: 
      Serum, cheek cells, urine
    
Keywords: Epilepsy; Pregnancy