Study Outline

Green MONEAD Logo

Sponsored by:

National Institute of Neurological Disorders and Stroke (NINDS)

and

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)




Objectives

The overall goal of this study is to determine risks that are increased in women with epilepsy during pregnancy and in their children, and to examine the key contributing factors.

Adult women with epilepsy will be monitored during pregnancy and postpartum to measure maternal outcomes, and their children will be monitored from birth through age 6 years to measure their health and developmental outcomes. Two control groups will be enrolled for comparison, which include 1) healthy pregnant women without epilepsy and 2) non-pregnant women with epilepsy.

For the women with epilepsy, we will measure the following primary outcomes:

  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

For the children born to women with epilepsy, we will measure the following primary outcomes:
  1. Determine the long-term effects of in utero antiepileptic drug exposure on verbal intellectual abilities and other neurobehavioral outcomes
  2. Determine if small for gestational age and other adverse neonatal outcomes are increased
  3. Determine if breastfeeding when taking AEDs impairs the child’s ultimate verbal and other cognitive outcomes.

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. The results will enable clinicians to better manage women with epilepsy during pregnancy.


Design and Outcomes

baby holding adult's hand     

This multicenter investigation will employ a prospective, observational, parallel-group, cohort design to monitor clinical outcomes in the mothers with epilepsy and the outcomes in their children.

The specific outcomes in the mother that will be measured include: Seizure frequency and type; Obstetrical complications, including C-section rate; and Depression.

The specific outcomes in the children that will be measured include: Neurodevelopmental outcomes measured by the Language Scale of the Bayley Scales of Infant Development-III (BSID-3) at age 2 and Verbal Index at age 6 as well as other cognitive outcomes; Neonatal outcomes including birth weight; and Breastfeeding outcomes measured by the Language Scale of the BSID-3 at age 2 years and Verbal Index at age 6 years. Additional cognitive and behavioral measures for the child will be obtained age 2, 3, 4.5 and 6 years.

AED blood levels will be used as direct measures of drug exposure and to estimate individual drug exposure.


Interventions and Duration

This study will compare pregnant women with epilepsy, non-pregnant women with epilepsy, and pregnant women without epilepsy. This observational study will not employ any interventions; however, antiepileptic drug treatment for WWE will be recorded throughout the duration of the study.

Non-pregnant women with epilepsy will be followed for 18 months.

Pregnant women (with or without epilepsy) will be followed throughout pregnancy and until their child is 6 years old. Children of the pregnant women will ultimately be followed until they are 6 years old.

The child’s father and a first degree relative of each mother will be invited to participate in the study to provide additional family information.


Sample Size and Population

Subjects will include mother/child pairs enrolled during pregnancy (including approximately 100 healthy women and 350 women with epilepsy) and approximately 100 non-pregnant women with epilepsy. Children are classified into 4 groups with healthy mothers or mothers diagnosed with epilepsy on antiepileptic drug (AED) monotherapy, polytherapy, or no antiepileptic drug treatment.

The study will recruit and target of 550 women, as detailed in the table below.

Study Group* Target Sample Size Monotherapy
(LTG, LEV, CBZ, Other)**
Polytherapy No AED***
Pregnant women with epilepsy 350 280
(n=70/ AED group)
35 35
Non-pregnant women with epilepsy 100 80 10 10
Healthy pregnant women 100 N/A N/A 100

*Additionally, group proportions for key demographic factors such as age, race, education, and socioeconomic status will be monitored and assessed.
**CBZ=carbamazepine, LEV=levetiracetam, LTG=lamotrigine
***AED=antiepileptic drug
n=number; N/A=not applicable

 

List of Key Factors Assessed in the MONEAD Study

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) is performed.

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