Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)

Completed

• Conditions: Epilepsy; Pregnancy

• Registration Number: NCT01730170
• Lead Sponsor: Stanford University

Brief 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.

Study Timeline

• Study First Submitted: 2012-11-09
• Study First Submitted QC: 2012-11-20
• Study First Posted: 2012-11-21
• Study Start: 2013-01
• Primary Completion: 2022-12-12
• Study Completion: 2022-12-12
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-10
• Last Update Posted: 2023-07-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 565

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Change in seizure frequency over pregnancy vs. post-partum (comparable time periods for non-pregnant women with epilepsy).	Pregnant women with epilepsy:1st Trimester through 9 months post-partum; Nonpregnant women with epilepsy: Study enrollment through 18 months participation	Change in seizure frequency during pregnancy vs postpartum as measured by subject completed daily electronic seizure diaries
Child Intellectual Ability (3 and 6 YO)	When child is 3 and 6 Years of age	Child intellectual ability as measured by the Verbal Index Score at visit 10 (3YO) and visit 12 (6YO). All of the outcome measures for cognitive outcomes at the various ages are scale scores which are continuous with a mean of 100 and a standard deviation of 15.
Child Intellectual Ability (2YO)	When child is 2 Years of age	Child intellectual ability as measured by the Language Scale of the Bayley Scales of Infant Development -III at visit 9 (2YO). All of the outcome measures for cognitive outcomes at the various ages are scale scores which are continuous with a mean of 100 and a standard deviation of 15.
Child Intellectual Ability (4.5 YO)	When child is 4.5 Years of age	Child intellectual ability as measured by the Torrence Test of Creative Thinking at visit 11 (4.5YO). All of the outcome measures for cognitive outcomes at the various ages are scale scores which are continuous with a mean of 100 and a standard deviation of 15.
Rate of Depression	Pregnant women: 1st Trimester through 9 months post partum, again when child is 2 and 3 Years of age. Nonpregnant women with epilepsy: Study enrollment through 6months participation, then 12 months until 18 months participation	Rate of depression during pregnancy in pregnant women with epilepsy vs pregnant women without epilepsy screened by the Beck Depression Inventory and confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual-IV.
C-section Rate	Pregnant women with epilepsy & Pregnant women without epilepsy at child's birth	rate of C-sections in pregnant women without epilepsy vs pregnant women with epilepsy
Small for Gestational Age Rate	Child's birth	Rate of children considered small for gestational age (\<10%tile)born to women with epilepsy vs women without epilepsy
Breastfeeding Effects on verbal intellectual ability in children	Birth until the child is 2 Years of age, although we anticipate not all children will breastfeed until 2 Years	Measuring difference in verbal intellectual ability in breastfed children vs non-breastfed children born to women on aeds via the Bayley Scales of Infant Development III Language scale at 2 years of age and Differential Abilities Scale III at 3, 4.5 and 6 Years of age.

Trial Locations

Locations (20)

John Hopkins Bayview Medical Center; 🇺🇸 Baltimore, Maryland, United States

Medical College of Georgia at Georgia Regents University; 🇺🇸 Augusta, Georgia, United States

Northwestern Memorial Hospital-Northwestern University Feinberg School of Medicine; 🇺🇸 Chicago, Illinois, United States

University of Arizona - University Medical Center; 🇺🇸 Tucson, Arizona, United States

Keck Hospital of the University of Southern California; 🇺🇸 Los Angeles, California, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

New York University School of Medicine; 🇺🇸 New York, New York, United States

Columbia University Medical Center/NY Presbyterian Hospital; 🇺🇸 New York, New York, United States

Stanford University; 🇺🇸 Stanford, California, United States

Wake Forest Baptist Health-Wake Forest University School of Medicine; 🇺🇸 Winston-Salem, North Carolina, United States

Minnesota Epilepsy Group; 🇺🇸 Roseville, Minnesota, United States

University of Miami Hospital - University of Miami School of Medicine; 🇺🇸 Miami, Florida, United States

Emory University School of Medicine; 🇺🇸 Atlanta, Georgia, United States

Brigham & Women's Hospital - Harvard; 🇺🇸 Boston, Massachusetts, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

North Shore Jewish Medical Center; 🇺🇸 Manhasset, New York, United States

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

University of Alabama Birmingham Hospital- UAB; 🇺🇸 Birmingham, Alabama, United States

University of Cincinnati UC Health University Hospital; 🇺🇸 Cincinnati, Ohio, United States

University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States