Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)

Study Overview
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Brief Summary
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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
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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: Determine if women with epilepsy have increased seizures during pregnancy and delineate the contributing factors; Determine if C-section rate is increased in women with epilepsy and delineate contributing factors; Determine if women with epilepsy have an increased risk for depression during pregnancy and post-partum period and characterize risks factors; 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; Determine if small for gestation age and other adverse neonatal outcomes are increased in children of women with epilepsy; 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.

Official Title
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Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs

Conditions
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Epilepsy, Pregnancy

Participation Criteria
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Eligibility Criteria
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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: st choice: Sister of closest age to the mother in the trial nd Sister of next closest age rd Brother of closest age th Brother of next closest age th Mother th Father of pregnant mother in the study 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.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pregnant Women without Epilepsy<br>Women in their first trimester of pregnancy who are not diagnosed with epilepsy | |
| Nonpregnant Women with Epilepsy<br>Women diagnosed with epilepsy and not currently pregnant. | |
| Pregnant Women with Epilepsy<br>Women in their first trimester of pregnancy and diagnosed with epilepsy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seizure frequency over pregnancy vs. post-partum (comparable time periods for non-pregnant women with epilepsy). | Change in seizure frequency during pregnancy vs postpartum as measured by subject completed daily electronic seizure diaries | Pregnant women with epilepsy:1st Trimester through 9 months post-partum; Nonpregnant women with epilepsy: Study enrollment through 18 months participation | 
| C-section Rate | rate of C-sections in pregnant women without epilepsy vs pregnant women with epilepsy | Pregnant women with epilepsy & Pregnant women without epilepsy at child's birth | 
| Rate of Depression | 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. | 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 | 
| Child Intellectual Ability (2YO) | 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. | When child is 2 Years of age | 
| Child Intellectual Ability (4.5 YO) | 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. | When child is 4.5 Years of age | 
| Child Intellectual Ability (3 and 6 YO) | 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. | When child is 3 and 6 Years of age | 
| Small for Gestational Age Rate | Rate of children considered small for gestational age (<10%tile)born to women with epilepsy vs women without epilepsy | Child's birth | 
| Breastfeeding Effects on verbal intellectual ability in children | 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. | Birth until the child is 2 Years of age, although we anticipate not all children will breastfeed until 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Pregnancy