Late Effects of Prenatal Exposure to Drugs of Contemporary Abuse

Late Effects of Prenatal Exposure to Drugs of Contemporary Abuse

Late Effects of Prenatal Exposure to Drugs of Contemporary Abuse Stephen R Luber MD FAAP Clinical Associate Professor of Pediatrics University of Washington Medical School We will discuss off-label use of pharmaceuticals Speaker Bureau Shire E.I. Lilly Novartis Shionogi McNeill Clinical Research Support

Shire E.I.Lilly Novartis Merck Sanofi-Aventis Case Presentation DH 8 1/2 y.o male brought by foster-adopt mother and father of two years Child has existing DX of ADHD-mixed; Oppositional Defiant Disorder; Learning disabilities He is seen by an embedded mental health worker in the school weekly He has been on a variety of medication which seem to work for a short time only and to fail with numerous complaints of side effects Academically, he is performing at a 1st grade level He has been mainstreamed with significant take-out support in the third grade but is being transferred to a Behavioral Interventional

classroom IEP is in place with 504 Accommodation Limited Neuro-psych testing has been performed He is described as aggressive, difficult to discipline and unable to stay on task Parents are well dressed, caring and present with reasonable insight but are frustrated and want to know how to help the child Child was born locally at term to a 23 y.o. unmarried woman. Pregnancy was minimally monitored and with mother apparently with limited social and financial support. Mother admitted to a pack-a-day cigarette habit but denied alcohol, prescriptive or recreational med abuse Social worker interviewed mother in the hospital and she went home with her mother. Putative father incarcerated recently for drug related events. Child was placed in the system by CPS at four months of age for FTT, neglect, with no ongoing medical supervision. Mother found to be using methamphetamine, ETOH.

Multiple rescue intervention placements with attempts to preserve family over the next two years when parental rights terminated. Two prior children with different fathers in the system. Long term foster placement initiate at 2 with multiple placements due to unmanageable behavior Child noted to have evidence of physical and nutritional neglect multiple developmental delays, aggressive behavior, reluctant to engage, hoarding food, and minimal expressive language Active CPS supervision ends with social service caseworker directing remedial services At age three placed into ECAP program with secondary admission into school district developmental preschools. Received physical, occupational and speech therapy. Multiple school placements due to changes in foster care placements. Described as developmental delayed with delayed acquisition of fine motor and cognitive mile stones. Expressive language delayed. Child difficult to manage with frequent destructive temper tantrums, oppositional behavior and unable to integrate with play activities with other students. Bladder and stool continence seemed to be willfully used as social tool Placed into current home at age 6. Child has made consistent progress with both social and language skills

with relatively normal expressive language but still significantly delayed academically. Mainstreamed with significant take out remedial services but now entering BI classroom. Physical Exam unremarkable, no stigmata of FAS, Fragile-X. Prior Lab work WNL. Prior MRI EEG WNL. ADOS not suggestive of Spectrum Disorder Diagnosis, Prognosis, Therapeutic Plan ? Phenotype General Physical Exam Unremarkable Delayed fine motor skills Tripod grip of pen, coloring in lines Self help buttons, zippers Delayed onset of Speech Does not read social cues aggressive, little comprehension of

consequences of action Meets diagnostic criteria for ADHD and ODD Uneven response to stimulants, mood stabilization critical Use of long acting alpha agonists, Straterra Neuropysche Testing Often low normal wide subtest scatter Low working memory, processing speed Learns to read (decode) unable to read to learn (comprehension) Rote math skills OK word problems difficult Behavioral Evaluations BRIEF, BASC, Connors Extended, Vineland Significant Externalizing Issues Meets Diagnostic Criteria for PDD NOS (DSM-IV) Social-Communication (DSM-5)

Comorbidity-Confounders Genetic Preload Alcohol Usage >50% Methamphetamine Users Neglect Abuse PTSD Attachment Disorder Multiple Placement Foster Care vs Family Care Maternal Drug Screens Urine Toxicology Multiple panels Multiple sensitivities Marijuana 1-3 month sensitivity

Depends on fat proportion Usage pattern Test used Most compounds 2-3 days Active abuse only No standardization among or within hospitals May give indication of use intensity Blood Toxicology Useful for acute intoxication Specific compounds Level indicative of usage History Neonatal Abstinence Syndrome

Traditionally associated with opioids Heroin Methadone Buprenorphine OxyContin 1.1% pregnant women 2011 1.2/1000 2000 5.6/1000 2009 NAS 1.2 increased to 3.4/1000 NICU admissions increased tenfold 2205 to 2011 35% NICU admissions in Spokane Finnegan Scoring System tremors, irritability, high pitched crying, diarrhea Treatment

Non-pharmacologic Pharmacologic - morphine, methadone, phenobarbital Neonatal Drug Screens MECSTAT Must be ordered and collected 5,7,9,12 drug panels ETOH, Oxycodone 20 Week History No indication of intensity of use CORDSTAT Cord blood Sample always available Similar panels Reputed 20 weeks Not substantiated limited indication of intensity of use No standards

Early Models Fetal Alcohols Syndrome FAS Identified 1973 1-2/1000 live births Dose Related 20% with Classic Physiognomy Microcephaly, smooth philtrum, thin upper lip, maxiallary hypolpasia Average IQ 65 range 20-120 School problems disproportional to IQ

Fine motor issues, visual-spatial integration, verbal learning Hyperactive, impulsive, aggressive, externalizing behaviors Fetal Alcohol Effect FAE 80% with normal facies Positive cognitive deficits of full blown syndrome Opioids Prominent Neonatal Abstinence Syndrome Infant Neurobehavioral Deficits Toddler Behavioral Problems Decreasing Subtle Cognitive Deficits Measurable Through Middle School Other Environmental Factors Clearly Overwhelm History of Prenatal Exposure Long Term Prognosis Excellent if Other Variables Controlled

Cocaine and Crack Cocaine 1990s Stigmata of crack baby Less severe sequelae in majority of studies than anticipated Minimal Abstinence Syndrome Subtle but statistically significant neurobehavioral, cognitive, and language function Minimal effect on later school success Care environment and other exposures more predictive of long-term outcome Marijuana

Old News Minimal long term studies of isolated perinatal marijuana exposure Conventional wisdom was that it may affect neurodevelopmental outcome but little direct evidence. Extensive use among all socio-economic classes led to minimizing of effect but evidence of decreased cognitive abilities and decreased executive function led to quiet acceptance New News This is not your mothers marijuana THC content 10 to 30 times that of the sixties and early 70s Attention, impulsivity, memory, executive function deficits beginning to be quantified Methamphetamine Worldwide Problem More users than cocaine and opiates combines United States Eastern and Midwestern dominance with recent surge

in the South. More women the men are first time users of those seeking treatment are women 6.7% of women seeking treatment are pregnant 5% of pregnancies are affected Minimal neonatal abstinence syndrome from methamphetamine alone Treatment Placement Most Critical Multiple Events Family (1st degree versus more distant) Out of Family Role of State Agencies to reunite family School Support IEP 504 Accommodation

Early Learning Intervention Mainstream vs. Dedicated Classroom Resources Available? Counseling What works? Cognitive Behavioral Therapy, Applied Behavioral Analysis Embedded school mental health workers Pharmacologic Intervention Pharmacology Symptom Based Therapy Mood Stabilizer Second generation antipsychotics Risperidone, Aripiprazole, Ziprasidone

Anticonvulsants Trileptal, Depakote, Lamictal Lithium Long Acting Alpha-Agonists ADHD Stimulants, Strattera, Alpha-Agonists Insomnia Melatonin, Clonidine, Trazodone, Remeron Predatory Behavior Opiate Blocker Naltrexone Anxiety/Depression SSRI Fluoxetine, Citalopram, Sertraline Cocaine vs Methamphetamine

Inner-City Black Impoverished Poorly Educated Mothers Not inner city Rural White, Asian, Hispanic Working Class Educated Despite adjustments for demographic characteristics suggests these characteristics have a robust effect on behavior problems and predict later psychopathology

Infant Development, Environment and Lifestyle Study 2012 IDEAL UCLA, Univ of Hawaii, Univ of Tulsa, Brown Univ, Univ of Maryland, Univ of Iowa, NIMH 204 exposed 208 Control Prenatal Exposure defined by history and Meconium screens Comparison with denial and negative mec Exposure to tobacco, Ethol, and marijuana common to both groups Heavy use > 3 days/week IDEAL Exclusion Criteria Infant

Critical Illness Multiple Birth Chromosomal Anomaly Congenital Anomaly Mother <18 y.o. age Overt Psychosis Institutionalization for retardation or emotional disorder Analysis 3-5 Years Child Behavior Check List CBCL 70% follow-up at 3 76% at 5

Internalizing behaviors increase from three to five years Emotional reactivity Anxiety/depression Externalizing behaviors present at five not three ADHD increase from three to five years Caregiver Psychosocial Problems Common Predictor for all Negative Behaviors Analysis School Age 65% Follow up Dose related decrease in inhibitory control Alterations in fronto-striatal architecture Increased caregiver stress Increased CPS involvement

Decreased Academic Performance boys > girls

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