Competency IV: Effects of Alcohol on the Developing Embryo and Fetus Commonly Abused Substances * Alcohol * Tobacco * Heroin * Methadone * Cocaine * Marijuana * Prescription Drugs * Inhalants Definitions: Pathophysiology * Derangement of function seen in disease; alterations in function as distinguished from structural defects * Sources of information: autopsy, retrospective studies of affected children, in vivo experimental models, embryo cultures, organotypic slice cultures, dissociated cells, primary neuronal or glial cell cultures, and cultured cell lines Pathophysiology * Possible Mechanism of alcohol related damage to the fetus * cell death by necrosis/ aberrant apoptosis direct toxic and indirect effects * free radical formation and oxidative stress * mitochondrial damage * interference with growth factors and chemical message system-GABA serotonin * cell adhesion molecular activity * vitamin A metabolism-competition for ADH * alcohol withdrawal NMDA and excitotoxicity * altered transport and uptake of calcium and glucose Definitions: Teratology * Teratogen- substances or conditions that disrupt typical development in offspring as a result of gestational exposure. They may cause death, malformations, growth deficiency and functional deficits. * Teratology- study of birth defects Principles of Teratology Contributing Factors * Dosage (blood alcohol level) * Pattern of drinking * Timing during the gestation * Genetic sensitivity * Maternal metabolism (chronic use of alcohol) * Nutrition * Parity * Active teratogenic metabolites * Synergy with other agents Alcohol Crosses the Placenta * Alcohol passes freely from the mother to the fetus. * The fetal liver cannot metabolize alcohol efficiently. * Blood alcohol concentrations (BAC) are approximately equivalent within the mother and fetus. * Fetus is more susceptible to alcohol than mother. (Cohen-Kareem, 2002) Metabolism of Alcohol * Enzymes involved in ethanol metabolism-alcohol dehydrogenase (ADH), catalase, and cytochrome P450 * These are the most obvious molecular targets of ethanol interaction in neural tissue * Examples: competitive pathways for certain classes of ADH to metabolize alcohol or synthesize retinoic acid from retinol (Critical to neural crest derivatives) * Direct and indirect toxic effects of alcohol use Possible Nutritional Effects of Alcohol Consumption > Decreased dietary intake > Impaired metabolism and absorption of nutrients- folate, B6, B1, B3, A > Altered nutrient activation and utilization K, Mg, Ca, Zn, PO4 and Glucose > Any pregnant woman using alcohol must be assessed for nutritional risk Genetics * Genetic determinants may be important in determining in a women’s susceptibility to having a child with FAS * Genetic polymorphisms associated with alcohol dehydrogenase may confer protection or susceptibility to the prenatal effects of a alcohol (Jones 2003) * Alcohol metabolism pathways: * Alcohol is oxidized by alcohol dehydrogenase to acetaldehyde * Acetaldehyde is oxidized by acetaldehyde dehydrogenase to actetate Fertilization Pre-implantation Fetal Developmental Chart Hepatic Development Pre- and Postnatal Developmental Overview Developmental Overview Therapeutic Interventions- Pharmacotherapeutic and Nutritional * Prevention, screening and intervention are first choices * Targeted pre- and postnatal natal approach in confirmed or highest risk pregnancies * supplementation with antioxidants * treatment with serotonin (5HT) agonists (buspirone) * D-NAP * choline for postnatal treatment, as well as behavioral therapies * retinoic acid a dilemma Fetal and Neonatal Physiology * Within 1 month of fertilization, the gross structural characteristics of all major organs are in place. Cellular development continues and some organs are still immature at birth (esp nervous system, kidneys, and liver) * There are a number of special functional problems in the adjustment of the fetus to extrauterine life: > Circulatory Readjustment > Onset of breathing and lung expansion Midline Serotonergic Neuronal Development * Dual role of serotonin: * as a neutotransmitter throughout life and in signalling during development-to produce differentiation and migration of even postmitotic neurons * serotonin has critical role in CNS development-a deficiency leads to cascaded deficiencies in forebrain development Midline Serotonergic Neuronal Development * Neurons that synthesize serotonin (5- hydroxytryptamine or 5-HT) may be particularly vulnerable to early alcohol insult * Embryonic/ fetal midline deficits are associated with brain deficits, including microencephaly, ventricular enlargement, underdevelopment of several brain areas and cortical thinning * Most extreme of these deficits is holoprosencephaly Neonatal Physiology > Adjustments at birth: • Nutrition and metabolism • Fluid and acid-base balance and renal function • Liver function • Metabolic rate and body temperature • Immunity and endocrine problems Neonatal Alcohol Withdrawal * Significant cardiovascular, metabolic and neurologic clinical signs (Gleason, 2005): * Hypoglycemia * Irritability * Tremors * Seizures * Autonomic dysregulation/temp instability * Blood pressure abnormalities * Excessive glucocorticoid release * Altered behavioral state organization Additional complications in the Newborn can be alcohol related * Heart defects * Skeletal malformations * Cleft lip and palate * Hip displacement and scoliosis * Hearing and visual problems * Otitis media * Pneumonia Medical Assessment of Child * Prematurity * Quality of prenatal and delivery care * Maternal experiences * Breastfeeding * Associated medical and neurological problems Differential Diagnosis * Rule out other disorders: * Syndromes with similar dysmorphia * Multiple etiologies of growth retardation and CNS dysfunction * Specify co-occurring disorders: * FAS-related mental health conditions reported * Other lifelong consequences/secondary disabilities Central Nervous System Dysfunction * CNS Criteria * Structural * Neurological * Functional Variable Profiles of Brain Damage * The brain damage profile with FASD is extremely variable * There are three interrelated sources contributing to this (Goodlett et.al. 2005): 1) Maternal Factors- age, parity, history of alcohol dependence, and patterns of alcohol use/ abuse (quantity, frequency, duration, developmental timing, and pattern of binge drinking Variable Profiles of Brain Damage * Sources (cont) 2) Alcohol abuse may occur in the context of other potentially deleterious conditions: poverty, smoking or other drug use, nutritional deficiencies, poor prenatal care or support, disadvantaged postnatal environment. These may be correlated or coactive with fetal alcohol exposure and increase the risk for FAS. Variable Profiles of Brain Damage * Sources (cont) 3) Maternal- fetal genetic interactions: studies have shown that maternal ADH2*3 alleles, coding for a more efficient alcohol dehydrogenase enzyme, decrease the risk of having a child with FAS. Issues in Court Ordered Prenatal Intervention > Fetal Rights > Maternal Rights > State Interests > When to Intervene: Standards of Care > Types of Intervention: Mandatory Tox. Screening, Criminalization, Civil Commitment, Medical Intervention Legal Issues > Since 1985, 240 women in 35 states have been criminally prosecuted for using drugs or alcohol during pregnancy (70 to 80 percent minorities). > Balance women’s right to bodily integrity with society’s interest in healthy pregnancies. > What fosters the best outcome for women and children?