The Infant of Drug Dependent Mother Ma. Teresa C. Ambat, MD TTUHSC-Neonatology 9/12/2008 Objectives Describe strategies how to identify neonates in whom substance abuse is suspected Recognize perinatal and long term complications associated with fetal exposure to major drugs of abuse Recognize signs and symptoms of neonatal abstinence syndrome Identify treatment strategies for NAS Question 1. The National Household Survey on Drug Abuse: indicated that 45% of women of childbearing age in the United States have used an illicit drug over their lifetime. Of the following, the annual estimate of prenatal exposure to a substance of abuse is highest for: A. Alcohol Marijuana Nicotine Cocaine Heroin B. C. D. E. Epidemiology Prevalence of gestational use of drugs of abuse varies ranges from 1% to 27% Significant number remain regular users, even in the third trimester Tobacco [19.8%], Ethanol [13%], cannabis [9.3%], cocaine [10%], heroin [1%]) Identification of substance use Maternal self-reports, and few confounders Identify medical, obstetric, and behavior patterns suggestive of substance use Obtain history of past and present substance use in a nonjudgmental manner Questions limited to frequency and amount of specific substances Patterns suggestive of substance use Identification of substance use Maternal interview usually underestimates the extent of exposure Rates of alcohol and illicit drug use varied with the use of different validated screening instruments: MAST, CAGE, TACE Physicians’ records yielded the lowest prevalence estimates suggesting lack of attention devoted to addiction disorders Question 2. The duration of time for detecting a drug of abuse in the maternal urine varies, depending on the time of intake, dose and mode of administration, and metabolism of the drug. Of the following, the duration of time after birth for the detection of a drug of abuse in the maternal urine is longest for: A. Amphetamine Benzodiazepine Methadone Opiate Marijuana B. C. D. E. Identification of substance use Indication for toxicology screening Self-reporting of substance use Multiple characteristics suggesting substance use Compliance requirements with treatment recommendations Urine is the preferred source for drug testing - easily available and in large quantities Most substances are measurable in urine for < 72 hours after use, except for marijuana Identification of substance use Time interval before drug elimination in urine Drug Detectable in urine Alcohol <24h Amphetamines <48h Barbiturates: Short acting Long acting <48h <7days Benzodiazepines <72h Cocaine <72h Marijuna: Single use Chronic use Opiates: Morphine, Heroin Methadone <72h <30days <48h <96h Question 3. Various matrices for the detection of fetal exposure to drugs of abuse have been developed and tested for their sensitivities and specificities. Of the following, the matrix that is most sensitive for the detection of fetal exposure to benzoylecgonine is neonatal: A. B. C. D. E. Blood Gastric aspirate Hair Meconium Urine Question 4. Testing of neonatal meconium for a drug of abuse depends on deposition of the drug into the meconium that begins at the commencement of fetal swallowing and continues until after delivery. Of the following, the earliest gestational age at which exposure to cocaine has been detected in meconium in a fetus is: A. B. C. D. E. 12 weeks 16 weeks 20 weeks 24 weeks E. 28 weeks. Identification of substance use Meconium testing 93% sensitive (82% PPV) compared with combined maternal and neonatal urine testing Meconium and hair analyses - highest sensitivities in detecting use of cocaine and opiates (80-100%),but not cannabis (20%) Fetal exposure to cocaine detected by meconium testing was documented as early as 16 wks Other matrices: hair and nail, blood/cord blood, amniotic fluid Identification of substance use Perinatal pharmacology Any substance unbound to proteins passes freely from the maternal compartment placenta fetal compartment Concentrations in the fetal circulation > the maternal serum Effects from any substance depend on the gestational timing and the extent of drug distribution Toxic or teratogenic effects expressed as fetal demise, dysmorphism, growth restriction, or behavioral changes Except for maternal alcohol, a birth defect syndrome has not been described for other illicit substances Perinatal pharmacology Substances of abuse may be intentionally or inadvertently taken at toxic doses Difficult to ascribe specific effects to a certain drug due to impurity of most illicit drugs and use of multiple substances Accurate evaluation of dosage and the exact period of exposure are rarely possible Alcohol Alcohol use during pregnancy: 12.9%, binge drinkers: 4.6% Difficult to assess by laboratory tests Alcohol Ethanol - an anxiolytic analgesic with CNS depressant effect Impairs placental function Interferes with transport of AA Alters placental expression of EGF and PGF Inhibits DNA and protein synthesis Inhibits phospholipase A2, decreases PGI production, increases HCG production Complications of Fetal Alcohol Exposure Antenatal SAB Aneuploidy Stillbirth Breech IUGR Abnormal HR pattern fetal breathing, movement Intrapartum Abruptio Premature labor Neonatal Prematurity LBW, SGA Abstinence syndrome FAS FAE Abnormal EEG Long term Post natal growth restriction Low Bayley/Fagan scores ADHD Language problem Behavior problem Poor academic performance Adolescent: difficulty in memory, calculation Question 5. Fetal alcohol syndrome is the leading identifiable nonhereditary cause of mental retardation and neurologic deficit. Define the 3 specific criteria to qualify for a diagnosis of FAS. A. growth retardation B. specific mid-facial features, C. non-specific developmental aberrations Fetal Alcohol Syndrome FAS – leading identifiable nonhereditary cause of mental retardation and neurologic deficit Diagnostic criteria: 1. growth retardation, 2. specific midfacial features, 3. non-specific developmental aberrations Smooth philtrum, thin upper lip and short palpebral fissure – 100% sensitivity Diagnostic criteria (FAS and Alcohol related effects 1. FAS + confirmed maternal alcohol exposure A. Confirmed maternal alcohol exposure Characteristic facial anomalies: short palpebral fissures, flat upper lip, flat philtrum, flat midface Growth restriction: LBW/SGA, decelerating weight over time not due to nutrition, disproportional weight to height CNS neurodevelopmental anomalies: decreased HC at birth, structural brain anomalies, neurologic hard or soft signs (impaired fine motor skills, NSHL, poor tandem gait, poor eye-hand coordination) B. C. D. Diagnostic criteria (FAS and Alcohol related effects 2. FAS without confirmed maternal alcohol exposure B, C and D as above 3. Partial FAS + confirmed maternal alcohol exposure A. Confirmed maternal alcohol exposure Some components of characteristic facial anomalies C or D as above or Evidence of complex pattern of behavior or cognitive anomalies inconsistent with developmental level and cannot be explained by familial background or environment alone B. C. D. Diagnostic criteria (FAS and Alcohol related effects 4. Alcohol-Related Birth Defects (ARBD) A. Confirmed maternal alcohol exposure + 1 or more congenital anomalies (Cardiac, skeletal, renal, ocular, auditory, others) Every malformation has been described in patients with FAS. Etiologic specificity to alcohol teratogenesis remains uncertain. 5. Alcohol-related neurologic disorder (ARND) A. Confirmed maternal exposure and D and or E Tobacco Prevalence during pregnancy: 20% Nicotine – primary psychoactive chemical Central effects Binds to nicotinic Ach receptors release of neurotransmitters (Ach, NE, GABA, glutamate) Dopamine release in mesolimbic dopaminergic pathway Peripheral effects Releases epinephrine from adrenal cortex physiologic response flight or fight reaction Suppresses insulin release hyperglycemia, affects appetite Tobacco Fetal Effects Poor maternal nutrition affects growth and development Nicotine a vasoconstrictor reduces placental blood flow decreased fetal O2 hypoxia/ischemia CO + Hb carboxyhemoglobin hinder O2 delivery to fetus Nicotine readily crosses placental barrier Nicotine Ach receptors are present early in gestation affecting brain development (neurotoxic) Complications of Fetal Exposure to Tobacco Fetal SAB Stillbirth Placental decidual necrosis Intrapartum Neonatal Long term Abruptio Premature labor IUGR CHD Deformities of extremities, polycsyctic kidneys, gastroschisis, skull deformities PPHN Low test scores (cognitive, language, general academic achievement) Conduct disorder Adolescentonset drug dependence SIDS Marijuana Dried material from hemp plant, Cannabis sativa Smoked in cigarette or pipe passes rapidly into blood rapid high d-9-tetrahydrocannabinol (THC) - primary psychoactive component THC binds to cannabinoid receptors (CB1) modify release of neurotransmitters Marijuana Fetal and Neonatal Effects THC crosses placenta easily and present in amniotic fluid High lipid solubility, slow elimination prolonged fetal exposure Cannabinoid receptors present in early gestation modify neurotransmitters (serotonin, dopamine, GABA) altered neuronal growth, maturation and differentiation structural or functional abnormalities Impact generally subtle, adverse outcomes usually associated with heavy or frequent use Question 6. Children who have been exposed prenatally to substances of abuse may have physical deformities as well as neurodevelopmental deficits. Of the following, the substance of abuse most associated with intestinal atresia, infarction and necrotizing enterocolitis is: A. B. C. D. E. Alcohol Heroin Marijuana Cocaine Nicotine. Complications of Fetal Exposure to Marijuana Antenatal Intrapartum Neonatal Long term Precipitous or dysfunctional labor Meconium stained AF Prematurity Fine tremors Disrupted sleep Poor abstract, visual reasoning, Poor memory and verbal skills Poor motor skills Abnormal attention behavior Small risk for SIDS Cocaine Alkaloid extracted from leaves of Erythroxylon coca bush Chemical name: methylbenzoylecgonine Forms Coca paste – 1st extraction product, 80% cocaine Cocaine HCl – powder soluble in water, can be snorted and injected Alkaloidal base (free-basing) Crack cocaine – most popular abused form Cocaine - Pharmacology Affects 3 neurotransmitters: norepinephrine, dopamine, serotonin Inhibits reuptake of NE, D accumulation at synapse prolonged stimulation of receptors NE stimulation: tachycardia, HTN, diaphoresis, tremors Dopamine stimulation: increased alertness, euphoria, enhanced feeling of well-being, sexual excitement, heightened energy Cocaine - Pharmacology Decreases reuptake of tryptophan affecting serotonin biosynthesis Dec serotonin: decreased need for sleep (serotonin regulates sleep-wake cycle) Cocaine-Pharmacology Low molecular weight, high lipid solubility crosses placenta by simple diffusion Elimination of cocaine and metabolites slow increased fetal toxicity Decreases placental perfusion Congenital malformation not increased Complications of Fetal Exposure to Cocaine Antenatal Stillbirth Abortion Inc uterine vascular resistance Infection/STD Placental infarcts IUGR Abnormal fetal breathing Intrapartum Abruptio Premature labor PROM Shortened labor Meconium stained amniotic fluid Neonatal PT, LBW, SGA Small HC Postnatal growth restriction CNS: cerebral infarction, seizures, cortical atrophy, IVH Abnormal EEG and BAER NEC Intestinal perforation Long term Expressive/ receptive language problem Low verbal comprehension Poor recognition, memory, info processing visual attention Behavior problem (distractibility, ADHD) Amphetamines Methyphenyethylamine – stimulant of norepinephrine, dopamine and serotonin release Metamphetamine (meth, speed, ice, crystal) – N-methyl homologue of amphetamine Higher CNS stimulation, less PNS and cardiovascular stimulation Euphoria, aggressive behavior, arrhythmias, anxiety, seizures, shock, stroke, abdominal cramps, insomnia, death Complications of Fetal Exposure to Amphetamines / Methamphetamines Antenatal Fetal death Retroplacental hemorrhage Intrapartum Neonatal Long term Prematurity Neonatal death Drug intoxication (abnormal sleep, tremors, poor feeding, hypertonia, sneezing, highpitched cry, loose stools, fever, yawning, hyperreflexia, excoriation) Dec IQ Aggressive behavior/peer related problems Poor academic performance Club drugs Methylene-dioxymethamphetamine or MMDA (ecstasy) Gamma hydroxybutyrate (GHB) Ketamine hydrochloride Used by young people during all-night dance parties Few data on fetal and neonatal effects One study indicated increased risk of congenital defects (musculoskeletal, CVS) Opioids Opiate or narcotic – any natural or synthetic drug that has morphine like pharmacologic actions Natural opiates – morphine, codeine Synthetic opiates – heroin, methadone, propoxyphene, pentazocine, meperidine, oxycodon, hydromorphone, fentanyl Neonatal Abstinence Syndrome Generally associated with withdrawal from heroin or methadone Similar signs associated with other narcotics, alcohol, benzodiazepines and barbiturates Associated with noradrenergic hyperactivity CNS, respiratory, GI, vasomotor and cutaneous systems manifestations CNS signs predominate and appear early Neonatal Narcotic Withdrawal or Abstinence Syndrome Onset within 72 hrs (usually within 24-48 hrs) Factors influencing onset: amount of narcotics, timing of the last dose before delivery, character of labor, type of analgesia/anesthesia, maturity and nutritional status of infant Peaks by the 3rd day Decreases in intensity by 5th – 7th day, but may not completely disappear until 8-16 weeks Manifestations of Neonatal Narcotic Withdrawal CNS Hyperactivity, hyperirritability, excessive crying, highpitched cry, increased muscle tone, exaggerated reflexes, tremors, sneezing, hiccups, yawning, short, non-quiet sleep, fever Respiratory Tachypnea, excess secretions Manifestations of Neonatal Narcotic Withdrawal GI Vasomotor system Disorganized sucking, vomiting, drooling, sensitive gag, hyperphagia, diarrhea, abdominal cramps Stuffy nose, flushing, sweating, sudden circumoral pallor Cutaneous Excoriated buttocks, scratches, pressure-point abrasions Complications of Neonatal Narcotic Withdrawal Abnormalities in serum pH/electrolytes and dehydration Weight loss Aspiration pneumonia Respiratory alkalosis Convulsion Mortality – 27/1000 LB Causes: immaturity, prematurity, HMD, MAS, PPHN, congenital malformations Non-narcotic Hypnosedatives Hypnosedatives Barbiturates Non-barbiturate sedatives/tranqulizers Bromide, Chloral hydrate, chlordiaxepoxide, diazepam, ethchlorvynol, glutethimide, ethanol Non-narcotic abstinence syndrome Passive addiction even with therapeutic doses (e.g. phenobarbital) Manifestations of withdrawal can be intense and life threatening Convulsion more frequent Observed 7-10 days after birth as a result of slow clearance Question 7. A 4 day old, SGA presented with generalized tonic, clonic seizure. There was no prenatal care. On exam, he was found to be irritable, inconsolable, weak suck and swallow and uncoordinated. He was also noted to be hypertonic with tremors. What significant maternal history could have contributed to the above findings? A. Use of amphetamines Use of marijuana Use of SSRI for depression Maternal seizure disorder Use of cocaine B. C. D. E. SSRI Prescribed for depression Inhibits serotonin reuptake at presynaptoic junction increased concentrations at the synaptic cleft potentiates serotonergic transmission No major birth defects Prenatal exposure and withdrawal associated with neurobehavioral effects (behavioral changes, altered autonomic activity) Diagnosis of Neonatal Abstinence Syndrome Scoring tools Lipsitz scale Finnegan scale Neonatal abstinence score Score at first appearance of NAS symptoms then q3-4 hrs Specific to narcotic withdrawal Differential diagnoses: hypoglycemia, hypocalcemia, hypomagnesemia, sepsis, meningitis Treatment of NAS Supportive Quiet, dimly lit environment, comfortable side lying position, swaddled Nutrition and fluid and electrolyte balance IV fluids may be required Pharmacotherapy Average scores >8 over 3 scoring intervals or >12 over 2 scoring intervals Goal: decreased irritability, feeding tolerance, sleeping bet feeding without sedation Treatment of NAS Diluted tincture of opium (DTO) – 0.4mg/ml morphine equivalent Phenobarbital Starting dose 0.1ml/kg (2 drops/kg) q4 hrs Increment of 2 drops/kg q3-4 hrs until desired effect Taper gradually after 3-5 days of stabilization 2nd line drug Anticonvulsant, NAS by sedatives or hypnotics Paregoric Deleterious additives: camphor, ethanol, glycerin, benzoic acid, isoquinolones Other concerns Maternal support Breast feeding – generally discouraged if noncompliant Drug-dependent mothers as caregivers Social service referral Potential child abuse Follow-up References Chasnoff IJ. Prenatal Substance Exposure: Maternal Screening and Neonatal Identification and Management. NeoReviews 4 (9), 2003. Chan D, Klein J, Koren G. New Methods for Neonatal Drug Screening. NeoReviews 4 (9), 2003. Rayburn WF. Maternal and Fetal Effects from Substance Use. Clin Perinatol 34, 2007. Ostrea EM. The infant of drug dependent mother.