The Infant of Drug Dependent Mother

1. The Infant of Drug Dependent Mother Ma. Teresa C. Ambat, MD TTUHSC-Neonatology 9/12/2008

2. 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

3. Question • 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: • Alcohol • Marijuana • Nicotine • Cocaine • Heroin

4. 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%])

5. 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

6. Patterns suggestive of substance use

7. 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, T-ACE • Physicians’ records yielded the lowest prevalence estimates suggesting lack of attention devoted to addiction disorders

8. 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:   • Amphetamine • Benzodiazepine • Methadone • Opiate • Marijuana

9. 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

10. Identification of substance use Time interval before drug elimination in urine

11. 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: • Blood • Gastric aspirate • Hair • Meconium • Urine

12. 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: • 12 weeks • 16 weeks • 20 weeks • 24 weeks • E. 28 weeks.

13. 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

14. Identification of substance use

15. 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

16. 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

17. Alcohol • Alcohol use during pregnancy: 12.9%, binge drinkers: 4.6% • Difficult to assess by laboratory tests

18. 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

19. Complications of Fetal Alcohol Exposure

20. 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

21. Fetal Alcohol Syndrome • FAS – leading identifiable nonhereditary cause of mental retardation and neurologic deficit • Diagnostic criteria: 1. growth retardation, 2. specific mid-facial features, 3. non-specific developmental aberrations • Smooth philtrum, thin upper lip and short palpebral fissure – 100% sensitivity

22. Diagnostic criteria (FAS and Alcohol related effects • FAS + confirmed maternal alcohol exposure • 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)

23. Diagnostic criteria (FAS and Alcohol related effects • FAS without confirmed maternal alcohol exposure B, C and D as above 3. Partial FAS + confirmed maternal alcohol exposure • 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

24. Diagnostic criteria (FAS and Alcohol related effects 4. Alcohol-Related Birth Defects (ARBD) • 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

25. 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

26. 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)

27. Complications of Fetal Exposure to Tobacco

28. 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

29. 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

30. 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: • Alcohol • Heroin • Marijuana • Cocaine • Nicotine.

31. Complications of Fetal Exposure to Marijuana

32. 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

33. 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

34. Cocaine - Pharmacology • Decreases reuptake of tryptophan  affecting serotonin biosynthesis • Dec serotonin: decreased need for sleep (serotonin regulates sleep-wake cycle)

35. 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

36. Complications of Fetal Exposure to Cocaine

37. 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

38. Complications of Fetal Exposure to Amphetamines / Methamphetamines

39. 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)

40. 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

41. 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

42. 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

43. Manifestations of Neonatal Narcotic Withdrawal • CNS • Hyperactivity, hyperirritability, excessive crying, high-pitched cry, increased muscle tone, exaggerated reflexes, tremors, sneezing, hiccups, yawning, short, non-quiet sleep, fever • Respiratory • Tachypnea, excess secretions

44. Manifestations of Neonatal Narcotic Withdrawal • GI • Disorganized sucking, vomiting, drooling, sensitive gag, hyperphagia, diarrhea, abdominal cramps • Vasomotor system • Stuffy nose, flushing, sweating, sudden circumoral pallor • Cutaneous • Excoriated buttocks, scratches, pressure-point abrasions

45. 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

46. Non-narcotic Hypnosedatives • Hypnosedatives • Barbiturates • Non-barbiturate sedatives/tranqulizers • Bromide, Chloral hydrate, chlordiaxepoxide, diazepam, ethchlorvynol, glutethimide, ethanol

47. 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

48. 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? • Use of amphetamines • Use of marijuana • Use of SSRI for depression • Maternal seizure disorder • Use of cocaine

49. 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)

50. 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