1. MATERNAL & NEONATAL WITHDRAWAL SYNDROME BY: Dr. F.Goudarzi Clinical Toxicologist SUMS

2. 2 TREATMENT OF THE PREGNANT WOMAN MEANS THAT ONE IS CARING FOR TWO PATIENTS, NOT ONE * IT IS SUGGESTED THAT PHYSICIANS ADDRESS THE ISSUE OF ALCOHOL AND DRUG USE DURING PREGNANCY WITH ALL WOMEN OF CHILD BEARING AGE

3. What is MNAS? Presence of withdrawal behaviors in neonates exposed to dependency-producing substances in utero. These behaviors include central nervous hypersensitivity, gastrointestinal dysfunction and vague autonomic symptoms. 25-40 % of infants with known exposure are asymptomatic or display only mild symptoms

4. Substances that can cause MNAS Opiates- (55-94% of neonates exposed in utero will have withdrawal symptoms) Alcohol Tobacco Benzodiazepines Barbiturates SSRIs (neonatal behavioral syndrome) ?Amphetamines ?Cocaine ?Marijuana TCA

5. 5 SEDATIVE/HYPNOTICS BENZODIAZEPINE &PHENOBARBITAL WITHDRAWAL NO DIFFERENCE BETWEEN PREGNANT AND NON-PREGNANT WOMAN, ALTHOUGH SEVERE WITHDRAWAL CAN PRODUCE STATUS EPILEPTICUS AND FETAL RESPIRATORY ARREST CAN LAST 3 TO 5 WEEKS VERY MUCH LIKE ACUTE ALCOHOL WITHDRAWAL TIME COURSE AND SEVERITY DEPEND ON DOSE OF DRUG DURATION OF USE (DOES NOT WORSEN AFTER ONE YEAR OF USE) DURATION OF DRUG ACTION

6. 6 FETAL EFFECTS FROM BARBITURATES CLEFT PALATE HYPOSPADIAS (PENILE ORIFICE IS TOO LOW) MICROCEPHALY (SMALL HEAD SIZE) SHORT NOSE

7. 7 FETAL EFFECTS FROM BENZODIAZEPINES ????CLEFT LIP AND PALATE

8. 8 OPIOIDS

9. 9 OPIOIDS WITHDRAWAL IN THE MOTHER –EARLY & MIDDLE PHASE RESTLESS SLEEP DILATED PUPILS ANOREXIA GOOSEFLESH IRRITABILITY TREMOR

10. 10 OPIOIDS WITHDRAWAL IN THE MOTHER - LATE PHASE INCREASE IN ALL PREVIOUS SIGNS AND SYMPTOMS INCREASE IN HEART RATE INCREASE IN BLOOD PRESSURE NAUSEA AND VOMITING DIARRHEA ABDOMINAL CRAMPS LABILE MOOD DEPRESSION MUSCLE SPASM WEAKNESS BONE PAIN

11. 11 OPIOIDS WITHDRAWAL IT IS NOT RECOMMENDED TO TAPER PREGNANT WOMEN OFF OF METHADONE, BUT THE SAFEST TIME IS THE 2 ND TRIMESTER (TIPS2) BEFORE 14 WEEKS AND AFTER 32 WEEKS THERE IS AN INCREASED INCIDENCE OF SPONTANEOUS ABORTION AND PREMATURE LABOR

12. 12 OTHER WITHDRAWAL AGENTS CLONIDINE NO TERATOGENIC EFFECTS LONG TERM USE NOT RECOMMENDED BUPRENORPHINE APPEARS SAFE WITH NO TERATOGENIC EFFECTS, BUT NOT APPROVED FOR USE YET ( JONES AND JOHNSON 2001) NEVER USE NARCAN UNLESS AS A LAST RESORT SPONTANEOUS ABORTION PREMATURE LABOR STILLBIRTH

13. 13 FETAL EFFECTS OF OPIOIDS LOW BIRTH WEIGHT FETAL DISTRESS PREMATURITY NEONATAL ABSTINENCE SYNDROME STILLBIRTH SUDDEN INFANT DEATH SYNDROME MECONIUM ASPIRATION

14. 14 NEONATAL ABSTINENCE SYNDROME 60-80% OF OPIOIDS EXPOSED INFANTS 72 HOURS AFTER BIRTH CNS EFFECTS IRRITABILITY HYPERTONIA (INCREASED MUSCLE TONE) HYPERREFLEXIA ABNORMAL SUCK POOR FEEDING SEIZURES ( 1 TO 3%) GI EFFECTS DIARRHEA VOMITING

15. 15 METHADONE DOSING STRATEGIES IN THE PREGNANT WOMAN INITIAL 10 TO 40 MG EXTRA 5 TO 10 MG IN 3 TO 4 HOURS IF SIGNS AND SYMPTOMS OF WITHDRAWAL REPEAT 5 TO 10 MG Q 3 TO 4 H PRN STABILIZE AT THIS DOSE FOR SEVERAL DAYS DECREASE BY 2.5 MG Q 7 TO 10 DAYS AND MONITOR OB STATUS

16. 16 NEONATAL ABSTINENCE SYNDROME MEDICATIONDOSING INDUCTIONTITRATIONSTABILIZATIONTAPERING TINCTURE OF OPIUM0.1 ML/KG (2 DROPS/KG) Q 4 H WITH FEEDINGS INCREASE BY 0.1 ML/KG Q4H AS NEEDED Q 4 H WITH FEEDINGS FOR 3 TO 5 DAYS TAPER GRADUALLY BY REDUCING DOSE NOT FREQUENCY PAREGORIC (0.4 MG/ML) 0.1 ML/KG ( 2 DROPS/KG) Q 4H WITH FEEDINGS INCREASE BY 0.1 ML/KG Q 4H PRN Q4H WITH FEEDINGS FOR 3 TO 5 DAYS TAPER GRADUALLY BY REDUCING DOSE NOT FREQUENCY METHADONE0.05 TO 0.1 MG/KG Q 6H INCREASE BY 0.05 MG/KG Q 6 H PRN WHEN STABLE, GIVE TOTAL DAILY DOSE ONCE DAILY OR ½ BID TAPER GRADUALLY TO 0.05 MG/KG, THEN D/C MED

17. Diagnosis Maternal history of drug use Positive identification of substance in maternal or neonatal specimen Scoring  Once diagnosed- consult social services

18. 18 TIME TO ONSET OF MATERNAL WITHDRAWAL SIGNS *MATERNAL WITHDRAWAL DEPENDS ON THE DRUG, FREQUENCY OF USE, AND DURATION OF USE. TIMES CAN VARY SIGNIFICANTLY. DRUGTIME ALCOHOL6 to 60 HOURS BARBITUATE4 to 10 DAYS DIAZEPAM1 to 12 DAYS OPIOID12 to 72 HOURS

19. 19 TIME TO ONSET OF NEONATAL WITHDRAWAL SIGNS USUALLY THE ONLY WITHDRAWAL SYNDROME THAT REQUIRES TREATMENT IS OPIOID WITHDRAWAL DRUGTIME ALCOHOL3 to 12 HOURS BARBITUATE4 to 7 DAYS DIAZEPAM1 to 12 DAYS OPIOID48 to 72 HOURS

20. Clinical Presentation Onset of symptoms varies with the substance being used by the mother, the quantity, frequency and duration of intrauterine exposure, timing and amount of the last maternal use, as well as maternal and infant metabolism and excretion CNS Tremors, irritability, increased wakefulness, high-pitched crying, hypertonicity and hyperactive reflexes, seizures, yawning, sneezing and skin excoriation Gastrointestinal Poor feeding, uncoordinated and constant suck, vomiting or regurgitation, diarrhea, dehydration  Autonomic Signs increased sweating. Nasal stuffiness. Rhinorrhea, mottling, temperature instability, fever, tearing

21. W - wakefulness I - irritability T -tremors, twitching, tachypnea H - hyperventilation, hypertonia, hyperpyrexia, hyperaccusis, hiccups hyperaccusis, hiccups D - diarrhea, diaphoresis, R - rub marks A - alkalosis W - weight loss A - apnea L - lacrimation, S - seizures (myoclonic), sneezing, skin mottling

22. Frequency of Clinical Signs Disturbed sleep – 53% Mottling 53% Excess sucking 45% Tremors 43% Tachypnea – 43% Hypertonia 41% Fever 40% Seizures 2-11% (often later)

23. 23 STIMULANTS

24. 24 STIMULANTS WITHDRAWAL IN THE MOTHER DYSPHORIA FATIGUE UNPLEASANT DREAMS INSOMNIA HYPERSOMNIA (INCREASED SLEEP) INCREASED APPETITE PSYCHOMOTOR RETARDATION AGITATION

25. 25 MATERNAL EFFECTS OF STIMULANT AND COCAINE ABRUPTIO PLACENTAE PREMATURE LABOR SPONTANEOUS ABORTION DECREASE DURATION OF DELIVERY GREATER NUMBER OF OBSTETRICAL COMPLICATIONS

26. NAS video clip

27. 27 ALCOHOL WITHDRAWAL

28. 28 MATERNAL WITHDRAWAL THE RATE OF ALCOHOL METABOLISM MAY BE FASTER DURING PREGNANCY, SO BE AWARE THAT WITHDRAWAL CAN START SOONER THAN EXPECTED.

29. 29 MINOR WITHDRAWAL IN THE MOTHER TIME 6 to 60 HOURS SYMPTOMS TREMORS INSOMNIA NAUSEA ANOREXIA ANXIETY WEAKNESS

30. 30 MINOR WITHDRAWAL IN THE MOTHER SIGNS ACTION TREMOR INATTENTION EASY STARTLE PLETHORA CONJUNCTIVAL INJECTION INCREASED REFLEXES

31. 31 EARLY WITHDRAWAL IN THE MOTHER TREATMENT WATCH FOR DT’S EVALUATE FOR OTHER ILLNESSES AND INJURIES LIGHT SEDATION WITH BENZODIAZEPINES THIAMINE ELECTROLYTE BALANCE PATIENTS MUST UNDERSTAND THAT THEY NEED FURTHER TREATMENT

32. 32 LATE WITHDRAWAL IN THE MOTHER DELIRIUM TREMENS HIGH RISK FOR DT’S IF BLOOD ALCOHOL LEVEL GREATER THAN 300 mg% OR WITHDRAWAL SEIZURES PROFOUND CONFUSION AND MISPERCEPTIONS DISORIENTATION HALLUCINATIONS PARANOID DELUSIONS MOTOR HYPERACTIVITY TREMOR, RESTLESS, AGITATED, INCREASED REFLEXES AUTONOMIC HYPERACTIVITY INCREASED HEART RATE, PROFUSE SWEATING, DILATED PUPILS MORTALITY OF THE MOTHER IS 10 to 15% IF UNTREATED, 1 to 2% IF TREATED

33. 33 FASD BINGE DRINKING (5 OR MORE DRINKS ON ONE OCCASION) IS ESPECIALLY DETRIMENTAL TO THE FETUS THERE IS NO PROVEN “SAFE” AMOUNT OF ALCOHOL TO USE DURING PREGNANCY ALCOHOL HAS BEEN FOUND IN BREAST MILK

34. NICOTINE AND TOBACCO

35. 35 NICOTINE AND TOBACCO IF THE PREGNANT WOMAN CANNOT STOP SMOKING USING BEHAVIORAL INTERVENTIONS, THEN NICOTINE REPLACEMENT PRODUCTS CAN BE USED

36. 36 NICOTINE WITHDRAWAL SYMPTOMS IN THE MOTHER

37. 37 CANNABINOIDS

38. 38 CANNABINOIDS WITHDRAWAL IN THE MOTHER 10 HOURS AFTER USE TREMOR OF THE TONGUE AND EXTREMITIES INSOMNIA SWEATS LATERAL GAZE NYSTAGMUS EXAGGERATED DEEP TENDON REFLEXES

39. MNASS Used to initiate, adjust and wean pharmacologic treatment. Scoring should begin within 4 hours after birth and continue every 4 hours until the onset of symptoms. At the onset of symptoms scoring should be done every 3 hours for 24 hours and then every 4 hours for the duration of treatment. Observation should be made after feedings, newborns must be awake and calm to asses muscle tone, respirations and Moro reflex. Newborns should be observed for 20 to 30 minutes before scoring is determined.

41. Management Supportive Swaddling ( decreases the added stimulation of startled movements) Reduction of environmental stimuli ( decreased light and noise) Frequent small feeding Frequent diaper change are necessary to reduce skin excoriation Monitor intake, output and weigh daily to assess hydration and caloric status related to vomiting, diarrhea and poor feeding status. Pharmacologic intervention is indicated for evidence of acute withdrawal such as seizures, poor feeding (excess weight loss), severe diarrhea, vomiting, dehydration, inability to sleep and fever not due to any infectious etiology 3 consecutive NAS scores of 8 or more or the average of 3 consecutive NAS scores is 8 or more. or 2 consecutive NAS scores of 12 or more or the average of 2 consecutive score is 12 or more. Pediatric consult is recommended when considering pharmacologic treatment. Cardio respiratory monitoring.

42. Pharmacologic Therapies in Neonatal Abstinence Syndrome Paregoric 0.2-0.5 ml/dose q 3-4 p.o. or 4-6 drops q 4-6h; may increase by 2 drops until clinical improvement Improves most of the withdrawal symptoms especially diarrhea, taper dose by 10-20% per day over 2-4 week after symptoms stable for 3-5 days. Neonatal Opium Dilution 0.4% solution (contains 0.4 mg morphine equivalent per ml ) guidelines: 0.8 ml/kg/day for NAS 8-10 1.2 ml/kg/day for NAS 11-13 1.6 ml/kg/day for NAS 14-16 2.0 ml/kg/day for NAS >16 Doses given orally every 3-4 h with feeds ( not prn) Phenobarbital 15-20 mg/kg/day loading dose to achieve level of 20-40 mg/ml. Maintenance dose =2-8 mg/kg/day. Taper dose by 10-20% per day after symptoms stable for 3-5 days. Diazepam 0.3-0.5 mg/kg q 8 h; initial dose i.m then p.o Allows rapid suppression of symptoms, decreased suck, avoid in jaundice or premature infants.

43. Pharmacologic Therapies in Neonatal Abstinence Syndrome Methadone 0.1-0.5 mg/kg/day divided q 4 to 12 h Increase by 0.05mg/kg/dose until symptoms are well controlled Taper dose by 10-20% per day over 1 mo Treatment usually longer (5 days-4 mo) Long half-life (26 h ) Chlorpromazine 0.5-0.7 mg/kg/dose loading then 2-2.8 mg/kg/day in divided doses q 6 h Decrease dose over 2-3 wk Clonidine 0.5-1 ug/kg single dose then 3-5 ug/kg/day divided dose q 4-6 h Increase by 0.5 ug/kg over 1-2 days until maintenance dose is achieved

44. Weaning Guidelines Once NAS are consistently 6-8, maintain the same therapeutic dose 48 hours before weaning. Wean by 10% of maximum dose every 1-2 days. If symptoms increase, return to effective dose. Therapeutic agents should be gradually decreased over a 2-6 week period. Neonatal opium solution should be weaned first, then Phenobarbital.