Sh. Pourarian Neonatologist

Epidemiology

A survey in 1985 by the national institute of drug Abuse (NIDA) showed. 23 million people in U.S. used illicit drugs 250000 women used intravenous drugs 90% of them were in reproductive age 6000-10000 newborns are born to opiate-addicted mother each year.

Cont.

Epidemiology

 Marijuana and cocaine are the most frequently abused illicit drugs in pregnancy.  Although opioid abuse in pregnancy is less common, but their effect on mother and her fetus can be life threatening.

In utero exposure to opioids and other drugs may lead to fetal dependence and fetal and neonatal withdrawal.

Neonatal abstinence syndrome is a term generally applied to neonatal withdrawal from heroine or methadone, but similar signs are also seen in withdrawal from other substances: Other narcotics, alcohol, benzodiazepines, barbiturates.

Natural opiates:

Morphine Codeine

Narcotic Drugs

Synthetic opiates:

Heroin Methadone Pentazocine (Talwin) Meperidine (Demerol) Oxycodone Morphinone (Dilaudid) Fentanyl (immovar)

Non- narcotic drugs

   

Hypnosedatives

Barbiturate

Nonbarbiturate sedatives and tranquilizers

Bromide Chloral hydrate Chlordiazepoxide (Librium) Diazepam (Valium) Ethchlorvynol (Placidyl) Glutethimide (Doriden)

Alcohol

Ethanol

Cocaine (Crack)

Narcotics:

Any natural or synthetic drug that has morphinlike pharmacologic actions: opiate or narcotic.

Antenatal problems

1. Intrauterine asphyxia:

Still birth, Meconium- stained amniotic fluid Fetal distress, low apqar score, neonatal aspiration pneumonia.

 Continuous fetal well being monitoring is needed.

Factors causes fetal asphyxia.

a.

Methadone  sleep disturbances ↑REM > quite sleep  b.

↑ hyperactive  ↑20% in fetal O 2 consumption.

Fetal withdrawal coincides with maternal withdrawal  hyperactivity  ↑O 2 consumption

Manifestations

Bradycardia, ↑ sys. and dias. BP, continuous deep breathing movement, neck tone, desynchronization of electrocortical activity. 2. Abruptia placenta, placenta previa, preeclampsia  insufficiency  fetal distress.

placental 3. Meconium stained amniotic fluid 4. Intrauterine infection : a. life style b. ↑PROM c. Opiates  compromise immune function CMI d. Venereal dis., Hepatitis, AIDS response Humoral immune

Neonatal problems

Heroin:

 Diacetylmorphine, is a semisynthetic opioid  It has morphinlike properties but it’s crosses CNS more rapidly.  Deactivated in liver  Morphine  Readily across the placenta  30% LBW, 5% SGA (↓No. of cells, normal size)  Direct growth inhibiting effect on the fetus  No increase in congenital anomalies Cont.

 Heroin injected IV intensifies the risks due to :overdose acute bact. Endocarditis, Hep. B,C and HIV / AIDS, infections.

 Heroin is also can snorted or smoked, make the drug even more attractive.

 Facilitate contraction of sexually transmitted dis.

 ↑Prenatal risks: Extrauterine preg, PLP, PROM, uterine irritability, breech presentation, antepartum hemorrhage, toxemia, anemia, bact. Infections, LBW, still birth

Clinical manifestations

50-75% of infants develop withdrawal syndrome.

Onset of symptoms : 24-48 hrs of life, or as late as 4wks, depend on several factors:

a

. The dosage of heroine (<6 mg/day  no or mild symptom)

b

. The duration of maternal addiction: (<1y 55%, >1y 73% incidence of withdrawal)

c

. The time of last maternal dose: ↑incidence if drug taken within 24 hrs of birth.

Cont.

d

. Type and amount of anesthesia or analgesia given to the mother, maturity and nutritional state of the infant.

 Less RDS due to accelerated lung maturation, surfactant  Less Hyperbili. Due to induction of GT enzyme.

 Thrombocytosis, ↑ platelet aggregation  Abnormal TFT: ↑ triiodothyronine and thyroxin levels  Withdrawal symptoms Cont.

Methadone

 Used for therapy for heroine addicted patient  Block the euphoric effects.

 Placental limitation of transport  Incidence of withdrawal is 70-90%  Higher birth weight, less IUGR< Heroin addicted  Head circumference < 3% percentile  No congenital anomalies  Thrombocytosis, ↑platelet aggregating activity, after the first week, persisted for 16 wks.

Cont.

Methadone

 Abnormal thyroid function: ↑T3,T4  The time of onset of withdrawal symptoms depend: a. The time of the last maternal dose b. The dosage of drug: if > 20 mg/day  symptoms  Withdrawal symptoms  Some infants have late withdrawal, which may be of two types: a.

Shortly after birth, improve, and recur at 2-4wks. b.

Are not seen at birth, but develop 2-3 wks later.

Non-Narcotic Hypnosedatives:

Differences:

In adult:

1.Rate of developing physical dependent not ↑with the drug dose.

2.But ↑with prolonged and continuous administration over months or years  produce addiction

In newborn

3. Passive addiction in therapeutic dose used by the mother.

4. The withdrawal manifestation: more intense and life threatening, Convulsion is more frequent 5. Unlike the narcotics, addiction may be induced by physicians.

Barbiturates

 Depends on their action classified to 3 groups: ultrashort, intermediate, long acting  The intermediate- acting are the most abused  The long-acting (phenobarbital) is not abused, mostly used for insomnia, relief of anxiety, anticonvulsant, sedation for toxemia  Barbiturate cross the placenta readily  ↑Level found in brain, liver, adrenal of fetus Cont.

The manifestations of W. symptoms are similar but with diff. onset: Intermittent type: 1 st day    Long acting: 7 days (2-14 days) Metabolized in the liver, T ½ is twice in N.B.

Infants are full term, AGA, Good apqar scores.

2 stages of phenobarbital withdrawal symptoms: Acute : irritability, hiccups, mouthing movements Subacute: voracious appetite, regurgitation, gagging, sweating, disturbed sleep pattern, last 2-4m. Cont.

Manifestations of neonatal narcotic withdrawal

Central nervous system signs

Hyperactivity Hyperirritability – excess crying, high- pitched outcry Increased muscle tone Exaggerated reflexes Seizures 2-11% Tremors Sneezing, hiccups, yawning Short , non-quiet sleep Fever

Respiratory sings

Tachypnea Excess secretions

Manifestations of neonatal narcotic withdrawal

Gastrointestinal signs

Disorganized, vigorous sucking Vomiting Drooling Sensitive gag Hyperphagia Diarrhea Abdominal cramps (?)

Vasomotor signs

Stuffy nose Flushing Sweating Sudden, circumoral pallor

Cutaneous sings

Excoriated buttocks Facial scratches Pressure-point abrasion

Differential diagnosis

1.

2.

3.

4.

Metabolic disturbances: ↓ Glu, ↓Ca, ↓ Mg, sepsis meningitis, S.A Hemorrhage, Infectious diarrhea, intestinal obstruction. CBC, X-ray, CSF and Blood culture Mothers who took: tricyclic antidepressant and lithium during pregnancy  toxicity= similar to withdrawal syndrome Mothers on phenothiazine (chlorpromazine)  extrapyramidal dysfunction  Tremor, grimace, ↑muscle tone.

Diagnosis

1.

Maternal interview: - Routine interview - Structural interview

Lab test

Thin – layer chromatography, immunoassay, gas chromatography,…

a. Urine

- limitations; benefits - False negative: 32-63% in N.B

b. Meconium

Drug metabolized in liver  In urine  Amniotic fluid  bile  GI GI Ideal specimen for drug testing till 3 days Sensitive, quantitative, rapid

c. Hair

Mother, neonate: Mostly in chronic users.

1.

Treatment

Management of the antenatal and neonatal complications: Asphyxia, fetal distress, Mec. asp., cong. Anomalies * Use of Narcan is contraindicated for birth asphyxia.

2.

Routine serologic test: syphilis, HIV, Hepatitis B

Treatment

The goal of Rx 1.

↓ irritability 2.

3.

Feeding tolerance without vomiting or diarrhea Sleeping between feedings without sedation

Symptomatic treatment

Supportive care: Alone or together with pharmacotherapy a.

Quite environment, free from noxious stimuli b.

Tight swaddling, holding, rocking c.

Hand to mouth facilitor pacifier

d.

Placing in a slightly darkened quiet area e.

Hypercaloric formula (24 cal/30 ml) as needed f . Monitoring of temp, HR, RR, Q4h g .

Check for diarrhea, vomiting Q8h h.

Be aware of SIDS Cont.

لودج

لودج

لودج

 Infants should be scored at first appearance of NAS  Then repeated every 3-4 hrs based on feeding time  Pharmacotherapy is based on serial scoring of withdrawal signs: 8 or higher over three scoring intervals.

12 or higher over tow scoring intervals

 If scores > 8 the scores must be checked Q 2hr  If the desired effect has been obtained for 72hrs, the dosage must be tapered gradually without altering dosing interval  D/C

B. Medications

1.Neonatal morphine solution (NMS

): drug of choice for narcotic withdrawal Preparation: 0.4 mg/ml oral morphine dilution: Add 1 ml of 4 mg/ml inject able solution of morphine + 9 ml of normal saline.

2.

Neonatal opium solution (NOS):

Hydroalcoholic solution 10 mg/ml + 25 Fold sterile water  0.4 mg morphine / ml The dilution is stable for 2 weeks

3. Paregoric:

Contains : 0.4 % opium = 0.04% Morphine + other additives Dose as for NMS or NOS Cont.



Dosing scheme for NMS or NOS

Score 8-10 11-13 14-16 17 or greater NMS or NOS 0.8 ml/kg/d divided Q4h/feeding 1.2 ml/kg/d divided Q4h/feeding 1.6 ml/kg/d divided Q4h/feeding 2.0 ml/kg/d divided Q4h/feeding Increased by 0.4 ml until controlled Cont.

a.

Increase 2 drop/kg (0.1 ml/kg) Q 3-4 hr b.

If > 2.0 ml/kg/day  add phenobarbital c.

If infant score remain < 8 for 72 hrs.  wean by 10% of total dose daily.

d.

If weaning  score > 8  restart the last effective dose e.

D/C NMS or NOS if the daily dose < 0.3 ml/kg/day

4.Phenobartital

 Is not the drug of choice of opiod withdrawal  Recommended for anticonvulsant therapy.

 If NAS induced by sedative or hypnotics  It may used as a second – line drug for NAS when NMS fails to alleviate the symptoms  Dose : 20 mg/kg  ↑10 mg/kg Q 8-12 hr /dose  40mg/kg

Cumulative Sum of loading doses Maintenance phenobarbital 20 mg/kg 5 mg/kg/d 30 mg/ kg 40 mg/ kg 6.5 mg/kg /d 8 mg/kg/d * Phenobarbital can be given PO or IM/24hr * Taper by 10% every day after improving of symptoms Cont.

5. Morphine and phenobarbital

 Infants withdrawing from multiple drugs  NMS dose: 0.05 ml/kg Q 4hr phenobarbital dose: 10 mg/kg Q12  Tapering of morphine first  then phenobarbital  Less sever withdrawal  Shorter mean duration of hospital stay  Reduced hospital cost. Cont.

Morphine: 0.1 -0.2 mg/kg can be effective in the Rx of seizures or chock due to acute NAS.

6. Chlorpromazine

No longer used because of its side effects.

It is useful to control the vomiting. Diarrhea Dose: 1.5-3 mg/kg / day Q4h , IM  Po

7. Methadone

Is not used for withdrawal from narcosis It is safe for methadone treated mother breast fed. Dose 0.1 mg/kg/dose  ↑0.025 mg/kg dose Q4h

8. Diazepam:

Is not used because of side effects 0.1-0.3 mg/kg IM  till symptoms are controlled.

9. Lorazepam:

Used for sedation alone or with NMS or NOS. Dose: 0.05-0.1 mg/kg /dose/IV.

Complications

 Alterations in serum electrolyte, pH, dehydration  Profound wt. loss  Aspiration pneumonia  Respiratory alkalosis  Neurobehavioral abnormalities

Long term outcome

1. Syndrome of late-onset withdrawal  2-4 wks of age with or without previous symptoms  Similar to early withdrawal symptoms  Voracious appetite, poor wt. gain for (8-16wks) Cont.

2. Systemic hypertension At 2 wks of age  continue  12 wks 3. Child abuse and sudden infant death syndrome Thermal burns, cigarette burns, traumatic ecchymosis in first 8 months and 8% ↑incidence of SIDS Cont.

4. Growth and psychomotor development  At 12 m. of age  not differ from others  At 3-6 y of age  retardation in Ht, wt, HC  Neurologic abnormality, poor fine and gross motor coordination, balance problem, delayed language development  Otitis media, abnormal eye movement. Cont.

At preschool age ↓ perception, ↓ short term memory, ↓ organization, behavioral abnormality, aggressiveness, hyperactivity, socioeconomic problem, poor school performance, no difference in IQ test. 5. Breast feeding - D/C if the mother has been abused drug continuously - If she is HIV positive 6. Maternal support

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