ontwenningssyndromen bij de pasgeborene neonatal withdrawal syndrome neonatal abstinence syndrome karel allegaert UZ Leuven

illicit drug use during pregnancy 6.4 % overall 2.8 % during pregnancy opioids 90 % symptoms medical treatment SSRI’s

Definitie ? A generalized disorder characterized by central nervous system hyper-irritability, gastro-intestinal dysfunction, respiratory distress and vague autonomic symptoms Finnegan & Weiner (1993)

alcohol effecten op hersenontwikkeling effecten extra-CNS gedragsproblematiek opioids neonatale abstinentie problematiek SSRI’s peripartale effecten van SSRI’s

Slide 4 The discriminating features are considered definitive signs of FAS, while the associated signs are not sufficient to determine the presence of FAS. Microcephaly is not a facial feature but a central nervous system characteristic. It is important to note that it is not any one characteristic that makes the FAS facies distinctive, but rather the “gestalt” or the overall presentation of the facies.

pathogenese direct toxische effecten van alcohol toxische effecten of acetaldehyde placentaire dysfunctie ? IUGR prostaglandin synthesis apotosis (‘geprogrammeerde celdood) Slide 9 How does alcohol produce its teratogenic effects? The mechanism(s) for alcohol teratogenecity remains unknown. Several mechanisms have been proposed. Alcohol has a direct toxic effect on the fetus and exposure at critical periods of development results in varied presentations of FAS. First trimester exposure generally results in skeletal and visceral abnormalities, whereas exposure at later stages of brain development results in behavioral defects. Acetaldehyde is the first metabolite in alcohol metabolism and it rapidly crosses the placenta. It is thought to be more embryotoxic than alcohol. Changes in placental weight and morphology(e.g. Intervillous thrombi, villitis) have been observed in alcoholic women. These changes alter placental function, particularly transport function. Alcohol also causes umbilical vessels to collapse decreasing placental/fetal blood flow and hence hypoxia. Hypoxia has been implicated to induce growth retardation. Human placental enzyme CYP2E1 which is involved in alcohol metabolism has been shown to be variably induced by alcohol and may lead to increase in acetaldehyde production. Alcohol can increase prostaglandin synthesis which inhibits placental/fetal blood flow. Alcohol causes blockade of N-methyl-D-aspartate (NMDA) glutamate receptors and excessive activation of GABA-A receptors. This results in deliberate cell death or apoptosis. The fetus is most vulnerable during synaptogenesis (6 month gestation to several years after birth)

Slide 7 FAS does not represent all individuals exposed to alcohol in utero but represents those on the severe end of the spectrum of effects. Some individuals are unaffected while others may have partial expression of FAS referred to as Fetal Alcohol Effects(FAE). FAE is further subdivided into Alcohol Related Birth Defects(ARBD) which primarily presents with physical anomalies and Alcohol Related Neurodevelopmental disorder(ARND) which has more central nervous system damage.

Klinische tekens van FAS Groei prenatale groeirestrictie 94 postnatale groeirestrictie 96 CZS microcefalie 94 ontwikkelingsvertraging 89 Faciaal epicanthus plooi 52 midfaciale hypoplasie 65 kort, naar boven gekanteld neusje 75 hypoplasie philtrum 91 smalle bovenlip 90 Cardiaal cardiopathie 48 Varia gehoorsproblematiek (cond + neuro) 75 + 6 oorschelp/gehoorgang afwijkingen 23 n opticus hypoplasie 76 Naar Volpe, Neurology of the Newborn

Zilverkleuring weergave apoptose activiteit CZS controle vs 24 h na ethanol

Microcefalie Majeure neuropathologische presentaties van FAS Migratiestoornissen (neuronaal > gliale) Midline prosencephalie afwijkingen, agenesis corpus callosum septo-optische dysplasie holoprosencephaly Neurale buis defecten

verstoorde slaap-waak ritmes ‘excessive arousal’ voedingsproblemen zuigeling verstoorde slaap-waak ritmes ‘excessive arousal’ voedingsproblemen failure to thrive (groeipotentieel) schoolgaand kind hyperactiviteit aandachtsstoornisen mentale retardatie volwassenen mentale problemen gedragsproblematiek geheugenproblematiek Slide 16 Hyperactivity may be found in up to 80% of children. Mental retardation occur in about half of FAS patients(IQ less than 60).

alcohol effecten op hersenontwikkeling effecten extra-CNS gedragsproblematiek opioids neonatale abstinentie problematiek SSRI’s (anti-epileptica) peripartale effecten van SSRI’s

A generalized disorder characterized by central nervous system hyper-irritability, gastro-intestinal dysfunction, respiratory distress and vague autonomic symptoms symptomen gerelateerd aan uitgebreidheid karakteristieken coccaine (XTC) methadone (opioid) heroine (opioid)

heroine vs methadone

Accurate Observation + Assessment Supportive Care a. Environment of Care b. Therapeutic Handling c. Symptomatic Care Pharmacological Intervention

Finnegan score

Detoxification Detoxification should be undertaken with the maximum speed that can be tolerated by the infant, causing minimal distress to avoid prolonged hospitalisation and prolonged separation from family step 1 : stabilisation step 2 : reduction

Continue Observation Scoring until discharge Scores > 12 then Score 2 hourly Scores remain > 12 for next 2 consecutive scores Start Oral Morphine 4 hourly Starting Level : Level 4 Scores Remain > 12 for next 2 consecutive scores Increase Morphine to next level ( i.e. Level 5 ) Scores Stabilise < 12 = REDUCTION Scores < 12 Continue Observation Scoring until discharge

Level 6: 60mcg / kg / dose 4 hourly Oral Morphine Regime Level 6: 60mcg / kg / dose 4 hourly Level 5: 5omcg / kg / dose 4 hourly Level 4: 40mcg / kg / dose 4 hourly Level 3: 30mcg / kg / dose 4 hourly Level 2: 20mcg / kg / dose 4 hourly Level 1: 10mcg / kg / dose 4 hourly Starting Level = level 4

Stabilisation has been achieved when the infant is consolable, has rhythmic sleep and feed cycles, a steady weight gain and is clinically stable

DAS < 9 DAS > 9 Reduce to next level of Morphine NAS Infant on Morphine Replacement Calculate Daily the Average Score DAS > 9 Remain on same level of Morphine DAS < 9 Reduce to next level of Morphine Stop Medication after 24 h at level 1 Morphine if DAS < 9 Observe for further 24 Hours Scores Remain < 9

Duration of Morphine Therapy in days Year Maximum Minimum Average 95-96 43 12.6 24.9 96-97 44.4 21.2 32.8 97-98 20.8 3.4 13.7 98-99 18 4.3 7.8 99-00 17.8 3.3 6.8 00-01 4.2 8.3* * 3 babies excluded as incomplete data

opioide middelen ‘cold turkey’ timing ifv PK pathogenese = opioid receptor onbesproken maternele verslavingsproblematiek beschermende maatregelen andere peripartale medische problemen wiegendood risico screeningsmogelijkheden

alcohol effecten op hersenontwikkeling effecten extra-CNS gedragsproblematiek opioids neonatale abstinentie problematiek SSRI’s (anti-epileptica) peripartale effecten van SSRI’s

alcohol effecten op hersenontwikkeling effecten extra-CNS gedragsproblematiek opioids neonatale abstinentie problematiek SSRI’s (anti-epileptica) peripartale effecten van SSRI’s

Teratology Around 50% of all pregnancies in Western world are UNPLANNED ‘Baseline risk’ - in general population for major congenital malformation is 1-3% A teratogen is an agent that may have harmful effects on the developing fetus

Canada's leading teratology research and counseling program 150-200 callers daily, open to public Each week 10 to 20 women seen in clinic www.motherisk.org

The developing human

Breastfeeding: case 2 Woman 34 yrs old, G1P1 History: major depression No Rx during pregnancy Couple of weeks after delivery Postnatal depression: Rx venlafaxine (Efexor) Breastfeeding compatible? te Winkel et al. Farmacotherapie bij kinderen, 2010, 25-27

Guideline for drug therapy during lactation Is drug therapy really necessary? Choose the safest drug Risk to infant possible? Consider blood levels Consider monitoring child Minimize exposure by taking drug right after breastfeeding

Q2. Which parameter is best indicator for risk to baby? Milk:plasma ratio Half-life of drug in mother Relative infant dose Half-life of drug in child

M/P = milk/plasma ratio Di = Estimated infant dose Drugs in lactation Dose (Dm) Milk Infants’plasma Dose (Di) Time M/P Concentration Mothers’ plasma M/P = milk/plasma ratio Di = Estimated infant dose Concentrationm x M/P x Volumemilk RID= relative infant dose = Dm (mg/kg/day ) / Di (mg/kg/day) *100%

Venlafaxine Drug info Maternal dose 75-225 mg/day Venlafaxine metabolized to (also active) O-desmethyl-venlafaxine RID (relative infant dose) = 5-7.5% Effect in neonate (n=21) : Serum levels (including metabolite): 1-15% of maternal levels Effect on weight gain n=2 No effects on sleep, behavior or neurodevelopment

are all books equal? Farmacotherapeutisch kompas: Venlafaxine gaat over in de moedermelk. Tijdens gebruik geen borstvoeding geven. AAP (American Academy of Pediatrics: the effect on nursing infants is unknown but may be of concern

More sources: Briggs: Refers to AAP guidelines Monitor for adverse events Lactmed (toxnet.nlm.nih.gov ) Drug found in plasma of infant No proven drug-related effect Monitor for excessive sedation and adequate weight gain Possibly serum levels to rule out toxicity

Drugs and breastfeeding

Q2. Which parameter is best indicator for risk to baby? Milk:plasma ratio Half-life of drug in mother Relative infant dose Half-life of drug in child