6 Slide 4The 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.
10 pathogenese direct toxische effecten van alcohol toxische effecten of acetaldehydeplacentaire dysfunctie? IUGRprostaglandin synthesisapotosis (‘geprogrammeerde celdood)Slide 9How 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)
11 Slide 7FAS 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.
12 Klinische tekens van FAS Groei prenatale groeirestrictie 94postnatale groeirestrictie 96CZS microcefalie 94ontwikkelingsvertraging 89Faciaal epicanthus plooi 52midfaciale hypoplasie 65kort, naar boven gekanteld neusje 75hypoplasie philtrum 91smalle bovenlip 90Cardiaal cardiopathie 48Varia gehoorsproblematiek (cond + neuro)oorschelp/gehoorgang afwijkingen 23n opticus hypoplasie 76Naar Volpe, Neurology of the Newborn
15 Zilverkleuring weergave apoptose activiteit CZS controle vs 24 h na ethanol
16 Microcefalie Majeure neuropathologische presentaties van FAS Migratiestoornissen (neuronaal > gliale)Midline prosencephalie afwijkingen,agenesis corpus callosumsepto-optische dysplasieholoprosencephalyNeurale buis defecten
17 verstoorde slaap-waak ritmes ‘excessive arousal’ voedingsproblemen zuigelingverstoorde slaap-waak ritmes‘excessive arousal’voedingsproblemenfailure to thrive (groeipotentieel)schoolgaand kindhyperactiviteitaandachtsstoornisenmentale retardatievolwassenenmentale problemengedragsproblematiekgeheugenproblematiekSlide 16Hyperactivity may be found in up to 80% of children. Mental retardation occur in about half of FAS patients(IQ less than 60).
18 alcoholeffecten op hersenontwikkelingeffecten extra-CNSgedragsproblematiekopioidsneonatale abstinentie problematiekSSRI’s (anti-epileptica)peripartale effecten van SSRI’s
19 A generalized disorder characterized by central nervous system hyper-irritability,gastro-intestinal dysfunction,respiratory distress andvague autonomic symptomssymptomen gerelateerd aanuitgebreidheidkarakteristiekencoccaine (XTC)methadone (opioid)heroine (opioid)
28 DetoxificationDetoxification 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 familystep 1 : stabilisationstep 2 : reduction
29 Continue Observation Scoring until discharge Scores > 12 then Score 2 hourlyScores remain > 12 for next 2 consecutive scoresStart Oral Morphine 4 hourly Starting Level : Level 4Scores Remain > 12 for next 2 consecutive scoresIncrease Morphine to next level ( i.e. Level 5 )Scores Stabilise < 12 = REDUCTIONScores < 12Continue Observation Scoring until discharge
30 Level 6: 60mcg / kg / dose 4 hourly Oral Morphine RegimeLevel 6: 60mcg / kg / dose 4 hourlyLevel 5: 5omcg / kg / dose 4 hourlyLevel 4: 40mcg / kg / dose 4 hourlyLevel 3: 30mcg / kg / dose 4 hourlyLevel 2: 20mcg / kg / dose 4 hourlyLevel 1: 10mcg / kg / dose 4 hourlyStarting Level = level 4
31 Stabilisation has been achieved when the infant is consolable, has rhythmic sleepand feed cycles, a steady weight gain andis clinically stable
32 DAS < 9 DAS > 9 Reduce to next level of Morphine NAS Infant on Morphine ReplacementCalculate Daily the Average ScoreDAS > 9Remain on same level of MorphineDAS < 9Reduce to next level of MorphineStop Medication after 24 h at level 1 Morphine if DAS < 9Observe for further 24 HoursScores Remain < 9
33 Duration of Morphine Therapy in days YearMaximumMinimumAverage95-964312.624.996-9744.421.232.897-9820.83.413.798-99184.37.899-0017.83.36.800-014.28.3** 3 babies excluded as incomplete data
43 alcoholeffecten op hersenontwikkelingeffecten extra-CNSgedragsproblematiekopioidsneonatale abstinentie problematiekSSRI’s (anti-epileptica)peripartale effecten van SSRI’s
44 TeratologyAround 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
45 Canada's leading teratology research and counseling program callers daily, open to publicEach week 10 to 20 women seen in clinic
47 Breastfeeding: case 2 Woman 34 yrs old, G1P1 History: major depression No Rx during pregnancyCouple of weeks after delivery Postnatal depression: Rx venlafaxine (Efexor)Breastfeeding compatible?te Winkel et al. Farmacotherapie bij kinderen, 2010, 25-27
48 Guideline for drug therapy during lactation Is drug therapy really necessary?Choose the safest drugRisk to infant possible?Consider blood levelsConsider monitoring childMinimize exposure by taking drug right after breastfeeding
49 Q2. Which parameter is best indicator for risk to baby? Milk:plasma ratioHalf-life of drug in motherRelative infant doseHalf-life of drug in child
50 M/P = milk/plasma ratio Di = Estimated infant dose Drugs in lactationDose(Dm)MilkInfants’plasmaDose (Di)TimeM/PConcentrationMothers’ plasmaM/P = milk/plasma ratioDi = Estimated infant doseConcentrationm x M/P x VolumemilkRID= relative infant dose = Dm (mg/kg/day ) / Di (mg/kg/day) *100%
51 Venlafaxine Drug info Maternal dose 75-225 mg/day Venlafaxine metabolized to (also active) O-desmethyl-venlafaxineRID (relative infant dose) = 5-7.5%Effect in neonate (n=21) :Serum levels (including metabolite): 1-15% of maternal levelsEffect on weight gain n=2No effects on sleep, behavior or neurodevelopment
52 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
53 More sources: Briggs: Refers to AAP guidelines Monitor for adverse eventsLactmed (toxnet.nlm.nih.gov )Drug found in plasma of infantNo proven drug-related effectMonitor for excessive sedation and adequate weight gainPossibly serum levels to rule out toxicity
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