Forbrug af afhængighedsskabende medicin under graviditet og risiko for barnet

Forbrug af afhængighedsskabende medicin under graviditet og risiko for barnet Årsmøde for de regionale familieambulatorier 6. november 2014 Hindsgavl Slot, Middelfart Ebba Holme Hansen Professor Institut for Farmaci Københavns Universitet ebba.holme@sund.ku.dk

Agenda Hvorfor vigtigt at kende til medicin og bivirkninger hos det ufødte og nyfødte barn? Hvad er afhængighed? Medicin der kan give afhængighed Forbrug af medicin under graviditet Bivirkninger ved medicin hos det ufødte og nyfødte barn Afrunding Dias 2

Dias 3 Ebba Holme Hansen 6/11-2014

Dias 4 Ebba Holme Hansen 6/11-2014

Dias 5 Ebba Holme Hansen 6/11-2014

Talidomidkatastrofen 1957 ff Talidomidblev markedsført først mod forkølelse, derefter morgenkvalme hos gravide. Mere end 10.000 alvorligt misdannede børn blev født i mange lande. Dias 6

Den forsinkede evidensudvikling -Hvornår ved vi, at medicin er afhængighedsskabende?

Mrs. Winslow's Soothing Syrup was an indispensable aid to mothers and child-care workers. Containing 65 mg of morphine per 30ml, it effectively quieted restless infants and small children. completely harmless Dias 8

Dias 9 Ebba Holme Hansen 6/11-2014

Cocaine Toothache Drops (1885) Dias 10

Den fundamentale behandling af angst Dias 14

RISIKO FOR AFHÆNGIGHED VED BENZODIAZEPIN- BEHANDLING probably less than one case per 50 million patient months (John Marks, 1978)

Selvrapporteret sammenhæng mellem brug af beroligende midler og vanedannelse (73 patienter i almen praksis i %) Problemer med at ophøre med medicinering Ingen problemer 52 Savnede medicinen de første dage 18 Meget svært ved at ophøre 30 I alt 100

Kendt dansk psykiater: Ebba, du ved jo godt, at man ikke kan stole på, hvad patienterne siger Dias 17

Benzodiazepinbivirkninger, forsigtighedsregler o.l. (Kilde: Lægeforeningens Medicinfortegnelse, 1963 f.f.) 1963-1975 + En vis risiko for toleransforøgelse, tilvænning og abstinenssymptomer + Risiko for respirationsdepression + Alkohol kan potensere + Virker relativt stærkt på ældre 1977 + Obs: Trafikfarlige stoffer 1981 + Svimmelhed, døsighed og træthed 1983 + Amnesi + Flebotoksicitet(i.v.adm.) + Forsigtighed sidst i graviditet - 1996 + Ataksi + Konfusion + Paradokse reaktioner, specielt hos børn og ældre + Amning: Bør kun gives på tvingende indikation + Blodtryksfald - 2004 + Samme som 1996, men udvidet og skærpede formuleringer

Definition of dependence in DSM and ICD Manifestation criteria Time criteria Number of manifestations required ICD-10 (1992) Tolerance, withdrawal symptoms, preoccupation with drug use, compulsion to take the drug, uncontrolled use, persistent use despite problems One month or if less than a month then manifestations should have occurred together repeatedly within a 12-month period Three or more of the manifestations DSM-IV (1994) Tolerance, withdrawal symptoms, much time spent to obtainthe drug, not able to cut down use, uncontrolled use, continued use despite problems, normal activities are given up Manifestations occur at any time in the same 12- month period Three or more of the manifestations Dias 19

Kontrovers: Afhængighed vs Seponeringssymptomer Dias 20

Udvalgte seponeringssymptomer(nielsen et al. Addiction 2011) Sleep Benzodiazepines Sleep disturbance Nightmares SSRIs Sleep disturbance Nightmares,vivid dreaming Balance Ataxia Dizziness Lightheadedness Vertigo Ataxia Dizziness Lightheadedness Vertigo Dias 21

Benzodiazepines Affective Agitation Aggression Irritability, restlessness Mental tension Anxiety, panic attacks, agoraphobia, dysphoria Depressed mood, depression Nervousness Derealization, perceptual disturbance,paranoid reaction, delirium Confusion Poor concentration Poor memory SSRIs Agitation Aggression, anger Irritability Feeling tense Anxiety, sudden panic Low mood, emotional lability, depression Nervousness Detachment Confusion Decreased concentration, slowed thinking Memory problems, amnesia Bouts of crying Dias 22

Criteria for substance withdrawal (DSM-IV) (A)The development of a substance-specific syndrome due to the cessation of (or reduction in) substance use that has been heavy and prolonged (B)The substance-specific syndrome causes clinically significant distress or impairment in social, occupational or other important areas of functioning (C)The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder Dias 23

Lægemiddelgrupper - WHO terminologi Opioider N02A Beroligende N05BA Sovemedicin N05CD Benzodiazepiner BZD Antidepressiva N06AB SSRI Psykostimulantia N06B Dias 24

Hvad fortæller litteraturen om forbrug af afhængighedsskabende medicin blandt gravide danske kvinder? Meget lidt! Foruroligende lidt! Dias 25

Metoder til undersøgelse af medicinforbrug under graviditet Spørgeskemaer Analyse af patientjournaler Registerstudier Danmark har unikke muligheder for kobling af registeroplysninger på individniveau via CPR Lægemiddelstatistikregisteret Medicinsk fødselsstatistikregister Landspatientregisteret Sociale registre Dias 26

Niels H. Jørgensen 2010 (upubliceret) Kandidatspeciale i samfundsfarmaci, Københavns Universitet Gravides medicinforbrug Jimenez-SolemE, Andersen JT, Petersen M, BroedbaekK, Andersen NL, et al. Prevalence of antidepressant use during pregnancy in Denmark, a nation-wide cohort study. PLoSONE 2013;8(4): e63034. Registerstudie baseret på Fertilitetsdatabasen Lægemiddeldatabasen Koblet på individniveau 523.742/1.279.840 gravide kvinder 1997-2005/2010 Dias 27

Andel af gravide der fik receptmedicin 1997-2005 % 0,9 0,8 0,7 0,6 Smertemedicin 0,5 N02A - Opioider 0,4 N02B - "svage" smertestillende 0,3 0,2 0,1 0 0 1 2 3 4 Trimester

% Andel af gravide der fik receptmedicin 1997-2005 1,40 1,20 1,00 Psykofarmaka 0,80 0,60 N05A - Antipsykotisk N05B -"Beroligende" N05C - Sovemedicin N06A - Antidepressiva N06B - Psykostimulantia 0,40 0,20 0,00 0 1 2 3 4 Semester

Point prevalence of pregnant women in treatment with an antidepressant based on estimated treatment periods Dias 30

Litteraturen om risici for det ufødte og nyfødte barn Lidt Opioider Noget Benzodiazepiner o.l. Meget Antidepressiva Meget lidt - Psykostimulantia Præget af uoverensstemmelser og mangel på konsistens Dias 31

Metoder til undersøgelse af risici ved medicinbehandling under graviditet Kliniske afprøvninger Case kontrol Recept monitorering Case rapporter Bivirkningsdatabaser Dias 32

RISICI VED BRUG AF MEDICIN FOR CENTRALNERVESYSTEMET UNDER GRAVIDITET Reference: KällénB, Borg N, Reis M. The Use of Central Nervous System Active Drugs During Pregnancy. Pharmaceuticals 2013;6:1221-1286 Dias 33

Brug af opioider- risici Tidligt i graviditeten Klumpfod, specielt ved tramadol 2. -3. trimester Svangerskabsforgiftning Placentaafstødning (ikke for kodein) Blødninger omkring fødselstidspunkt Igangsættelse af fødsel For tidlig fødsel Barnet/stort for svangerskabstidspunkt Neonatale diagnoser Respiratorisk diagnose Hypoglykæmi CNS diagnose Lav 5 min. Apgarscore Dias 34

Brug af Benzodiazepiner- risici Tidligt i graviditeten Generelt: ingen evidens for teratogene risici Øget risiko for forsnævret maveport Alprazolam: risiko for hjertedefekter 2.-3. trimester Svangerskabsforgiftning Blødninger omkring fødselstidspunkt Igangsættelse af fødsel For tidlig fødsel Lav fødselsvægt Lille for svangerskabstidspunkt Neonatale diagnoser - Respirationsproblemer - Hypoglykæmi - CNS diagnoser - Lav 5 min. Apgarscore Abstinenser/seponeringssymptomer(NAS) Floppy baby syndrom Dias 35

Brug af psykostimulantia- risici NB: Misbrug (amfetamin, dexamfetamin, metylfenidat) Tidligt i graviditeten Svage tegn på kardiovaskulæremisdannelser v. psykostimulantia Svage tegn på øget neonatal sygelighed v. psykostimulantia(få data) 2.-3. trimester Case rapporter: For tidlig fødsel Lav fødselsvægt Børn små for tidspunkt i graviditet Dias 36

Brug af antidepressiva(ssri) - risici Tidligt i graviditeten Medfødte misdannelser lav eller ingen risiko (NB paroxetin defekt hjerteskillevæg) Bør undgås ved planlagt graviditet. Ikke tilstrækkelig grund til at afbryde graviditet 2. -3. trimester For tidlig fødsel Lav fødselsvægt Abstinenser Klynken, gråd mv. Neonatale diagnoser Respirationsproblemer Hypoglykæmi Lav Apgar score CNS diagnoser Vedvarende hypertension(sjælden) Dias 37 Øget behov for intensiv behandling

Jimenez-SolemE. Exposure to antidepressants during pregnancy prevalences and outcomes. Dan Med J 2014 Sep;61(9):B4916. The overall conclusion is that antidepressants are not associated with increased risks of congenital malformations and perinatal mortality. We cannot rule out a possible causal relation, and treatment must therefore be based on an individual assessment of each woman analysing possible risks versus possible benefit. Dias 38

Seponeringssymptomer antidepressiva Generelle Mave-tarm Søvnrelaterede Balancerelaterede Bevægelsesrelaterede Følelsesrelaterede Psykose Dias 39

Paradoks Bør ikke anvendes til behandling af børn og unge under 18 år Store mængder data fra gravide kvinder indikerer ingen toksicitet malformationer bør dog ikke anvendes under graviditet, medmindre det er yderst nødvendigt efter overvejelser af benefit/risk forholdet Dias 40

Risiko for barn Risiko for mor

Risiko for barn Risiko for mor

I RATIONEL KLINIK: Den randomiserede, kontrollerede kliniske undersøgelse er den gyldne standard ved test af lægemiddelterapi MEN Viden om nye bivirkninger fås fra case rapporter, herunder bivirkningsdatabaser (Aagaard & Hansen BMC ClinicalPharmacology 2009, 9:4) Dias 43

Aagaard L, Hansen EH. Adverse drug reactions from psychotropic medicines in the paediatric population: analysis of reports to the Danish Medicines Agency over a decade. BMC Research Notes 2010;3:176.

Setting and methods Data from the Danish ADR database in the Danish Medicines Agency (DKMA) containing all spontaneous reports from physicians, pharmaceutical companies, pharmacists, other health care professionals, consumers and lawyers Children aged 0-17 (up to 18) years 1998 to 2007 Medications belonging to ATC groups N05 (N05A, N05B, N05C) & N06 (N06A, N06B) WHO terminology Adverse reactions classified by System Organ Class (SOC) MedDRA terminology Dias 45

ADRs for psychotropic medines 1997-2006 by age and gender Number of ADRs 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Age Dias 46 Girls Boys

Number of adverse drug reactions reported for psychotropic medication in the paediatric population by age and seriousness (in italic) (1998 to 2007) contd. Age groups (years) <1 1<2 2-10 11<17 Total HYPNOTICS AND SEDATIVES (N05B/N05C) Diazepam 1(1) 0 0 0 1(1) Oxazepam 3(3) 0 0 0 3(3) Buspirone 1(1) 0 0 0 1(1) Chloral hydrate 0 0 3(3) 0 3(3) Midazolam 0 0 1(1) 2(2) 3(3) Total 5(5) 0 4(4) 2(2) 11(11)

Number of adverse drug reactions reported for psychotropic medication in the paediatric population by age and seriousness (in italic) (1998 to 2007) contd. Age groups (years) <1 1<2 2-10 11<17 Total ANTIDEPRESSANTS (N06A) Ebba Holme Hansen 6/11-2014 Imipramine 0 0 1(1) 0 1(1) Clomipramine 1(1) 0 0 0 1(1) Amitriptyline 2(2) 0 0 0 2(2) Fluoxetine 14(14) 0 0 1(1) 15(15) Citalopram 17(17) 4(4) 5(2) 10(6) 36(29) Paroxetine 5(4) 0 0 6(2) 11(6) Sertralin 11(11) 0 9(3) 25(20) 45(34) Escitalopram 1(1) 1(1) 0 0 2(2) Oxitriptan 0 0 0 3 3 Mirtazapin 1(1) 0 0 12(8) 13(9) Venlafaxin 1(1) 0 0 3 4(1) Total 53(52) 5(5) 15(6) 60(37) 133(100)

Number of adverse drug reactions reported for psychotropic medication in the paediatric population by age and seriousness (in italic) (1998 to 2007) contd. Age groups (years) <1 1<2 2-10 11<17 Total PSYCHOSTIMULANTS (N06B) Methylphenidate 0 0 85(35) 44(17) 129(52) Modafinil 0 0 0 7(7) 7(7) Atomoxetine 0 0 23(7) 20(11) 43(18) Total 0 0 108(42) 71(35) 179(77) Total N05 and N06 70(69) 10(10) 135(53) 214(109) 429(241)

Serious ADRs from psychotropic medicines reported for children below two years of age (1998 to 2007) ATC Medicines Adverse drug reaction No Indication of use Age of child N05A Levopromazine Priapism 1 Headache 0 Olanzapine Atrial septal defects 1 NA 1 Risperidon Blood glucose decreased 1 Schizophrenia 0 Convulsion 1 NA 0 Decreased appetite 1 Schizophrenia 0 Drug exposure during pregnancy 1 NA* 0 Failure to thrive 1 Schizophrenia 0 Feeding disorder, neonatal 1 Schizophrenia 0 Haemoglobin increased 1 NA 1 Hypoxia 1 NA 0 Pneumonia 1 NA 1 Polycythaemia 1 NA 1 Somnolence 1 Schizophrenia 0 Tension 1 NA 1 Drug withdrawal syndrome, neonatal Ebba Holme Hansen 6/11-2014 1 Depression 0 Sulpirid Agitation, neonatal 1 Depression 0 Zuclopemthixol Supraventricular tachycardia 1 Schizophrenia 0 N05B Buspirone Ventricular septal defect 1 Depression 0 Diazepam Apnoea 1 Convulsions 0

Serious ADRs from psychotropic medicines reported for children below two years of age (1998 to 2007) (contd.) ATC Medicines Adverse drug reaction No Indication of use Age of child Oxazepam Congenital acrochordon 1 Anxiety depression 0 Chondropathy 1 Anxiety depression 0 Drug exposure during pregnancy 1 Anxiety depression 0 N06A Amitriptyline Epilepsy 1 Depression 0 Febrile convulsion 1 Depression 0 Clomipramine Psychomotor retardation 1 NA 0 Citalopram Tremor, neonatal 3 Panic disorder 1 Drug withdrawal syndrome, neonatal 2 Depression/Panic disorder Hypotonia, neonatal 2 Depression 0 0/1 Irritability 2 Panic disorder 0/1 Apnoea 1 NA* 0 Asthenia 1 NA 0 Chorioamnionitis 1 Depression 0 Convulsion, neonatal 1 Depression 0 Hypertonia 1 Panic disorder 1 Hypocalcaemia 1 Depression 0 Neonatal asphyxia 1 Depression 0 Neonatal respiratory depression Ebba Holme Hansen 6/11-2014 1 NA* 0

Serious ADRs from psychotropic medicines reported for children below two years of age (1998 to 2007) (contd.) ATC Medicines Adverse drug reaction No Indication of use Age of child Oral candidiasis 1 Depression 0 Pallor 1 NA* 0 Premature labour 1 Depression 0 Ventricular septal defect 1 Depression 0 Escitalopram Atrial septal defect 1 NA 1 Fluoxetine Drug exposure during pregnancy 1 NA* 0 Drug withdrawal syndrome, neonatal Ebba Holme Hansen 6/11-2014 3 Depression 0 Tremor 2 Depression 0 Agitation, neonatal 1 Depression 0 Bradycardia, neonatal 1 Depression 0 Deafness neurosensory 1 NA 0 Drug exposure during pregnancy 1 NA* 0 Dyskinesia, neonatal 1 Depression 0 Feeding disorder, neonatal 1 Depression 0 Hypertonia, neonatal 1 Depression 0 Neonatal disorder 1 Depression 0 Persistent foetal circulation 1 Depression 0 Upper limb deformity 1 Depression 0

Serious ADRs from psychotropic medicines reported for children below two years of age (1998 to 2007) (contd.) Ebba Holme Hansen 6/11-2014 ATC Medicines Adverse drug reaction No Indication of use Age of child Paroxetine Klinefelter s syndrome 1 NA 0 Neonatal respiratory failure 1 NA* 0 Psychomotor retardation 1 NA 0 Sertraline Respiration abnormal 2 Depression 0 Cerebral palsy 1 Depression 0 Circulatory collapse 1 Depression 0 Cyanosis 1 Depression 0 Drug withdrawal syndrome, neonatal Drug exposure during pregnancy 1 Depression 0 1 Depression 0 Muscle spasms 1 Anxiety 0 Myoclonus 1 Anxiety 0 Persistent foetal circulation 1 Depression 0 Pulmonary hypertension 1 Depression 0 Mirtazapine Cerebral palsy 1 Depression 0 Venlafaxine Agitation, neonatal 1 Depression 0 *Indication for use not listed, but recorded as Maternal drugs affecting foetus ; NA:not available

Active substances w. serious ADRs reported 1998-2007 but not mentioned in SPCs 2009 ATC group Active substance N05A Antipsychotics N05B Sedatives Ziprasidone Quetiapine Olanzapine Risperidone Oxazepam Buspirone Dias 54

Active substances w. serious ADRs not in SPC info N06A Antidepressants Amitriptyline Citalopram Escitalopram Fluoxetin Mirtazapine Paroxetine Sertraline N06B - Dias 55

Conclusions excerpts: More than one half of ADRs from psychotropic medicines were serious ADRs in infants were due to medicine use during pregnancy Several serious ADRs did not appear in the Product Information (SPC) Prescribing physicians should be warned about health hazards for off-springs related to the prescribing of psychotropic medicines for pregnant women. Dias 56

Læge/ medicinudskrivelse Mor og far Sundhedsvæsenet iøvrigt Politikere Myndigheder/ Sundhedsstyrelsen Producenter Medier

Therapeutic drugs in pregnancy: Caution is the watchword Dias 58 Tak for opmærksomheden