Antidepressiva & misdannelser! Lars Henning Pedersen Adjunkt, læge, ph.d. Afd. GynObs, Klinisk Institut Aarhus universitet

Transkript

1 Antidepressiva & misdannelser! Lars Henning Pedersen Adjunkt, læge, ph.d. Afd. GynObs, Klinisk Institut Aarhus universitet

2 Er antidepressiva teratogene? 1. Biologi! 2. Epidemiologi! 3. Klinik!! (1+2+3= 30 min)!

3 To ekstremer: 1.!

4 To ekstremer: 2.! [ ] overall there is no increase in the rates of major malformations in infants exposed to selective serotonin reuptake inhibitor (SSRI) antidepressants and other antidepressants during pregnancy.! Einarson et al, J Popul Ther Clin Pharmacol 2011!

5 Biologi

6 BIOLOGI Serotonin har embryologisk betydning: These data indicate a role of 5-HT and 5-HTT on heart development. Abnormal 5-HT level or misuse of 5-HT uptake blocker may alter the heart development.! Sari & Zhou, Int J Dev Neurosc, 2003!!

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8 BIOLOGI Serotonergic Signaling in LR Asymmetry Ændringer i serotonin homeostasen -> heterotaxi symmetric Gene Expression Is Randomized in Xenopus by Inhibition of 5-HT Signaling through R3 or R4 were exposed to blockers of R3 or R4 during early stages and processed for in situ hybridization with the laterality markers XNR-1. Embryos exposed to vehicle only (controls) exhibited the normal left-sided pattern of XNR-1 (A) expression. In contrast, embryos he activity of MAO, R3, or R4 was inhibited exhibited bilateral (C), right-sided (D), or absent (E) expression of XNR-1 in addition to ed expression (B). This effect was statistically significant (see numerical data and analysis in Table S9). Red arrows indicate regions ion; white arrows indicate lack of expression. Fukumoto et al, Curr Biol (2005)! 5). These results indicate that the right ventral mercially available serotonin antibodies did not in fact ere, or its descendants, is most sensitive to distinguish among serotonin and closely related mole- ulation of serotonergic signaling and that cules such as precursors and metabolites of serotonin.

9 [43]. Regulation of outflow tract extension is provided at least in part by signals from neural crest cells (NCC) [44]. Cardiac NCC are derived from neuroepithelial cells in the hindbrain that migrate through caudal pharyngeal arches in close proximity to the SHF. Eventually, NCC populate the aorticopulmonary septum that divides the outflow tract into the aortic and pulmonary channels [45 47]. As NCC pass in proximity to the SHF, they regulate proliferation of these cells through FGF8 signaling [44]. If NCC are Crista neuralis celler migrerer til outflow tract BIOLOGI f 5-HT is s occursmitter r organs iac procted by s of the left ven- 1]. (The ed from signalts, such riety of entricule outlet s (TGA), ar valve on trunrevious d to the tion and n PITX2 lts proffecting and isoich were y play a the outlls in the lanchnic onsible through of this -related lmonary the SHF uting to Fig. 3. Drawing of a 28 day (postfertilization) embryo showing the location of the secondary heart field (SHF), which lies in splanchnic mesoderm ventral to the floor of the pharynx. The SHF contributes cells that lengthen the outflow tract and these (Sadler, Repro Tox, 2011)! Kirby, Science, 1983!

10 BIOLOGI Sadler s konklusion ese target tissues. Birth defects VSD, DORV, TGA, l-tga, ASD ventricular inversion dextrocardia Dextrocardia ight l and VSD, mitral and tricuspid valve defects (mitral insufficiency tricuspid atresia); positioning and leaflet defects Tetralogy of Fallot TGA, Pulmonary atresia and stenosis hions Common truncus arteriosus and other outflow tract defects at Anomalous right pulmonary artery; IAA Type B or genetic abnormalities. Sadler, Repro Tox, 2011!

11 BIOLOGI Depression har embryologisk betydning: Alkohol!!Malm 2011 (ObGyn): 10 gange øget forekomst af!alkohol skader hos SSRI behandlede!!! Misdannelser:!!(alkohol spektrum)!!septale hjertemisdannelser!

12 BIOLOGI Depression har embryologisk betydning (forts.) Kost, (f.eks.)!!!folat & neuralrørsdefekter!!(medical Research Council Vitamin Study, Lancet 1991)!! HPA-aksen (?)!

13 BIOLOGI Sertraline! Paroxetine! Fluoxetine! Citalopram!

14 Epidemiologi

15 EPIDEMIOLOGI SSRI- før og efter 2005 Paroxetin! Källen & Olausson 2007!

16 EPIDEMIOLOGI Paroxetin septale og RVOT (NEJM 2007)! ObGyn 2011!

17 PAROXETINE AND CARDIAC DEFECT META-AN on adjustment of t abstraction; therefo maternal age and a confounders (metaother individual con Paroxetine and Fourteen cohort included in this an from the studies r above the null (Tab the forest plot (Fig trated in the above Casper et al., 2003; studies were relativ inverse-variance we and Otterblad, 200 et al., 2008 studies tively high weights. Table 1 presents t the funnel plot sym sented) and homog metry was not evid Mazumdar s test (p (p 5 0.2). Duval an imputed two hypot

18 EPIDEMIOLOGI Kontroverser: Scialli: The scientific evidence [ ] does not support the conclusion that paroxetine causes cardiovascular defects!! Berard: [ ] evidence-based literature shows consistent epidemiologic evidence that paroxetine use during pregnancy increases the risk of cardiac malformations in newborns!! Birth Def Res (Part A) 88 (2010)!

19 EPIDEMIOLOGI Rodet billede for de øvrige SSRI Scandinavien! Nordeng 2012! Malm 2011! Källen! Kornum 2010! Pedersen 2009! Amerika! Colvin 2011! Louik 2007! Alwan 2007! Motherrisk! Oberlander!

20 EPIDEMIOLOGI Oversigt (?) Review Obstetrics TABLE Summary of fetal outcome studies on selective serotonin reuptake inhibitors selective serotonin norepinephrine reuptake inhibitors 9,10,13,14,15-43 Negative studies that show no malformation risks (n) Positive studies that show malformation risk (n) Malformation Paroxetine (15) Paroxetine (8) Congenital anomalies (general)... Fluoxetine (12)... Citalopram (9) Cardiovascular gastroschisis anencephaly... Sertraline (8)... Fluvoxamine (7) Sertraline (2) Anencephaly, cardiovascular... Escitalopram (4) Fluoxetine (3) Cardiac, general... Venlafaxine (2) Selective serotonin reuptake Cardiovascular, craniosynostosis inhibitors in general (6)... Citalopram (3) Cardiovascular, neural tube defects... Koren. Antidepressant use during pregnancy and lactation. Am J Obstet Gynecol the date that the an pensed to calculate t may introduce an e studies. Women with dep have a 2- to 3-fold having ultrasound diograms than he therefore a much hi detection of cardiac are the most comm formations. Moreo pression and anxi more likely than h tend emergency de infants, where ped more opportunity t mur and be able to f source of ascertain augmented by the news that SSRIs ca which facilitates mo

21 EPIDEMIOLOGI Hjertemisdannelser Fluoxetin, sertralin og citalopram er alle fundet associeret med hjertemisdannelser i nogle studer!! Fluoxetin, sertralin og citalopram er alle ikke fundet associeret med hjertemisdannelser i nogle studer!!

22 EPIDEMIOLOGI Eksempel, Malm et al 2011 Fluoxetine : VSD (adjusted OR 2.03, 95% CI ) Citalopram: neuralrørs defekter (adjusted OR 2.46, 95% CI ). Paroxetine: Right ventricular outflow tract defects (adjusted OR 4.68, 95% CI ) 316 Fetal Cardiology (a) Figure Major aortopulmonary collateral artery in pulmonary atresia with

23 EPIDEMIOLOGI Eksempel, Sertralin Alwan 2007:!!Anencephali, craniosynostose og!omphalocele, OR=2.0 ( )! Louik 2007:!!Omphalocele, OR=5.7 ( )!!Septale, OR=2.0 ( )! Danske studier (Kornum 2010, Pedersen 2009):!!Septale OR>2!

24 EPIDEMIOLOGI Echocardiografi, Merlob 2009 Nonsyndromic congenital heart defects were identified by echocardiography in 8 of 235 (3.40%) newborns exposed in utero to SSRIs and in 1083 of 67,636 (1.60%) non-exposed newborns.!! paroxetin > fluoxetin!

25 EPIDEMIOLOGI QT-interval, Dubnow-Raz 2008 What This Study Adds! The mean QTc was significantly longer in the group of newborns exposed to SSRI antidepressants as compared with control subjects. Ten percent of SSRI-exposed newborns had a markedly prolonged QTc interval (>460 milliseconds) compared with none of the unexposed newborns. The longest QTc interval observed was 543 milliseconds.!!

26 EPIDEMIOLOGI Dosis? Gestational exposure to paroxetine is associated with major congenital malformations and major cardiac malformations for only first trimester exposure above 25 mg/day Berard et al, Birth Defects Research (Part B) 2007 Pedersen et al (BMJ 2009): >1 type SSRI Ingen sammenhæng: Oberlander et al (Birth Def Res 2008) Diav-Citrin et al (BJCP 2008)

27 EPIDEMIOLOGI Neuralrørsdefekter Malm 2011 (citalopram) aor=2.46 ( ) Alwan 2007* (alle SSRI/ sertralin) aor=2.4 ( )? Føtal ultralyd (*Citalopram, N=7)

28 EPIDEMIOLOGI Andre præparater Tricykliske:! Reis & Källen 2010: VSD OR 1.8 ( )! (Clomipramin)!! Venlafaxin:! Mindre styrke end for SSRI, ikke associationer!! Mirtazapin, duloxetin etc.:! Begrænset styrke!

29 EPIDEMIOLOGI Pladen fuld af fejlkilder: Eksponeringsmisklassifikation!! Confounding! by indication (Jimenez Solem 2012)!! Informations bias (diagnose)! Selektions bias (aborter etc.)!

30 Smith GC, Pell JP. Parachute use to prevent death and major trauma! related to gravitational challenge: systematic review of randomised controlled trials.! BMJ 2003;327(7429): !!

31 Klinik

32 KLINIK Worst- og best case kan føre til samme konklusion Worst case:! Klasse effekt pga. 5- HTT effekt! Effekt < RR 3! Absolut risiko < 3%! Best case:! Ingen effekt (RR=1.0)! (paroxetin)! Fortsat tvivl!

33 KLINIK Klinisk betydning In postnatal series, the prognosis for isolated VSDs is extremely favorable, with a high rate of spontaneous closure (up to 90% of cases, if the smallest muscular defects are included) and normal life expectancy both for untreated nonrestrictive VSDs and for large ones if operated!! Ultrasound of Congenital Abnormalities Paladini & Volpe. 2007!

34 KLINIK Hvad betyder OR=3 for den enkelte? 1. Begrænset klinisk betydning! men! 2. Det kan tolkes som en generel cardiotoksisk effekt! -> Absolut risiko sv.t. prægestationel diabetes!!

35 KLINIK Føtal ultralyd

36 KLINIK Er præparaterne lige sikre? A commonly asked question is whether any particular SSRI-SNRI is safer than the other when it comes to fetal risk. Presently, there is no compelling evidence for any of these drugs to be more or less safe. As a rule of thumb, medications that have been in use for longer periods (eg, fluoxetine) have larger series and longer experience and may be preferred by some physicians for that reason.! Koren & Nordeng, AJOG 2012!

37 KLINIK Præparaterne ikke klinisk lige anvendelige Paroxetin må frarådes! Farmakokinetik, struktur eller bias?! Førstevalg???!!

38 KLINIK Konklusion mht. misdannelser Biologi: antidepressiva eller depression! Epidemiologi:!! tvivl om sikkerheden, men! vi har god evidens for den (begrænsede) risiko i det værst tænkelige scenario! Vi er trygge ved at diabetikkere bliver gravide, men tilbyder ekstra svangre kontrol. Tilsvarende kan depressive gravide (i medicinsk behandling) tilbydes ekstra prænatal diagnostik.!

39 Tak Det Frie Forskningsråd: Sundhed og Sygdom!! Royal Prince Alfred Hospital, Sydney!! Jørn Olsen, Tine Brink Henriksen, Jannie Dalby Salvig, Jon Hyett, Olav Bjørn Petersen, Poul Videbech.!