Central Medical Journal of Obstetrics and Gynecology

Case Report *Corresponding authors Veronica Tucci, Section of Emergency Medicine, Baylor College of Medicine; Ben Taub General Hospital, Teratogenic Potential of 1504 Taub Loop, Houston, Texas 77030, USA, Email: Submitted: 16 July 2016 Commonly Prescribed Accepted: 17 Novemeber 2016 Published: 19 Novemeber 2016 Psychotropic Drugs ISSN: 2333-6439 Copyright Syed Moiz Ahmed1, Nidal Moukaddam2, Ameigh V. Worley3, © 2016 Tucci et al. 4 2 5 Krupa R. Patel , Asim Shah , and Veronica Tucci * OPEN ACCESS 1Emergency and Accident Centre, Pakistan Institute of Medical Sciences, Pakistan 2Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Keywords Medicine, USA • Psychotropic drugs 3Department of Obstetrics and Gynecology, Wake Forest University, USA • Teratogenicity 4Department of Pharmacy, Ben Taub General Hospital, USA • Major congenital malformations 5Section of Emergency Medicine, Baylor College of Medicine, USA • Cleft lip/palate

Abstract Increasing use of psychotropic medications during has highlighted the issue of teratogenic risks associated with these drugs. No drug has been deemed completely safe for use during pregnancy by the FDA as all of them have been shown to cross the ; however research has shown that different psychotropic drugs contribute variably towards the development of major congenital malformations in the fetus. Most of this risk is associated with the use of these drugs during the first trimester. In this case report we present a female patient whose fetus developed cleft lip and palate possibly due to the use of prescription medications for her psychiatric illness, and then review the literature regarding the teratogenic potential of the commonly prescribed psychotropic medications during pregnancy.

ABBREVIATIONS the teratogenic potential of commonly prescribed psychotropic medications. TID: Three Times a Day; SSRIS: Selective Serotonin Reuptake Inhibitors; FDA: Food and Drug Administration; TCAS: Tricyclic CASE PRESENTATION

1P0A0L0, presented to her Antidepressants; OR: Odds Ratio; CI: Confidence Interval; ACOG: obstetrician at 20 weeks of gestation for a well pregnancy check. A 21 year old Hispanic female G American College of Obstetrics and Gynecology; NTDs: Neural TubeINTRODUCTION Defects; CNS: Central Nervous System checkup. During a detailed history she mentions that she had beenShe hasdiagnosed poor social with bipolar support, disorder and this and was severe her anxiety first prenatal and has Increased morbidity has been reported from psychiatric been on Valproic acid 1000 mg at bedtime and Clonazepam 1 mg illnesses during the pregnant state in women [1], with prevalence TID. The obstetrician performed an anomaly scan and found that ranging from 15-29% [2-14]. To prevent any untoward effects the fetus has cleft lip and palate. The patient has no family history of these conditions on both pregnancy outcomes and the of congenital malformations, and she regularly took folic acid developing fetus, there has been increased use of psychotropic supplementation throughout her pregnancy. She does not use medications during pregnancy. It is estimated that about 3.5% any drugs of abuse. The obstetrician believes that the congenital of all women in the Western world use psychotropic medication malformation is as a result of her prescription medications. during pregnancy [15]. This has raised concerns about the The patient is informed of the congenital anomaly and the most teratogenic effects of these drugs, and the dilemmas that the probable cause for it. She has been referred to a psychiatrist for physicians face in weighing the risk between adverse effects from counselling. untreated psychiatric illness and the adverse effects resulting from the use of psychotropic medications in a pregnant patient. DISCUSSION In this case report, we will present a case in which congenital This scenario is a perfect example of what obstetricians malformation in the fetus is suspected due to the possible use of have to face on a regular basis. Most of the teratogenic damage psychotropic drugs, and discuss the current literature supporting

done by drugs is typically during the first trimester during Cite this article: Ahmed SM, Moukaddam N, Worley AV, Patel KR, Shah A, et al. (2016) Teratogenic Potential of Commonly Prescribed Psychotropic Drugs. Med J Obstet Gynecol 4(4): 1091. Tucci et al. (2016) Email: Central which organogenesis is taking place. So if a woman is already taking such medications at the time of conception, by the time Antidepressants are a class of psychotropic drugs which have already taken place, thereby increasing the risks of congenital been studied most extensively for their teratogenic potential. pregnancy is confirmed, most or all of the organ development has Selective serotonin reuptake inhibitors (SSRIs) are usually the potential of the commonly prescribed psychotropic drugs (Table associatedfirst line antidepressants with an increased used risk in of pregnancy congenital because malformations studies malformations. Here we will first discuss the teratogenic [19-29].show that, Paroxetine, with the exception on the otherof paroxetine, hand, has most been SSRIs shown are not to

1) andTraditionally, then in light the of that Food literature and Drug review Administration the present case. (FDA) 2.3cause million cardiac controls anomalies, with especially around atrial 4000 and neonates ventricular exposed septal to for causing birth defects (Table 2) [16]. More recently in 2014, defects [28,30-32]. In one meta-analysis comparing almost placed medications into five categories based on their potential system was too simplistic and abolished it under the Pregnancy paroxetine in utero, showed a significantly increased risk of however, the FDA determined that the five category classification 1.9) [33]. Another meta-analysis comparing 1.6 million controls and Lactation Labeling Final Rule (PLLR). The PLLR established cardiac malformations with an odds ratio of 1.5 (95% CI: 1.1- labeling requirements for the pregnancy and lactation sections for with 18,000 exposed neonates revealed similar results (RR 1.4, subsections for pregnancy exposure and risk, lactation, and 95% CI: 1.1-1.9) [34]. Therefore, while all SSRIs are classified as prescription drugs and biological agents and utilizes descriptive withcategory an increased C by FDA, risk paroxetine of congenital is classified malformations as category and D. cardiac Some Labeling changes from this rule begin on June 30, 2015 [18]. recent evidence also indicates that fluoxetine might be associated effects to reproductive potential for females and males [17]. defects [27], however the results are inconclusive. In light of the Manufacturers with drugs approved before June 30, 2001 are evidence, among SSRIs, sertraline and citalopram are usually the required to remove the within 3 years of the and safe for use during lactation as well [19]. Escitalopram and labeling requirements with respect to pregnancy and lactation in first line agents, as they have little or no teratogenic potential effective date of the final rule.We provide examples of the new pregnancy and are thus not prescribed routinely. FDA for Parkinson’s induced psychosis, whereas Aristada is an fluvoxamine are relatively studied less for their effects during atypicalBoxes 1 andantipsychotic 2. Nuplazid indicated is a medication for schizophrenia. recently approved by the

With regards to tricyclic antidepressants (TCAs), most Table 1

Drugs : Teratogenic effects of psychotropicBrand Name drugs.FDA Pregnancy Teratogenic Effects Category Anxiolytics and Hypnotics Benzodiazepines:

Diazepam especially oral clefts. Lorazepam Valium D Some studies have reported increased risk of major congenital malformations, Alprazolam D Chlordiazepoxide Xanax D Clonazepam LibriumAtivan D Clorazepate Klonopin D Estazolam Tranxene D Flurazepam Prosom X Oxazepam Dalmane X Quazepam Serax D Temazepam Doral X Triazolam Restoril X Halcion X Non-Benzodiazepines: Buspirone Chloral Hydrate Buspar Eszopiclone B Zaleplon Lunesta C Zolpidem Sonata C Ambien C No/limited human studies available. B No/limited human studies available. No/limited human studies available. Antiepileptics and Mood Stabilizers Tegretol D

Lamotrigine Lamictal C ClasicallySpina bifida, associated cleft palate, with hypospadias, Ebstein’s anomaly. and cardiac Other malformations. cardiac malformations include Lithium D coarctationIncreased risk of aortaof craniofacial and mitral defects, atresia. especially oral clefts. Associated with neural tube defects, cardiac defects, hypospadias, oral clefts, polydactyly, and craniosynostosis. Valproic Acid Depakene D

Med J Obstet Gynecol 4(4): 1091 (2016) 2/9 Tucci et al. (2016) Email: Central

Antidepressants Tricyclics and Heterocyclics: Most studies show no association between the use of TCAs during pregnancy and Amitriptyline structural anomalies in fetuses. Amoxapine C Clomipramine Asendin C Desipramine AnafranilElavil C Norpramin C Sinequan C Maprotiline Tofranil C NortriptylineImipramine Ludiomil B Protriptyline Pamelor C C Selective Serotonin Reuptake Inhibitors: Vivactil Citalopram malformation. Escitalopram Celexa Most of the SSRIs have been shown not to increase the risk of any major congenital Fluoxetine Lexapro C Little/no teratogenic potential. Prozac C C Paroxetine anomalies.Few human studies available. Fluvoxamine Paxil C Slightly increases the risk of major congenital malformations and cardiac Luvox D Sertraline Few human studies available. Zoloft Little/noHas been linkedteratogenic to increased potential. risk of cardiovascular malformations, especially atrial Others: C and ventricular septal defects. Bupropion Mirtazapine Slightly increases the risk of congenital defects. Nefazodone Remeron B Trazodone SerzoneWellbutrin C Venlafaxine Desyrel C No increased risk of major malformation has been reported. Effexor C No increased risk of major malformation has been reported. C No increased risk of major malformation has been reported. No increased risk of major malformation has been reported Antipsychotics Data from adequate and well controlled studies is limited. Typical: Chlorpromazine Thorazine C Most human studies show no increase in teratogenic risk. Fluphenazine Prolixin C Animal studies show teratogenic potential, but the limited human studies done

Haloperidol Haldol C show that it is relatively safe to use in pregnancy. Loxapine Loxitane C Phocomelia and aortic valve defects have been reported. Perphenazine Trilafon C Pimozide Orap C Thioridazine Mellaril C Thiothixene C Stelazine C Navane Atypical: Trifluoperazine Aripiprazole Abilify C No teratogenic potential, but can cause agranulocytosis. Clozapine Clozaril B Not enough data available. Olanzapine Zyprexa C Quetiapine Seroquel C NoNot teratogenic enough data potential available. known. Risperidone Risperdal C Not enough data available. Ziprasidone Geodon C Not enough data available. Abbreviations:

SSRIs: Selective Serotonin Reuptake Inhibitors; TCAs: Tricyclic Antidepressants studies show no association between their use during pregnancy

malformationsthat the use of in venlafaxine the fetus when [38-40], compared mirtazapine to the incidences [41,42], and in and structural anomalies in fetuses [35,36]. However, they birthstrazodone in the and general nefazodone population. [43] do Bupropion, not increase on the the risk other of majorhand, are usually reserved for refractory patients, i.e. those who are not responding to sequential trials of SSRIs, venlafaxine, and a report by GlaxoSmithKline, fetuses exposed to bupropion had a bupropion, because of their poor side effect profile and lethality 3.6%has been increased associated risk of to congenital increased abnormalities,risk of major malformations. while the risk for In in overdose [37]. Other antidepressants include venlafaxine, mirtazapine, control study examining infants who were exposed to bupropion cardiac anomalies increased by 1.3% [44]. A retrospective case- bupropion, trazodone and nefazodone. Limited studies have been performed on these newer antidepressants and have shown Med J Obstet Gynecol 4(4): 1091 (2016) 3/9 Tucci et al. (2016) Email: Central

Table 2:

Category FDA ClassificationsDefinition of Medication. Examples

A Folic Acid trimesters).Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later B Clozapine, Buproprion there are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have failed to demonstrate a risk to the fetus and C there are no adequate and well-controlled studies in humans, but potential Haloperidol, Fluoxetine Animal reproduction studies have shown an adverse effect on the fetus and

benefits may warrant use of the drug in pregnant women despite potential risks. Carbamezapine, Lithium, Valproic Acid for D There is positive evidence of human fetal risk based on adverse reaction data mood disorder from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Temazepam, Valproic Acid for migraine use X Studies in animals or humans have demonstrated fetal abnormalities and/or changed to X there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of N the drug in pregnant women clearly outweigh potential benefits. Not classified by the FDA

According to CDC about 37% of births in the US are the result of unintended , a number which has stayed fairly steady since 1982

Since the number is very high, it is recommended that all prescribers who see psychiatric patients or patients on psychiatric medications of reproductive age, should educate them about the risks associated with some psychiatric medications

Patients who are planning to be pregnant need to be educated about psychiatric medications which can adversely affect the fetus, namely valproic acid, carbamazepine, lithium, paroxetine and benzodiazepines

Since the teratogenic effects are most prevalent in the first trimester, it is much better to educate patients before they get pregnant, as otherwise by the time they see a physician it may be too late to avoid potential damage

Psychiatric illnesses usually get worse during pregnancy, therefore it is not recommended to stop psychiatric medications during pregnancy without checking with the prescriber

Patients also need to be educated about potential issues with breastfeeding, as they need to choose a medication which is both safe in pregnancy and after delivery

Figure 1

Psycho-education Pearls for Patients of Reproductive Age. from 1 month prior to conception to 3 months post-conception

malformations or oral clefts. While segregating the case-control byshowed Byatt increasedet al, the authors risk of leftpointed outflow out tractthat in heart utero defects, bupropion with studies from the same group revealed an association between exposurean odds ratio does of increase 2.6 (95% the CI: risk 1.2-5.7) of congenital [45]. In a heartrecent defects, review benzodiazepine use in pregnancy and the development of major malformations (OR 3.01; 95% CI: 1.32-6.84) and even oral clefts births in general population (0.82/1000) [46]. Onealone [49] (OR reports 1.79; 95%that in CI: utero 1.13-2.82) exposure [48]. to benzodiazepines Two studies using during the however this increase is small (2.1/1000) when compared to the data from Swedish Birth Registry report conflicting outcomes. Coming to anxiolytics and hypnotics, the literature on the first trimester increases the risk of major malformations with an meta-analysis of 23 studies, looking only at the cohort studies odds ratio of 1.79 (95% CI: 1.00-1.55), while the other [50] finds teratogenic effects of Benzodiazepines is ambiguous [47]. In a from the group showed no association between in utero no association whatsoever. Another recent study by Ban et al found no significant teratogenic potential of benzodiazepine use in first trimester [51]. Even in studies which report an increase in benzodiazepine exposure and increased risk of major congenital Med J Obstet Gynecol 4(4): 1091 (2016) 4/9 Tucci et al. (2016) Email: Central

Pregnancy

Risk Summary

‘There are no data on NUPLAZID use in pregnant women that would allow assessment of the drug- associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no adverse developmental effects were seen when Pimavanserin was administered orally to rats or rabbits during the period of organogenesis at doses up to 10- or 12-times the maximum recommended human dose (MRHD) of 34 mg/day, respectively. Administration of Pimavanserin to pregnant rats during pregnancy and lactation resulted in maternal toxicity and lower pup survival and body weight at doses which are 2-times the MRHD of 34 mg/day [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.’

Data

Animal Studies

‘Pimavanserin was not teratogenic in pregnant rats when administered during the period of organogenesis at oral doses of 0.9, 8.5, and 51 mg/kg/day, which are 0.2- and 10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC at mid and high doses, respectively. Maternal toxicity included reduction in body weight and food consumption at the highest dose. Administration of Pimavanserin to pregnant rats during pregnancy and lactation at oral doses of 8.5, 26, and 51 mg/kg/day, which are 0.14- to 14-times the MRHD of 34 mg/day based on AUC, caused maternal toxicity, including mortality, clinical signs including dehydration, hunched posture, and rales, and decreases in body weight, and/or food consumption at doses≥26 mg/kg/day (2 -times the MRHD based on AUC). At these maternally toxic doses there was a decrease in pup survival, reduced litter size, and reduced pup weights, and food consumption. Pimavanserin had no effect on sexual maturation, neurobehavioral function including learning and memory, or reproductive function in the first generation pups up to 14-times the MHRD of 34 mg/day based on AUC. Pimavanserin was not teratogenic in pregnant rabbits during the period of organogenesis at oral doses of 4.3, 43, and 85 mg/kg/day, which are 0.2- to 12-times the MHRD of 34 mg/day based on AUC. Maternal toxicity, including mortality, clinical signs of dyspnea and rales, decreases in body weight and/or food consumption, and abortions occurred at doses 12-times the MRHD of 34 mg/day based on AUC.’

Lactation

Risk Summary

Box 1

Risks of using Pimavanserin (Nuplazid) in Special Populations. in the general population is 6 per 10,000 births, while the use Therefore, these drugs should only be used during pregnancy if teratogenic risk, the absolute value is small. The risk of oral clefts needwith is regards clearly established. to chloral hydrate have been reported [58]. per 10,000 births [36] to 11 per 10,000 births [51]. Therefore, of benzodiazepines during pregnancy increases this risk up to 7 commonly prescribed during pregnancy are carbamazepine, In the group of anti-epileptics and mood stabilizers, the drugs thebenzodiazepines group which belong should to becategory avoided X in in pregnancy pregnancy [53]. especially during the first and the last trimester, especially those drugs in been classically associated with Ebstein’s anomaly (i.e. the , lithium, and . Lithium, for decades, has is only expected to carry a teratogenic potential if taken before 12 of theseWith drugs. regards Buspirone to non-benzodiazepine is categorized as class hypnotics B by FDA, limited based weeksmalformation of gestation, of tricuspid as the heartvalve isand fully the formed right ventricle). by then, and Lithium thus human studies are available to assess the true teratogenic risks any exposure to the fetus thereafter could not affect the structure

Bon by animal FDA, studiesbecause which of lack show of teratogenic no evidence risks of fetal shown damage in animal [54]. modelsSame is [55].the case Zaleplon, with Zolpidem, eszopiclone, which and is chloral classified hydrate as category belong of the heart. It has been shown to increase the risk ratio of cardiac to category C. Animal studies regarding zaleplon and eszopiclone malformations to 1.2-7.7, and the risk ratio for all congenital defects to 1.5-3 [59,60]. The prevalence of Ebstein’s anomaly in the general population is 1 per 20,000 live births [61], which show no teratogenic potential [56,57], while no animal studies jumps up to 1 per 1000 live births with first trimester lithium Med J Obstet Gynecol 4(4): 1091 (2016) 5/9 Tucci et al. (2016) Email: Central exposure [62]. Other reported cardiac defects are coarctation of aorta and mitral atresia. American College of Obstetrics and Lamotrigine use during pregnancy, but from what limited Gynecology (ACOG) [59] recommends that females with bipolar There have been fewer studies assessing the safety of should gradually taper dose of the drug if the episodes are mild data is available, it is clear that the risk of major congenital disorder who are currently on lithium and wish to conceive, riskmalformations of craniofacial is less defects. when Holmescompared et alto showedvalproate that exposure lamotrigine [71]. useIn utero during exposure pregnancy to lamotrigine increased has the been risk shown of oral to clefts increase by 10.4 the recommendedand infrequent. that In patients the drug who should suffer be tapered from moderate-severe but should be restartedepisodes once and haveorganogenesis a mild risk is complete. of relapse For in those short-term, women who it is foldsAmong (95% CI antipsychotics, 4.3-24.9) when compared the ones with that control are groups commonly [72]. suffer from severe and frequent manic episodes, lithium should clozapine, risperidone, quetiapine, olanzapine, ziprasidone, and prescribed are chlorpromazine, haloperidol, fluphenazine, wherebe continued continuation throughout of the drug pregnancy is necessary, irrespective adequate of thescreening risk it poses to the developing fetus. Briggs et al suggests that in cases not been performed in case of most of these drugs, but animal studiesaripiprazole. show Althoughteratogenic adequate potential and in well most controlled of them. studies have echocardiography [63]. tests should be performed such as level II ultrasound and fetal Chlorpromazine has been shown to cause congenital

Sodium valproate is a well-established teratogen with malformations in animal studies, including those involving the evidence from both animal and human studies. When compared increases the risk of congenital malformations four folds [64]. skeletal system, central nervous system (CNS), eye, and cleft to exposure to other anti-epileptics, valproate exposure of malformations and perinatal deaths in fetuses exposed to palate [73-75]. A few human studies show an increased incidence 9% when compared to groups not exposed to any anti-epileptics However, it increases the risk of major malformations by almost suggestschlorpromazine that chlorpromazine in utero [76-78], is not whereas teratogenic, most but fail still to elucidate it should increased risk of neural tube defects (NTDs), cardiac defects, beany used such cautiously association during [79-83]. pregnancy, In summary,by weighing most the risks evidence and hypospadias,[65]. In utero oralexposure clefts, to valproatepolydactyly, has and been craniosynostosis associated with

benefits of the drug. [46,64]. About 1-2% of the fetuses exposed to valproate in supplementationutero develop NTDs, decreases which the is 10-20risk of foldsNTDs increased among births risk in when the otherIn studies animal itstudies has been regarding reported fluphenazine, that exposure two to thestudies drug showed results generalcompared population, to births andin the so generalis recommended population in [66,67]. pregnant Folic females acid no teratogenic adverse effects in pregnancy [84]. However, in risk of NTDs in pregnant females who are on anti-epileptics and in dilated ventricles of the CNS, skeletal defects, oral clefts, and takeon valproate, folic acid even supplementation though studies [68]. have This shown is probably no decrease due toin the reduction in fetal weight and length [85,86]. In humans, no well controlled studies have been performed to test the teratogenic potential of the drug, however they are considered relatively safe generallyfact that folate prescribed supplementation is between 1500-2000mg.has only shown A some distinct value pattern if the to use during pregnancy [87,88]. ofdose facial of valproatedysmorphism is less along than with 750mg, a characteristic however the constellation dose that is linked to increased risk of cleft palate, micromelia [86,89], and CNSHaloperidol and skeletal use malformations in animal reproductive [86,90-92]. studies Among has human been in utero, which includes craniofacial, skeletal, urogenital, and studies, Kopelman et al. [93], reported multiple upper and lower of defects is also described in some fetuses exposed to valproate phocomelia was reported in another infant who was exposed to cardiovascular defects along with stunted development [63]. limb defects, and an aortic valve defect in one infant, and similarly butTherefore, in cases it where is recommended females are that already sodium on the valproate drug, it should haloperidol during first trimester [94]. However, limb reduction notbe avoidedbe discontinued during pregnancy,due to risk of especially relapse. theRather first it should trimester, be defects have not been reported with haloperidol use outside of substituted by another less teratogenic mood stabilizer such as the first trimester. an atypical antipsychotic [53]. teratogenic effects, and the human studies also deem the drug safe With regards to clozapine, animal studies have shown no potential, clozapine can cause fetal agranulocytosis and should Carbamazepine has a similar teratogenic profile as valproate, for use during pregnancy [95-97]. Despite the lack of teratogenic cleftbut less palate, in severity. hypospadias, In utero and exposure cardiac to malformations the drug has been[69]. to respond to other neuroleptic drugs. shown to increase the risk of NTDs (especially spina bifida), only be reserved for patients with severe schizophrenia who fail Risperidone use has also failed to show any teratogenic effects in both animal and human studies [98,99]. No adequate Up to 1% of the exposed fetuses develop spina bifida, which means an approximately 7 fold increased risk when compared described a ‘Fetal Carbamazepine Syndrome’ characterized by safety of Quetiapine, and so it should be used with caution [100]. to births in the general population [70]. Some studies have also Sameand well is thecontrolled case with studies Olanzapine have been [101,102], performed Ziprasidone, to assess andthe Aripiprazole [101-103]. facial dysmorphism, finger nail hypoplasia, and developmental carbamazepinedelays, however use theduring existence pregnancy of are this the syndrome same as for remains sodium to beroate. a controversy [59,63]. Recommendations regarding which medication was the culprit or offending agent and had the With respect to the current case, it is difficult to establish valp Med J Obstet Gynecol 4(4): 1091 (2016) 6/9 Tucci et al. (2016) Email: Central

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Cite this article Ahmed SM, Moukaddam N, Worley AV, Patel KR, Shah A, et al. (2016) Teratogenic Potential of Commonly Prescribed Psychotropic Drugs. Med J Obstet Gynecol 4(4): 1091.

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