Introduction Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth. Methods We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect. Results Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI) were 1.53 (1.40–1.66) for antidepressant use at any time and 1.96 (1.62–2.38) for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92–1.45)] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association. Discussion Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out.
References
[1]
Slattery MM, Morrison JJ (2002) Preterm delivery. The Lancet 360: 1489–1497. doi: 10.1016/s0140-6736(02)11476-0
[2]
Goyal N, Fiks A, Lorch S (2011) Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 128: e830–838. doi: 10.1542/peds.2011-0809
[3]
Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, Barfield W, Nannini A, et al. (2008) Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics 121: e223–232. doi: 10.1542/peds.2006-3629
[4]
Engle WA, Tomashek KM, Wallman C (2007) “Late-preterm” infants: a population at risk. Pediatrics 120: 1390–1401. doi: 10.1542/peds.2007-2952
[5]
Leone A, Ersfeld P, Adams M, Schiffer PM, Bucher HU, et al. (2012) Neonatal morbidity in singleton late preterm infants compared with full-term infants. Acta Paediatr 101: e6–10. doi: 10.1111/j.1651-2227.2011.02459.x
[6]
Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, et al. (2000) The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA 284: 843–849. doi: 10.1001/jama.284.7.843
[7]
Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes; Behrman RE, Butler AS, editors. Preterm Birth: Causes, Consequences, and Prevention. Washington (DC): National Academies Press (US); 2007.
[8]
Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N (2009) The cost of preterm birth throughout childhood in England and Wales. Pediatrics 123: e312–327. doi: 10.1542/peds.2008-1827
[9]
Olfson M, Marcus SC (2009) National patterns in antidepressant medication treatment. Arch Gen Psychiatry 66: 848–856. doi: 10.1001/archgenpsychiatry.2009.81
[10]
Petersen I, Gilbert RE, Evans SJ, Man SL, Nazareth I (2012) Pregnancy as a major determinant for discontinuation of antidepressants: an analysis of data from The Health Improvement Network. J Clin Psychiatry 72: 979–985. doi: 10.4088/jcp.10m06090blu
[11]
Bakker MK, Kolling P, van den Berg PB, de Walle HEK, de Jong van den Berg LTW (2008) Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands. Br J Clin Pharmacol 65: 600–606. doi: 10.1111/j.1365-2125.2007.03048.x
[12]
Munk-Olsen T, Gasse C, Laursen TM (2012) Prevalence of antidepressant use and contacts with psychiatrists and psychologists in pregnant and postpartum women. Acta Psychiatr Scand 125: 318–324. doi: 10.1111/j.1600-0447.2011.01784.x
[13]
Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, et al.. (2011) Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol 205: 51 e51–58.
[14]
Huybrechts KF, Palmsten K, Mogun H, Kowal M, Avorn J, et al. (2013) National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry 35: 265–271. doi: 10.1016/j.genhosppsych.2012.12.010
[15]
Hedges L, Olkin I (1985) Statistical Methods for Meta-analysis. Boston, Mass: Academic Press.
[16]
Borenstein M, Hedges L, Higgins J, Rothstein H (2009) Introduction to Meta-Analysis: John Wiley & Sons, Ltd.
[17]
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188. doi: 10.1016/0197-2456(86)90046-2
[18]
Deeks JJ, Higgins JPT, Altman DG (2008) Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. Chichester (UK): John Wiley & Sons.
[19]
Schneeweiss S (2006) Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics. Pharmacoepidemiology and Drug Safety 15: 291–303. doi: 10.1002/pds.1200
[20]
Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS, et al. (2000) Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry 48: 996–1000. doi: 10.1016/s0006-3223(00)00877-5
[21]
Goldstein DJ (1995) Effects of third trimester fluoxetine exposure on the newborn. J Clin Psychopharmacol 15: 417–420. doi: 10.1097/00004714-199512000-00005
McElhatton PR, Garbis HM, Elefant E, Vial T, Bellemin B, et al. (1996) The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod Toxicol 10: 285–294. doi: 10.1016/0890-6238(96)00057-3
[24]
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C (2008) Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study. Br J Psychiatry 192: 338–343. doi: 10.1192/bjp.bp.107.037101
[25]
Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, et al. (1998) Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA 279: 609–610. doi: 10.1001/jama.279.8.609
[26]
Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, et al. (1997) Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 336: 258–262. doi: 10.1056/nejm199701233360404
[27]
Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, et al. (2002) Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 159: 1889–1895. doi: 10.1176/appi.ajp.159.11.1889
[28]
Suri R, Altshuler L, Hendrick V, Rasgon N, Lee E, et al. (2004) The impact of depression and fluoxetine treatment on obstetrical outcome. Arch Womens Ment Health 7: 193–200. doi: 10.1007/s00737-004-0057-5
[29]
Zeskind PS, Stephens LE (2004) Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 113: 368–375. doi: 10.1542/peds.113.2.368
[30]
Calderon-Margalit R, Qiu C, Ornoy A, Siscovick DS, Williams MA (2009) Risk of preterm delivery and other adverse perinatal outcomes in relation to maternal use of psychotropic medications during pregnancy. Am J Obstet Gynecol 201: 1–8. doi: 10.1016/j.ajog.2009.06.061
[31]
Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, et al. (2003) Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 142: 402–408. doi: 10.1067/mpd.2003.139
[32]
Casper RC, Gilles AA, Fleisher BE, Baran J, Enns G, et al. (2011) Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development. Psychopharmacology (Berl) 217: 211–219. doi: 10.1007/s00213-011-2270-z
[33]
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL (1996) Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 335: 1010–1015. doi: 10.1056/nejm199610033351402
[34]
Colvin L, Slack-Smith L, Stanley FJ, Bower C (2011) Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy. Birth Defects Res A Clin Mol Teratol 91: 142–152. doi: 10.1002/bdra.20773
[35]
Costei AM, Kozer E, Ho T, Ito S, Koren G (2002) Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 156: 1129–1132. doi: 10.1001/archpedi.156.11.1129
[36]
Davis RL, Rubanowice D, McPhillips H, Raebel MA, Andrade SE, et al. (2007) Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy. Pharmacoepidemiol Drug Saf 16: 1086–1094. doi: 10.1002/pds.1462
[37]
Diav-Citrin O, Shechtman S, Weinbaum D, Wajnberg R, Avgil M, et al. (2008) Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study. Br J Clin Pharmacol 66: 695–705. doi: 10.1111/j.1365-2125.2008.03261.x
[38]
Djulus J, Koren G, Einarson TR, Wilton L, Shakir S, et al. (2006) Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. J Clin Psychiatry 67: 1280–1284. doi: 10.4088/jcp.v67n0817
[39]
Einarson A, Choi J, Einarson TR, Koren G (2010) Adverse effects of antidepressant use in pregnancy: an evaluation of fetal growth and preterm birth. Depress Anxiety 27: 35–38. doi: 10.1002/da.20598
[40]
Ericson A, Kallen B, Wiholm B (1999) Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 55: 503–508. doi: 10.1007/s002280050664
[41]
Ferreira E, Carceller AM, Agogue C, Martin BZ, St-Andre M, et al. (2007) Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates. Pediatrics 119: 52–59. doi: 10.1542/peds.2006-2133
[42]
Gavin AR, Holzman C, Siefert K, Tian Y (2009) Maternal depressive symptoms, depression, and psychiatric medication use in relation to risk of preterm delivery. Womens Health Issues 19: 325–334. doi: 10.1016/j.whi.2009.05.004
[43]
Kallen B (2004) Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 158: 312–316. doi: 10.1001/archpedi.158.4.312
[44]
Latendresse G, Ruiz RJ (2011) Maternal corticotropin-releasing hormone and the use of selective serotonin reuptake inhibitors independently predict the occurrence of preterm birth. J Midwifery Womens Health 56: 118–126. doi: 10.1111/j.1542-2011.2010.00023.x
[45]
Lennestal R, Kallen B (2007) Delivery outcome in relation to maternal use of some recently introduced antidepressants. J Clin Psychopharmacol 27: 607–613. doi: 10.1097/jcp.0b013e31815ac4d2
[46]
Lewis AJ, Galbally M, Opie G, Buist A (2010) Neonatal growth outcomes at birth and one month postpartum following in utero exposure to antidepressant medication. Aust N Z J Psychiatry 44: 482–487. doi: 10.3109/00048670903559593
[47]
Lund N, Pedersen LH, Henriksen TB (2009) Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes. Arch Pediatr Adolesc Med 163: 949–954. doi: 10.1001/archpediatrics.2009.164
[48]
Maschi S, Clavenna A, Campi R, Schiavetti B, Bernat M, et al. (2008) Neonatal outcome following pregnancy exposure to antidepressants: a prospective controlled cohort study. BJOG 115: 283–289. doi: 10.1111/j.1471-0528.2007.01518.x
[49]
Mulder EJH, Ververs FF, de Heus R, Visser GHA (2011) Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. Neuropsychopharmacology 36: 1961–1971. doi: 10.1038/npp.2011.67
[50]
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C (2006) Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 63: 898–906. doi: 10.1001/archpsyc.63.8.898
[51]
Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, et al. (1993) Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 269: 2246–2248. doi: 10.1001/jama.269.17.2246
[52]
Pearson KH, Nonacs RM, Viguera AC, Heller VL, Petrillo LF, et al. (2007) Birth outcomes following prenatal exposure to antidepressants. J Clin Psychiatry 68: 1284–1289. doi: 10.4088/jcp.v68n0817
[53]
Reis M, Kallen B (2010) Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med 40: 1723–1733. doi: 10.1017/s0033291709992194
[54]
Rurak D, Lim K, Sanders A, Brain U, Riggs W, et al. (2011) Third trimester fetal heart rate and Doppler middle cerebral artery blood flow velocity characteristics during prenatal selective serotonin reuptake inhibitor exposure. Pediatr Res 70: 96–9101. doi: 10.1203/pdr.0b013e31821ba11a
[55]
Simon GE, Cunningham ML, Davis RL (2002) Outcomes of prenatal antidepressant exposure. Am J Psychiatry 159: 2055–2061. doi: 10.1176/appi.ajp.159.12.2055
[56]
Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G (2005) Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol 193: 2004–2009. doi: 10.1016/j.ajog.2005.05.012
[57]
Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, et al. (2007) Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 164: 1206–1213. doi: 10.1176/appi.ajp.2007.06071172
[58]
Toh S, Mitchell AA, Louik C, Werler MM, Chambers CD, et al. (2009) Antidepressant use during pregnancy and the risk of preterm delivery and fetal growth restriction. J Clin Psychopharmacol 29: 555–560. doi: 10.1097/jcp.0b013e3181bf344c
[59]
Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O, et al. (2006) Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. Am J Obstet Gynecol 194: 961–966. doi: 10.1016/j.ajog.2006.02.019
[60]
Wisner KL, Sit DKY, Hanusa BH, Moses-Kolko EL, Bogen DL, et al. (2009) Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry 166: 557–566. doi: 10.1176/appi.ajp.2008.08081170
[61]
Klieger-Grossmann C, Weitzner B, Panchaud A, Pistelli A, Einarson T, et al. (2012) Pregnancy Outcomes Following Use of Escitalopram: A Prospective Comparative Cohort Study. Journal of Clinical Pharmacology 52: 766–770. doi: 10.1177/0091270011405524
[62]
Kieler H, Artama M, Engeland A, Ericsson ？r, Furu K, et al. (2012) Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. Bmj 344: d8012. doi: 10.1136/bmj.d8012
[63]
Einarson A, Choi J, Koren G, Einarson T (2011) Outcomes of infants exposed to multiple antidepressants during pregnancy: results of a cohort study. J Popul Ther Clin Pharmacol 18: e390–396.
[64]
El Marroun H, Jaddoe VWV, Hudziak JJ, Roza SJ, Steegers EAP, et al. (2012) Maternal Use of Selective Serotonin Reuptake Inhibitors, Fetal Growth, and Risk of Adverse Birth Outcomes. Arch Gen Psychiatry 69: 706–714. doi: 10.1001/archgenpsychiatry.2011.2333
[65]
Nordeng H, van Gelder M, Spigset O, Koren G, Einarson A, et al. (2012) Pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian mother and child cohort study. J Clin Psychopharmacol 32: 186–194. doi: 10.1097/jcp.0b013e3182490eaf
[66]
Roca A, Garcia-Esteve L, Imaz ML, Torres A, Hernandez S, et al. (2011) Obstetrical and neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors: The relevance of dose. Journal of affective disorders 135: 208–215. doi: 10.1016/j.jad.2011.07.022
[67]
Suri R, Hellemann G, Stowe Z, Cohen L, Aquino A, et al. (2011) A prospective, naturalistic, blinded study of early neurobehavioral outcomes for infants following prenatal antidepressant exposure. J Clin Psychiatry 72: 1002–1007. doi: 10.4088/jcp.10m06135
[68]
Grzeskowiak LE, Gilbert AL, Morrison JL (2012) Neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors. J Clin Psychopharmacol 32: 615–621. doi: 10.1097/jcp.0b013e31826686bc
[69]
Yonkers KA, Norwitz ER, Smith MV, Lockwood CJ, Gotman N, et al. (2012) Depression and Serotonin Reuptake Inhibitor Treatment as Risk Factors for Preterm Birth. Epidemiology 23: 677–685. doi: 10.1097/ede.0b013e31825838e9
[70]
Hayes RM, Wu P, Shelton RC, Cooper WO, Dupont WD, et al.. (2012) Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies. Am J Obstet Gynecol 207: 49 e41–49.
[71]
Wogelius P, Norgaard M, Gislum M, Pedersen L, Munk E, et al. (2006) Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 17: 701–704. doi: 10.1097/01.ede.0000239581.76793.ae
[72]
Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, et al. (2010) A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 67: 1012–1024. doi: 10.1001/archgenpsychiatry.2010.111
[73]
Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, et al. (2013) Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry 70: 436–443. doi: 10.1001/jamapsychiatry.2013.684
[74]
Blencowe H, Cousens S, Oestergaard M, Chou D, Moller A, et al. (2012) National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systmetic analysis and implications. The Lancet 479: 2162–2172. doi: 10.1016/s0140-6736(12)60820-4
[75]
West S, Savitz D, Koch G, Strom B, Guess H, et al. (1995) Recall accuracy for prescription medications: self-report compared with database information. American Journal of Epidemiology 142: 1103–1112.
[76]
West S, Strom B, Freundlich B, Normand E, Koch G, et al. (1994) Completeness of prescription recording in outpatient medical records from a health maintenance organization. Journal of Clinical Epidemiology 47: 165–167. doi: 10.1016/0895-4356(94)90021-3
[77]
Fowles J, Lawthers A, Weiner J, Garnick D, Petrie D, et al. (1995) Agreement between physicians’ office records and Medicare Part B claims data. Health Care Financ Rev 16: 189–199.
[78]
Romano PS, Mark DH (1994) Bias in the coding of hospital discharge data and its implications for quality assessment. Med Care 32: 81–90. doi: 10.1097/00005650-199401000-00006
[79]
Glynn R, Monane M, Gurwitz J, Choodnovskiy I, Avorn J (1999) Agreement between drug treatment data and a discharge diagnosis of diabetes mellitus in the elderly. American Journal of Epidemiology 149: 541–549. doi: 10.1093/oxfordjournals.aje.a009850
[80]
Fisher ES, Whaley FS, Krushat WM, Malenka DJ, Fleming C, et al. (1992) The accuracy of Medicare’s hospital claims data: progress has been made, but problems remain. Am J Public Health 82: 243–248. doi: 10.2105/ajph.82.2.243
[81]
Grigoriadis S, VonderPorten EH, Mamisashvili L, Tomlinson G, Dennis CL, et al. (2013) The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. J Clin Psychiatry 74: e321–341. doi: 10.4088/jcp.12r07968
[82]
Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, et al. (2009) The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 114: 703–713. doi: 10.1016/j.genhosppsych.2009.04.003
[83]
Palmsten K, Hernandez-Diaz S (2012) Can nonrandomized studies on the safety of antidepressants during pregnancy convincingly beat confounding, chance, and prior beliefs? Epidemiology 23: 686–688. doi: 10.1097/ede.0b013e318258fbb2
[84]
Coverdale JH, McCullough LB, Chervenak FA (2008) The ethics of randomized placebo-controlled trials of antidepressants with pregnant women: a systematic review. Obstet Gynecol 112: 1361–1368. doi: 10.1097/aog.0b013e31818c2a27
[85]
Nakhai-Pour H, Broy P, Bérard A (2010) Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ 182: 1031–1037. doi: 10.1503/cmaj.091208
[86]
Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH (2009) Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. Bmj 339: b3569. doi: 10.1136/bmj.b3569
[87]
Grigoriadis S, Vonderporten EH, Mamisashvili L, Tomlinson G, Dennis CL, et al. (2014) Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis. Bmj 348: f6932. doi: 10.1136/bmj.f6932
[88]
Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R (2005) Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 365: 482–487. doi: 10.1016/s0140-6736(05)17865-9
[89]
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21: 1539–1558. doi: 10.1002/sim.1186
