The risks of selective serotonin reuptake inhibitor use in infertile women: A review of the impact on fertility, pregnancy, neonatal health and beyond

Human Reproduction

Volumn 28, Issue 1, 2013, Pages 160-171

  Domar, A D ^a,b   Moragianni, V A ^a,b   Ryley, D A ^a,b   Urato, A C ^c  

^a BOSTON IVF   (United States)

^b BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^c TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

antidepressants; depression; infertility; selective serotonin reuptake inhibitors

Indexed keywords

FLUOXETINE; FOLIC ACID; PLACEBO; SEROTONIN UPTAKE INHIBITOR;

BIRTH DEFECT; CLINICAL EVALUATION; COGNITIVE DEFECT; COGNITIVE THERAPY; DEPRESSION; DRUG EFFICACY; DRUG SAFETY; DRUG USE; EVIDENCE BASED PRACTICE; EXERCISE; FEMALE FERTILITY; FEMALE INFERTILITY; HUMAN; MEDICAL LITERATURE; NEWBORN DISEASE; PATIENT COUNSELING; PERSISTENT PULMONARY HYPERTENSION; PREECLAMPSIA; PREGNANCY; PREGNANCY COMPLICATION; PREGNANCY OUTCOME; PREMATURE LABOR; PROGENY; PUERPERAL DEPRESSION; PULMONARY HYPERTENSION; REVIEW; RISK ASSESSMENT; SPONTANEOUS ABORTION;

EID: 84871199157     PISSN: 02681161     EISSN: 14602350     Source Type: Journal    
DOI: 10.1093/humrep/des383     Document Type: Review

References (108)

1. Alwan S, Reefhuis J, Rasmussen SA, Friedman J. National Bith Defects Prevention Study. Patterns of antidepressant medication use among pregnant women in a United States population. J Clin Pharmacol 2011; 2:264-270.
2. Anderson GM, Horne WC, Chatterjee D, Cohen DJ. The hyperserotonemia of autism. Ann N Y Acad Sci 1990;600:331-340; discussion 341-2.
3. Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf 2009; 18:246-252.
4. Andreescu C, Glick RM, Emeremni CA, Houck PR, Mulsant BH. Acupuncture for the treatment of major depressive disorder: a randomized controlled trial. J Clin Psychiatr 2011;72:1129-1135.
5. Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004; 306:879-881.
6. Barber C. The medicated Americans: antidepressant prescriptions on the rise. Sci Am 2008.
7. Cabral P, Meyer HB, Ames D. Effectiveness of yoga therapy as a complementary treatment for major psychiatric disorders: a meta-analysis. Prim Care Companion CNS Disord 2011;13.
8. Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003; 142:402-408.
9. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-587.
10. Chen TH, Chang SP, Tsai CF, Juang KD. Prevalence of depressive and anxiety disorders in an assisted reproductive technique clinic. Hum Reprod 2004;19:2313-2318.
11. Chiaffarino F, Baldini MP, Scarduelli C, Bommarito F, Ambrosio S, D'Orsi C, Torretta R, Bonizzoni M, Ragni G. Prevalence and incidence of depressive and anxious symptoms in couples undergoing assisted reproductive treatment in an Italian infertility department. Euro J Obstet Gyn Reprod Biol 2011;158:235-241.
12. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006;295:499-507.
13. Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196:544. e1-e5.
14. Coverdale JH, McCullough LB, Chervenak FA. The ethics of randomized placebo-controlled trials of antidepressants with pregnant women: a systematic review. Obstet Gynecol 2008;112:1361-1368.
15. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011;68:1104-1112.
16. De Vera MA, Bérard A. Antidepressant use during pregnancy and the risk of pregnancy induced hypertension. Br J Clin Pharmacol 2012; 74:362-369.
17. Demyttenaere K, Bonte L, Gheldorf M, Meuleman C, Vanderschuerem D, D'Hooghe T. Coping style and depression level influence outcome in in vitro fertilization. Fertil Steril 1998;69:1026-1033.
18. DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD. Medications versus cognitive behavior therapy for severely depressed outpatients: mega-analysis of four randomized trials. Am J Psychiatry 1999;156:1007-1013.
19. Domar AD, Seibel MM, Benson H. The mind/body program for infertility: a new behavioral treatment approach for women with infertility. Fertil Steril 1990;53:246-249.
20. Domar AD, Zuttermeister PC, Seibel MM, Benson H. Psychological improvement in infertile women following behavioral treatment: a replication. Fertil Steril 1992;58:144-147.
21. Domar AD, Friedman R, Zuttermeister PC. Distress and conception in infertile women: a complementary approach. J Am Med Womens Assoc 1999;54:196-198.
22. Domar AD, Clapp D, Slawsby E, Kessel B, Orav J, Freizinger M. The impact of group psychological interventions on distress in infertile women. Health Psychol 2000;19:568-575.
23. Dubnov-Raz G, Juurlink DN, Fogelman R, Merlob P, Ito S, Koren G, Finkelstein Y. Antenatal use of selective serotonin-reuptake inhibitors and QT interval prolongation in newborns. Pediatrics 2008; 122:e710-e715.
24. Dubnov-Raz G, Koren G, Finkelstein Y. Selective serotonin reuptake inhibitor exposure in pregnancy and neonatal adverse events. Arch Pediatr Adolesc Med 2010;164:394.
25. Ernst E, Lee MS, Choi TY. Acupuncture for depression? A systematic review of systematic reviews. Eval Health Prof 2011;34:403-412.
26. Facchinetti F, Tarabusi M, Volpe A. Cognitive-behavioral treatment decreases cardiovascular and neuroendocrine reaction to stress in women waiting for assisted reproduction. Psychoneuroendocrinology 2004;29:132-173.
27. Faramarzi M, Alipor A, Esmaelzadeh S, Kheirkhah F, Poladi K, Pash H. Treatment of depression and anxiety in infertile women: cognitive behavioral therapy versus fluoxetine. J Affective Dis 2008a;108:159-164.
28. Faramarzi M, Kheirkhah F, Esmaelzadeh S, Alipour A, Hijahmadi M, Rahnama J. Is psychotherapy a reliable alternative to pharmacotherapy to promote the mental health of infertile women? A randomized clinical trial. Eur J Obstet Gyn Reprod Biol 2008b;141:49-53.
29. Farzadi L, Ghasemzedah A. Two main independent predictors of depression among infertile women: an Asian experience. Taiwan J Obstet Gynecol 2008;47:163-167.
30. FDA advising of risk of birth defects with Paxil, 2005. http://www. fda. gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108527. htm.
31. FDA Advisory Committee Minutes, 2004. http://www. fda. gov/ohrms/dockets/ac/04/minutes/2004-4050M1. pdf?utm-campaign=Google2 &utm-source=fdaSearch&utm-medium=website&utm-term=neonatal toxicity/withdrawal SSRI&utm-content=1.
32. FDA Drug Safety Communication. Selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies, 2012. http://www. fda. gov/Drugs/DrugSafety/ ucm283375. htm.
33. FDA Public Health Advisory. Treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns, 2006. http://www. fda. gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatientsandProviders/DrugSafetyInformation forHeathcareProfessionals/PublicHealthAdvisories/ucm124348. htm.
34. Field T. Yoga clinical research review. Complement Ther Clin Pract 2011; 17:1-8.
35. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010;303:47-53.
36. Friedman BE, Rogers JL, Shahine LK, Westphal LM, Lathi RB. Effect of selective serotonin inhibitors on in vitro fertilization outcome. Fertil Steril 2009;92:1312-1314.
37. Gianfranco C, Vittorio U, Silvia B, Francesco D. Myo-inositol in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol 2011;26:526-530.
38. Hammerli K, Znoj H, Barth J. The efficacy of psychological interventions for infertile patients: a meta-analysis examining mental health and pregnancy rate. Hum Reprod Update 2009;15:279-295.
39. Haemmerli K, Znoj H, Beeger T. Internet-based support for infertile couples: a randomized controlled study. J Behav Med 2010; 33:135-146.
40. Hayes RM, Wu P, Shelton RC, Cooper WO, Dupont WD, Mitchel E, Hartert TV. Maternal antidepressant use and adverse outcomes: a cohort study of 228 876 pregnancies. Am J Obstet Gynecol 2012;207; 49:e1-e9.
41. Health Canada. Health Canada advises of potential adverse effects of SSRIs and other anti-depressants on newborns, 2004. http://www. hc-sc. gc. ca/ahc-asc/media/advisories-avis/-2004/2004-44-eng. php.
42. Hemels ME, Einarson A, Koren G, Lanctô t KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. Ann Pharmacother 2005;39:803-809.
43. Heninger G, Delgado P, Charney D. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 1996;29:2-11.
44. Herbert DL, Lucke JC, Dobson AJ. Depression: an emotional obstacle to seeking medical advice for infertility. Fertil Steril 2010;94:1817-1821.
45. Herbert DL, Lucke JC, Dobson AJ. Birth outcomes after spontaneous or assisted conception among infertile Australian women aged 28-36 years: a prospective, population-based study. Fertil Steril 2012; 97:630-638.
46. Hollon SD, DeRubeis RJ, Shelton RC, Amsterdam JD, Salomon RM, O'Reardon JP, Lovett ML, Young PR, Haman KL, Freeman BB et al. Prevention of relapse following cognitive therapy versus medications in moderate to severe depression. Arch Gen Psychiatry 2005; 62:417-422.
47. Hughes EG, da Silva AM. A pilot study assessing art therapy as a mental health intervention for subfertile women. Hum Reprod 2011; 26:611-615.
48. Institute of Medicine. Preterm birth: causes, consequences, and prevention, 2006.
49. Javnbakht M, Hejazi KR, Ghasemi M. Effects of yoga on depression and anxiety of women. Complement Ther Clin Prac 2009;15:102-104.
50. Jorm AF, Morgan AJ, Hetrick SE. Relaxation for depression. Cochrane Database Syst Rev 2008;8:CD007142.
51. Kallen B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf 2008;17:801-806.
52. Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002; 22:40-45.
53. Kirsch I. Antidepressants and the placebo response. Epidemiol Psychiatri Soc 2009;18:318-322.
54. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008;5:e45.
55. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, glaser R. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun 2011; 25:1725-1734.
56. Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, Nielsen RB, Nørgaard M, Stephansson O, Valdimarsdottir U et al. 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 2012;344:d8012.
57. Klock SC, Sheinin S, Kazer R, Zhang X. A pilot study of the relationship between selective serotonin reuptake inhibitors and in vitro fertilization outcome. Fertil Steril 2004;82:968-969.
58. Koszycki D, Bisserbe JC, Blier P, Bradwejn J, Markowitz J. Interpersonal psychotherapy versus brief supportive therapy for depressed infertile women: first pilot randomized controlled trial. Arch Womens Ment Health 2012;15:193-201.
59. Koyuncu H, Serefoglu EC, Yencilek E, Atalay H, Akbas NB, Sar?ca K. Escitalopram treatment for premature ejaculation has a negative effect on semen parameters. Int J Impot Res 2011;23:257-261.
60. Lacasse JR, Leo J. Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS Med 2005;2: e392.
61. Lapane KL, Zierler S, Lasatar TM, Stein M, Barbour MM, Hume AL. Is a history of depressive symptoms associated with an increased risk of infertility in women? Psychosom Med 1995;57:509-513.
62. Lee LJ. Neonatal fluoxetine exposure affects the neuronal structure in the somatosensory cortex and somatosensory-related behaviors in adolescent rats. Neurotox Res 2009;15:212-223.
63. Lemmens GMD, Vervaeke M, Enzlin P, Bakelants E, Vanderschueren D, D'Hooghe T, Demyttenaere K. Coping with infertility: a body-mind group intervention programme for infertile couples. Hum Reprod 2004;19:1917-1923.
64. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006; 160:173-176.
65. Mergl R, Henkel V, Allgaier AK, Kramer D, Hautzinger M, Kohnen R, Coyne J, Hegerl U. Are treatment preferences relevant in response to serotonergic antidepressants and cognitive-behavioral therapy in depressed primary care patients? Results from a randomized controlled trial including a patients' choice arm. Psychother Psychosom 2011;80:39-47.
66. Moncrieff J, Cohen D. Do antidepressants cure or create abnormal brain states? PLoS Med 2006;3:e240.
67. Moncrieff J, Cohen D. How do psychiatric drugs work? BMJ 2009; 338:1535-1537.
68. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev 2004;CD003012.
69. Mori A. Supporting stress management for women undergoing the early stages of fertility treatment: a cluster-randomized controlled trial. Jpn J Nurs Sci 2009;6:37-49.
70. Nahas R, Sheikh O. Complementary and alternative medicine for the treatment of major depressive disorders. Can Fam Physician 2011; 57:659-663.
71. Nakhai-Pour HR, Broy P, Bérard A. Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ 2010; 182:1031-1037.
72. Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006; 63:898-906.
73. Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study. Br J Psychiatry 2008; 192:338-343.
74. Osher Y, Belmaker RH. Omega-3 fatty acids in depression: a review of three studies. CNS Neurosci Ther 2009;15:128-133.
75. Palmsten K, Hernández-Díaz S. Can nonrandomized studies on the safety of antidepressants during pregnancy convincingly beat confounding, chance, and prior beliefs? Epidemiology 2012;23:686-688.
76. Parikh SV, Segal ZV, Grigoriadis S, Ravindran AV, Kennedy SH, Lam RW, Patten SB. Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication. J Affect Disord 2009;117:S15-S25.
77. Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age. Pediatrics 2010;125:e600-e608.
78. Petersen I, Gilbert RE, Evans SJ, Man SL, Nazareth I. Pregnancy as a major determinant for discontinuation of antidepressants: an analysis of data from the Health Improvement Network. J Clin Psychiatry 2011; 72:979-985.
79. Pratt LA, Brody DL, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005-2008, vol 76. US Department of Health and Human Services, Centers for Disease Control, NCHS Data Brief, 2011.
80. Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials. Reprod Toxicol 2006;22:571-575.
81. Ramezanzadeh F, Noorbala AA, Abedinia N, Rahimi Forooshani A, Naghizadeh MM. Psychiatric intervention improved pregnancy rates in infertile couples. Malays J Med Sci 2011;18:16-24.
82. Ravindran AV, Lam RW, Filteau MJ, Lesperance F, Kennedy SH, Parikh SV, Patten SB., Canadian Network for Mood and Anxiety Treatments (CANMAT). Clinical guidelines for the management of major depressive disorder in adults: V. Complementary and alternative medicine treatments. J Affect Disord 2009;117:S54-S64.
83. Reis M, Källén B. Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med 2010; 40:1723-1733.
84. Relwani R, Berger D, Santoro N, Hickmon C, Nihsen M, Zapantis A, Werner M, Polotsky AJ, Jindal S. Semen parameters are unrelated to BMI but vary with SSRI use and prior urological surgery. Reprod Sci 2011;18:391-397.
85. Roca A, Garcia-Esteve L, Imaz ML, Torres A, Hernández S, Botet F, Gelabert E, Subirà S, Plaza A, Valdés M et al. Obstetrical and neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors: the relevance of dose. J Affect Disord 2011;135:208-215.
86. Roggenbach J, Müller-Oerlinghausen B, Franke L. Suicidality, impulsivity, and aggression-is there a link to 5HIAA concentration in the cerebrospinal fluid? Psychiatry Res 2002;113:193-206.
87. Schroer S, Adamson J. Acupuncture for depression: a critique of the evidence base. CNS Neuro Ther 2011;17:398-410.
88. Serafini P, Lobo DS, Grosman A, Seibel D, Rocha AM, Motta ELA. Floutetine treatment for anxiety in women undergoing in vitro fertilization. Int J Gynceol Obstet 2009;105:136-139.
89. Sexton MB, Byrd MR, O'Donohue WT, Jacobs NN. Web-based treatment for infertility-related psychological distress. Arch Womens Ment Health 2010;13:347-358.
90. Shapiro D, Cook IA, Davydov DM, Ottaviani C, Leuchter AF, Abrams M. Yoga as a complementary treatment of depression: effects of traits and moods on treatment outcome. Evid Based Complement Alternat Med 2007;4:493-502.
91. Smith CA, Hay PP, Macpherson H. Acupuncture for depression. Cochrane Database Syst Rev 2010;CD004046.
92. Stewart DE, Boydell KM, McCarthy K, Swerdlyk S, Redmond C, Cohrs W. A prospective study of the effectiveness of brief professionally-led support groups for infertility patients. Int J Psychiatry Med 1992; 22:173-182.
93. Tanrikut C, Schlegel PN. Antidepressant-associated changes in semen parameters. Urology 2007;69:185. e5-e7.
94. Tanrikut C, Feldman AS, Altemus M, Paduch DA, Schlegel PN. Adverse effect of paroxetine on sperm. Fertil Steril 2010;94:1021-1026.
95. Toh S, Mitchell AA, Louik C, Werler MM, Chambers CD, Hernández-D? ́az S. Antidepressant use during pregnancy and the risk of preterm delivery and fetal growth restriction. J Clin Psychopharmacol 2009a;29:555-560.
96. Toh S, Mitchell AA, Louik C, Werler MM, Chambers CD, Hernandez-Diaz S. Selective serotonin reuptake inhibitor use and risk of gestational hypertension. Am J Psychiatry 2009b;166:320-328.
97. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-260.
98. Uebelacker LA, Epstein-Lubow G, Gaudiano BA, Tremont G, Battle CL, Miller IW. Hatha yoga for depression: critical review of the evidence for efficacy, plausible mechanisms of action, and directions for future research. J Psychiatr Prac 2010;16:22-33.
99. Urato AC. Antidepressants and pregnancy: continued evidence of harm-still no evidence of benefit. Ethical Hum Psychol Psychiat 2011; 13:190-193.
100. Volgsten H, skoog SA, Ekselius L, Lundkvist O, Sundstrom PI. Prevalence of psychiatric disorders in infertile women undergoing in vitro fertilization treatment. Hum Reprod 2008;23:2056-2063.
101. Vos T, Corry J, Haby MM, Carter R, Andrews G. Cost-effectiveness of cognitive-behavioural therapy and drug interventions for major depression. Aust N Z J Psychiatry 2005;39:683-692.
102. Wenner M. Are antidepressants safe for pregnant women? Sci Am 2010.
103. Wilkins KM, Warnock JK, Serrano E. Depressive symptoms related to infertility and infertility treatment. Psych Clin N Amer 2010;33:309-321.
104. Wilson KL, Zelig CM, Harvey JP, Cunningham BS, Dolinsky BM, Napolitano PG. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol 2011;28:19-24.
105. Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, Ramin S, Chaudron L, Lockwood C. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:703-713.
106. Yonkers KA, Gotman N, Smith MV, Forray A, Belanger K, Brunetto WL, Lin H, Burkman RT, Zelop CM, Lockwood CJ. Does antidepressant use attenuate the risk of a major depressive episode in pregnancy? Epidemiology 2011;22:848-854.
107. Yonkers KA, Norwitz ER, Smith MV, Lockwood CJ, Gotman N, Luchansky E, Lin H, Belanger K. Depression and serotonin reuptake inhibitor treatment as risk factors for preterm birth. Epidemiology 2012;23:677-685.
108. Zemrak WR, Kenna GA. Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health Syst Pharm 2008; 65:1029-1038.