Pharmacotherapy or Psychotherapy? Selective Treatment Depression in The Infertile Women with Recurrent Pregnancy Loss: A Triple-Arm Randomized Controlled Trial

Document Type : Original Article


1 Infertility and Health Reproductive Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, I.R.Iran

2 Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

3 Department of General Courses, Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran


Background: Recurrent pregnancy loss (RPL) and infertility are associated with significant psychiatric complications.
The study aimed to investigate the effectiveness of cognitive behavioral therapy (CBT) and sertraline
in the treatment of in depression, anxiety, and infertility stress of depressed infertile women with RPL in comparison
with usual care.
Materials and Methods: A triple-arm randomized controlled trial was carried out on the 60 depressed infertile
women with RPL, a population of Infertility Center of Babol city, Iran, who were randomly assigned into three
groups: pharmacotherapy with sertraline (n=20), psychotherapy with CBT (n=20), and a usual care as control
group (n=20). The participants of psychotherapy received CBT sessions (90 minutes each) over 10 weeks. The
participants in the pharmacotherapy group took 50 mg/day sertraline daily for 22 weeks. Outcomes were assessed
using the Beck Depression Inventory (BDI-II), fertility problem inventory (FPI), and State-Trait Anxiety
Inventory Form Y (STAI-Y) at the beginning of the trial, 10-weeks post-trial, and three months of follow-up.
Using statistical package for the social sciences (SPSS) software, data were analyzed.
Results: CBT considerably reduced the depression symptoms more than sertraline with a moderate effect size
at the post-trial (g=0.11, 95% CI: -0.03 to -0.50). Sertraline showed reduced the scores of state-anxiety more
considerably in comparison with control group by a large effect size of post-trial (g=-1.04, 95% CI: -1.70 to
-0.38). CBT reduced the total scores of FPI more considerably than sertraline, with a large, small size at follow
up-trial [95% CI=-0.03(-0.65, -0.58)]. Both CBT and sertraline were superior to the control group in reducing
depression and infertility stress.
Conclusion: Depression and infertility stress diminished under CBT and sertraline in depressed infertile women with
RPL, with a significant advantage of CBT. Sertraline was superior to CBT in reduction of anxiety (registration number:


  1. van Dijk MM, Kolte AM, Limpens J, Kirk E, Quenby S, van Wely M, et al. Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and metaanalysis.Hum Reprod Update. 2020; 26(3): 356-367.
  2. Rasmark Roepke E, Matthiesen L, Rylance R, Christiansen OB. Is the incidence of recurrent pregnancy loss increasing? A retrospective register-based study in Sweden. Acta Obstet Gynecol Scand. 2017; 96(11): 1365-1372.
  3. Adib Rad H, Basirat Z, Mostafazadeh A, Faramarzi M, Bijani A, Nouri HR, et al. Evaluation of peripheral blood NK cell subsets and cytokines in unexplained recurrent miscarriage. J Chin Med Assoc. 2018; 81(12): 1065-1070.
  4. Tamhankar VA, Liu B, Yan J, Li TC. A comparison of pattern of pregnancy loss in women with infertility undergoing IVF and women with unexplained recurrent miscarriages who conceive spontaneously. Obstet Gynecol Int. 2015; 2015: 989454.
  5. Pasha H, Basirat Z, Esmailzadeh S, Faramarzi M, Adibrad H. Marital intimacy and predictive factors among infertile women in northern Iran. J Clin Diagn Res. 2017; 11(5): QC13-QC17.
  6. Basirat Z, Faramarzi M, Esmaelzadeh S, Abedi Firoozjai SH, Mahouti T, Geraili Z. Stress, depression, sexual function, and alexithymia in infertile females with and without polycystic ovary syndrome: a casecontrol study. Int J Fertil Steril. 2019; 13(3): 203-208.
  7. Zarif Golbar Yazdi H, Aghamohammadian Sharbaf H, Kareshki H, Amirian M. Infertility and psychological and social health of iranian infertile women: a systematic review. Iran J Psychiatry. 2020; 15(1): 67-79.
  8. Kiani Z, Simbar M, Hajian S, Zayeri F. The prevalence of depression symptoms among infertile women: a systematic review and metaanalysis. Fertil Res Pract. 2021; 7(1): 6.
  9. Karaca A, Unsal G. Psychosocial problems and coping strategies among Turkish women with infertility. Asian Nurs Res (Korean Soc Nurs Sci). 2015; 9(3): 243-250.
  10. Haghparast E, Faramarzi M, Hassanzadeh R. Psychiatric symptoms and pregnancy distress in subsequent pregnancy after spontaneous abortion history. Pak J Med Sci. 2016; 32(5): 1097-1101.
  11. Adib-Rad H, Basirat Z, Faramarzi M, Mostafazadeh A, Bijani A. Psychological distress in women with recurrent spontaneous abortion: a case-control study. Turk J Obstet Gynecol. 2019; 16(3): 151-157.
  12. Wang HY, Qiao J, Sun XX, Wang SY, Liang XY, Sun Y, et al. Epidemiological survey and risk factor analysis of recurrent spontaneous miscarriages in infertile women at large infertility centers. Chin Med J (Engl). 2017; 130(17): 2056-2062.
  13. Faramarzi M, Kheirkhah F, Esmaelzadeh S, Alipour A, Hjiahmadi 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 Gynecol Reprod Biol. 2008; 141(1): 49-53.
  14. Nakano Y, Akechi T, Furukawa TA, Sugiura-Ogasawara M. Cognitive behavior therapy for psychological distress in patients with recurrent miscarriage. Psychol Res Behav Manag. 2013; 6: 37-43.
  15. Patel A, Dinesh N, Sharma PSVN, Kumar P, Binu VS. Outcomes of structured psychotherapy for emotional adjustment in a childless couple diagnosed with recurrent pregnancy loss: a unique investigation. J Hum Reprod Sci. 2018; 11(2): 202-207.
  16. Séjourné N, Callahan S, Chabrol H. The utility of a psychological intervention for coping with spontaneous abortion. J Reprod Infant Psychol. 2010; 28(3): 287-296.
  17. Barat S, Yazdani S, Faramarzi M, Khafri S, Darvish M, Rad MN, et al. The effect of brief supportive psychotherapy on prevention of psychiatric morbidity in women with miscarriage: a randomized controlled trial about the first 24-hours of hospitalization. Oman Med J. 2020; 35(3): e130.
  18. Kjaersgaard MI, Parner ET, Vestergaard M, Sørensen MJ, Olsen J, Christensen J, Bech BH, Pedersen LH. Prenatal antidepressant exposure and risk of spontaneous abortion - a population-based study. PLoS One. 2013; 8(8): e72095.
  19. Wu P, Velez Edwards DR, Gorrindo P, Sundermann AC, Torstenson ES, Jones SH, et al. Association between first trimester antidepressant use and risk of spontaneous abortion. Pharmacotherapy. 2019; 39(9): 889-898.
  20. Sugiura-Ogasawara M, Furukawa TA, Nakano Y, Hori S, Aoki K, Kitamura T. Depression as a potential causal factor in subsequent miscarriage in recurrent spontaneous aborters. Hum Reprod. 2002; 17(10): 2580-2584.
  21. Jeve YB, Davies W. Evidence-based management of recurrent miscarriages. J Hum Reprod Sci. 2014; 7(3): 159-69.
  22. First MB, Williams JBW, Karg RS, Spitzer RL. User's guide for the SCID-5-CV structured clinical interview for DSM-5® disorders: Clinical version. APA; 2016. Available from produts/interviewing/users-guide-for-the-structured-clinical-interv- (1)?sku=62524 (27 Sep 2021).
  23. Basirat Z, Faramarzi M, Chehrazi M, Amiri M, Ghofrani F, Tajalli Z. Differences between infertile women with and without PCOS in terms of anxiety, coping styles, personality traits, and social adjustment: a casecontrol study. Arch Gynecol Obstet. 2020; 301(2): 619-626.
  24. Kohlenberg RJ, Tsai M. Functional analytic psychotherapy: Creating intense and curative therapeutic relationships. Boston, USA; Springer: 1991.
  25. Newton CR, Sherrard W, Glavac I. The Fertility Problem Inventory: measuring perceived infertility-related stress. Fertil Steril. 1999; 72(1): 54-62.
  26. Beck AT, Steer RA, Brown GK. Beck depression inventory-II. San Antonio. 1996; 78(2): 490-498.
  27. Ghassemzadeh H, Mojtabai R, Karamghadiri N, Ebrahimkhani N. Psychometric properties of a Persian-language version of the beck depression inventory--second edition: BDI-II-PERSIAN. Depress Anxiety. 2005; 21(4): 185-192.
  28. Samani RO, Almasi-Hashiani A, Shokri F, Maroufizadeh S, Vesali S, Sepidarkish M. Validation study of the fertility problem inventory in Iranian infertile patients. Middle East Fertil Soc J. 2017; 22(1): 48-53.
  29. Spielberger CD, Vagg PR, Barker LR, Donham GW, Westberry LG. The factor structure of the state-trait anxiety inventory. Stress and anxiety. Washington, DC: Hemisplere. 1980.
  30. Abdoli N, Farnia V, Salemi S, Davarinejad O, Ahmadi Jouybari T, Khanegi M, et al. Reliability and validity of persian version of statetrait anxiety inventory among high school students. East Asian Arch Psychiatry. 2020; 30(2): 44-47.
  31. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Lawrence Erlbaum Associates; 1988: 20-26.
  32. Petrak F, Herpertz S, Albus C, Hermanns N, Hiemke C, Hiller W, et al. Cognitive behavioral therapy versus sertraline in patients with depression and poorly controlled diabetes: the diabetes and depression (DAD) study: a randomized controlled multicenter trial. Diabetes Care. 2015; 38(5): 767-775.
  33. San Lazaro Campillo I, Meaney S, McNamara K, O'Donoghue K. Psychological and support interventions to reduce levels of stress, anxiety or depression on women's subsequent pregnancy with a history of miscarriage: an empty systematic review. BMJ Open. 2017; 7(9): e017802.
  34. Pasha H, Faramarzi M, Esmailzadeh S, Kheirkhah F, Salmalian H. Comparison of pharmacological and nonpharmacological treatment strategies in promotion of infertility self-efficacy scale in infertile women: a randomized controlled trial. Iran J Reprod Med. 2013; 11(6): 495-502.
  35. Wenzel A. Cognitive behavioral therapy for pregnancy loss. Psychotherapy (Chic). 2017; 54(4): 400-405.