Human Reproduction Archives
Human Reproduction Archives
REVIEW ARTICLE Assisted Reproduction

Recurrent Pregnancy Loss: reviewing therapeutic approaches

Elaine Cristina Fontes de Oliveira, Mariana Seabra Leite Praça, Gabriela Martins Perez Garcia, Ines Katerina Damasceno Cavallo

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Objetive: to discuss recurrent pregnancy loss (RPL) causes and shed light on the current evidence in the management of each one. Methods: A comprehensive and non-systematic search of the theme was carried out through online databases (PubMed and Cochrane database), using the terms “recurrent pregnancy loss”, “treatment”, “genetic or chromosomal abnormalities”, “uterine factor”, “uterine septum”, “fibroid”, “myoma”, “cerclage”, “endocrine causes”, “polycystic ovary syndrome”, “thyroid”, “hypothyroidism”, “hyperprolactnemia”, “antiphospholipid syndrome”, “hereditary thrombophilia”, “inherited trombophilia”, “obesity”, “lifestyle”, “unexplained miscarriages”, “progestogens”, “vaginal progesterone”, “assisted reproductive technologies”, “in vitro fertilization”, preimplantation genetic screening”, “obstetric complications” and variants as keywords. Results: Couples with structural chromosomal rearrangements should be advised of the good reproductive prognosis after natural conception, so that in vitro fertilization plus preimplantation genetic diagnosis should not be offered as first-line treatment for them. Treatment of women with subclinical hypothyroidism may reduce the risk of miscarriage. Bromocriptine treatment can be considered in women with hyperprolactinemia. There is insufficient evidence to recommend metformin supplementation in pregnancy to prevent pregnancy loss in women with glucose metabolism defect. Treatment of Antiphospholipid Syndrome with low-dose aspirin started preconceptionally and heparin started after the first positive pregnancy test is recommended. The evidence to recommend the use of progesterone to improve live birth rate in women with RPL and luteal phase insufficiency is insufficient. Conclusion: The treatment for RPL should be directed to the cause of the miscarriages. Since the outcomes for most couples with unexplained RPL are favorable without treatment, therapy interventions that have not been proven are not recommended.


Abortion;  Abortion habitual; Thrombophilia; Obesity; Clinical protocols


1. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535):601-11. PMid:16905025.

2. Kolte AM, Bernardi LA, Christiansen OB, Quenby S, Farquharson RG, Goddijn M, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2015;30(3):495-8. http:// PMid:25376455.

3. Tulandi T, Al-Fozan HM. Definition and etiology of recurrent pregancy loss. Up to date [Internet]. 2021 [cited 2021 Nov 2]. Available from:

4. Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy loss. Fertil Steril. 2010;93(4):1234-43. PMid:19338986.

5. Porter TF, Scott JR. Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol. 2005;19(1):85-101. http:// PMid:15749068.

6. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod. 2006;21(9):2216-22. PMid:16707507.

7. Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol. 2019;59(1):36-44. ajo.12920. PMid:30393965.

8. Saravelos SH, Regan L. Unexplained recurrent pregnancy loss. Obstet Gynecol Clin North Am. 2014;41(1):157-66. http://dx.doi. org/10.1016/j.ogc.2013.10.008. PMid:24491990.

9. Popescu F, Jaslow CR, Kutteh WH. Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definitive cause of pregnancy loss in over 90% of patients. Hum Reprod. 2018;33(4):579-87. http:// PMid:29538673.

10. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ. 2000;320(7251):1708-12. PMid:10864550.

11. Maquard Marquard K, Westphal LM, Milki AA, Lathi RB. Etiology of recurrent pregnancy loss in women over the age of 35 years. Hum Reprod. 2010;94(4):1473-1477. PMID: 19643401.

12. Sugiura-Ogasawara M, Ozaki Y, Kitaori T. Diagnosis and treatment methods for recurrent miscarriage cases. Reprod Med Biol. 2009;8(4):141-4. PMid:29699318.

13. Royal College of Obstetricians and Gynecologists. Recurrent miscarriage, investigation and treatment of couples. London: RCGO; 2011. (Greentop Guideline; no. 17).

14. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103-11. PMid:22835448.

15. Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. PMid:31486805.

16. de Ziegler D, Frydman RF. Recurrent pregnancy losses, a lasting cause of infertility. Fertil Steril. 2021;115(3):531-2. http://dx.doi. org/10.1016/j.fertnstert.2020.12.004. PMid:33581853.

17. Munné S, Howles CM, Wells D. The role of preimplantation genetic diagnosis in diagnosing embryo aneuploidy. Curr Opin Obstet Gynecol. 2009;21(5):442-9. PMid:19606031.

18. Iews M, Tan J, Taskin J, Alfaraj S, AbdelHafez FF, Abdellah AH, et al. Does preimplantation genetic diagnosis improve reproductive outcome in couple with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review. Reprod Biomed Online. 2018;36(6):677-85. PMid:29627226.

19. Carbonnel M, Pirtea P, de Ziegler D, Ayoubi JM. Uterine factors in recurrent pregnancy losses. Fertil Steril. 2021;115(3):538-45. PMid:33712099.

20. Rackow BW, Arici A. Reproductive performance of women with müllerian anomalies. Curr Opin Obstet Gynecol. 2007;19(3):229- 37. PMid:17495638.

21. Turocy JM, Rackow BW. Uterine factor in recurrent pregnancy loss. Semin Perinatol. 2019;43(2):74-9. semperi.2018.12.003. PMid:30683511.

22. Krishnan M, Narice BF, Ola B, Metwally M. Does hysteroscopic resection of uterine septum improve reproductive outcomes: a systematic review and meta-analysis. Arch Gynecol Obstet. 2021;303(5):1131-42. PMid:33550465.

23. Rikken JFW, Verhorstert KWJ, Emanuel MH, Bongers MY, Spinder T, Kuchenbecker WKH, et al. Septum resection in women with a septate uterus: a cohort study. Hum Reprod. 2020;35(7):1578-88. PMid:32353142.

24. Penzias A, Bendikson K, Butts S, Coutifaris C, Falcone T, Fossum G, et al. Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline. Fertil Steril. 2017;108(3):416-25. fertnstert.2017.06.034. PMid:28865538.

25. Saravelos SH, Yan J, Rehmani H, Li TC. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod. 2011;26(12):3274-9. PMid:21954281.

26. Shahine L, Lathi R. Recurrent pregnancy loss: evaluation and treatment. Obstet Gynecol Clin North Am. 2015;42(1):117-34. http:// PMid:25681844.

27. Alfirevic Z, Stampalija T, Medley N. Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy. Cochrane Database Syst Rev. 2017;6(6):CD008991. PMid:28586127.

28. Amrane S, McConnell R. Endocrine causes of recurrent pregnancy loss. Semin Perinatol. 2019;43(2):80-3. semperi.2018.12.004. PMid:30665726.

29. Shahine L, Lathi R. Recurrent pregnancy loss evaluation and treatment. Obstet Gynecol Clin North Am. 2015;42(1):117-34. http:// PMid:25681844.

30. Palomba S, Falbo A, Orio F Jr, Zullo F. Effect of preconceptional metformin on abortion risk in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2009;92(5):1646-58. fertnstert.2008.08.087. PMid:18937939.

31. Vissenberg R, van den Boogaard E, van Wely M, van der Post JA, Fliers E, Bisschop PH, et al. Treatment of thyroid disorders before conception and early pregnancy: a systematic review. Hum Reprod Update. 2012;18(4):360-73. humupd/dms007. PMid:22431565.

32. Yoshihara H, Sugiura-Ogasawara M, Goto S, Kitaori T. Levothyroxine and subclinical hypothyroidism in patients with recurrent pregnancy loss. Am J Reprod Immunol. 2021;85(3):e13341. PMid:32894608.

33. van Dijk MM, Vissenberg R, Bisschop PH, Dawood F, van Wely M, Goddijn M, et al. Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage? Reprod Biomed Online. 2016;33(6):745- 51. PMid:27720162.

34. Dong AC, Morgan J, Kane M, Stagnaro-Green A, Stephenson MD. Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2020;113(3):587-600. fertnstert.2019.11.003. PMid:32192591.

35. Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil Steril. 1998;70(2):246-52. PMid:9696215.

36. Chen H, Fu J, Huang W. Dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history. Cochrane Database Syst Rev. 2016;7(7):CD008883. pub2. PMid:27455388.

37. Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev. 2017;31(6):406-17. http:// PMid:28784423.

38. Liu X, Qiu Y, Yu ED, Xiang S, Meng R, Niu K, et al. Comparison of therapeutic interventions for recurrent pregnancy loss in association with antiphospholipid syndrome: a systematic review and network meta-analysis. Am J Reprod Immunol. 2020;83(4):e13219. PMid:31872490.

39. Hamulyák EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev. 2020;5(5):CD012852. PMid:32358837.

40. Liu X, Chen Y, Ye C, Xing D, Wu R, Li F, et al. Hereditary thrombophilia and recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod. 2021;36(5):1213-29. PMid:33575779.

41. Tan WK, Lim SK, Tan LK, Bauptista D. Does low-molecular-weight heparin improve live birth rates in pregnant women with thrombophilic disorders? A systematic review. Singapore Med J. 2012;53(10):659-63. PMid:23112017.

42. Davenport WB, Kutteh WH. Inherited trombophilias and adverse pregnancy outcomes: a review of screening patterns and recommendations. Obstet Gynecol Clin North Am. 2014;41(1):133-44. PMid:24491988.

43. Ng KYB, Cherian G, Kermack AJ, Bailey S, Macklon N, Sunkara SK, et al. Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss. Sci Rep. 2021;11(1):7081. PMid:33782474.

44. Cavalcante MB, Sarno M, Peixoto AB, Araujo Júnior E, Barini R. Obesity and recurrent miscarriage: A systematic review and meta-analysis. J Obstet Gynaecol Res. 2019;45(1):30-8. PMid:30156037.

45. Devall AJ, Coomarasamy A. Sporadic pregnancy loss and recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol. 2020;69:30-9. PMid:32978069.

46. Coomarasamy A, Dhillon-Smith RK, Papadopoulou A, Al-Memar M, Brewin J, Abrahams VM, et al. Recurrent miscarriage: evidence to accelerate action. Lancet. 2021;397(10285):1675-82. PMid:33915096.

47. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev. 2019;2019(11):CD003511. PMid:31745982.

48. Saccone G, Schoen C, Franasiak JM, Scott RT Jr, Berghella V. Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials. Fertil Steril. 2017;107(2):430-8.e3. PMid:27887710.

49. Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373(22):2141-8. PMid:26605928.

50. Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton LJ, Gallos ID, et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med. 2019;380(19):1815-24. PMid:31067371.

51. Coomarasamy A, Devall AJ, Brosens JJ, Quenby S, Stephenson MD, Sierra S, et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020;223(2):167-76. ajog.2019.12.006. PMid:32008730.

52. Devall AJ, Papadopoulou A, Podesek M, Haas DM, Price MJ, Coomarasamy A, et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021;4(4):CD013792. PMid:33872382.

53. Kirshenbaum M, Orvieto R. Should we offer in vitro fertilization to couples with unexplained recurrent pregnancy loss? J Clin Med. 2019;8(11):2001. PMid:31744073.

54. Kaandorp SP, van Mens TE, Middeldorp S, Hutten BA, Hof MH, van der Post JA, et al. Time to conception and time to live birth in women with unexplained recurrent miscarriage. Hum Reprod. 2014;29(6):1146-52. PMid:24682612.

55. Perfetto CO, Murugappan G, Lathi RB. Time to next pregnancy in spontaneous pregnancies versus treatment cycles in fertile patients with recurrent pregnancy loss. Fertil Res Pract. 2015;1(1):5. PMid:28620510.

56. Murugappan G, Shahine LK, Perfetto CO, Hickok LR, Lathi RB. Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss. Hum Reprod. 2016;31(8):1668-74. PMid:27278003.

57. Ticconi C, Pietropolli A, Specchia M, Nicastri E, Chiaramonte C, Piccione E, et al. Pregnancy-related complications in women with recurrent pregnancy loss: a prospective cohort study. J Clin Med. 2020;9(9):2833. PMid:32882985.

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