Skip to main content
Log in

Early pregnancy failure: a review

  • Clinical Review
  • Published:
European Clinics in Obstetrics and Gynaecology

Abstract

The European Society for Human Reproduction and Embryology’s Special Interest Group Early Pregnancy recently published a revised terminology for the description of early pregnancy events as well as evidence-based guidelines for the investigation and medical treatment for patients with recurrent miscarriage (RM). This review, designed for clinicians working in the field of human reproduction, starts with the updated glossary of terms essential for an accurate assessment and documentation of clinical events. The revised terminology is summarized in this article. Many terms used in early pregnancy were old and had persisted before or since the introduction of ultrasound. Based on the data of recently published randomized controlled trials (RCTs) and meta-analysis, recommendations are provided for basic investigations of couples presenting with RM and for proposed therapies. The recommendations are likewise summarized in this article. A large number of therapies mentioned in the literature require more investigations under strict RCT conditions, whilst others are of no proven benefit or are associated with more harm than good.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Farquharson RG, Jauniaux E, Exalto N (2005) Updated and revised nomenclature for decription of early pregnancy events. Hum Reprod 20:3008–3011

    Article  PubMed  Google Scholar 

  2. Royal College of Obstetricians and Gynaecologists (2006) The management of early pregnancy loss. Green-top Guideline, Nr 25. RCOG, London

    Google Scholar 

  3. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21:2216–2222

    Article  PubMed  Google Scholar 

  4. O’Rahilly R, Muller F (2000) Prenatal ages and stages: measures and errors. Teratology 61:382–384

    Article  PubMed  CAS  Google Scholar 

  5. Pedersen JF (1982) Fetal crown rump length measurement by ultrasound in normal pregnancy. BJOG 89:926–930

    Article  CAS  Google Scholar 

  6. O’Rahilly R (1986) The embryonic period. Teratology 34:119 (Letter)

    Article  PubMed  CAS  Google Scholar 

  7. Macklon NS, Geraedts JPM, Fauser BCJM (2002) Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Updat 8:333–343

    Article  CAS  Google Scholar 

  8. Condous G, Timmerman D, Goldstein S, Valentin L, Jurkovic D, Bourne T (2006) Pregnancies of unknown location: consensus statement. Ultrasound Obstet Gynecol 28:121–122

    Article  PubMed  CAS  Google Scholar 

  9. Jauniaux E, Kaminopetros P, El-Rafaey H (1999) Early pregnancy loss. In: Rodeck CH, Whittle MJ (eds) Fetal medicine. Churchill Livingstone, p 835–847

  10. Chittacharoen A, Herabutya Y (2004) Slow fetal heart rate may predict pregnancy outcome in first-trimester threatened abortion. Fertil Steril 82:227–229

    Article  PubMed  Google Scholar 

  11. Duncan JM (1868) Researches in obstetrics. A & C Black, Edinburgh

    Google Scholar 

  12. Hutchon DJ, Cooper S (1997) Missed abortion versus delayed miscarriage. Br J Obstet Gynaecol 104:73

    Google Scholar 

  13. Brigham S, Conlon C, Farquharson RG (1999) A longitudinal study of pregnancy outcome following idiopathic recurring miscarriage. Hum Reprod 14:2868–2871

    Article  PubMed  CAS  Google Scholar 

  14. Bricker L, Farquharson RG (2002) Types of pregnancy loss in recurrent miscarriage: implications for research and clinical practice. Hum Reprod 17:1345–1350

    Article  PubMed  CAS  Google Scholar 

  15. Ugwumadu A, Manyonda I, Reid F, Hay P (2003) Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomized controlled trial. Lancet 361:983–988

    Article  PubMed  CAS  Google Scholar 

  16. Stirrat GM (1990) Recurrent miscarriage: definition and epidemiology. Lancet 336:673–675

    Article  PubMed  CAS  Google Scholar 

  17. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M (2000) Maternal age and fetal loss: population-based register linkage study. BMJ 320:1708–1712

    Article  PubMed  CAS  Google Scholar 

  18. Christiansen OB, Nybo Andersen AM, Bosch E, Daya S, Delves PJ, Hviid TV, Kutteh WH, Laird SM, Li TC, van der Ven K (2005) Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril 83:821–839

    Article  PubMed  Google Scholar 

  19. Aplin JD, Hey NA, Li TC (1996) MUC1 as a cell surface and secretory component of endometrial epithelium: reduced levels in recurrent miscarriage. Am J Reprod Immunol 35:261–266

    PubMed  CAS  Google Scholar 

  20. Quenby S, Vince G, Farquarson R, Aplin J (2002) Recurrent miscarriage: a defect in nature’s quality control? Hum Reprod 17:1959–1963

    Article  PubMed  Google Scholar 

  21. Stray-Pedersen B, Stray-Pedersen S (1984) Etiological factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 148:140–146

    PubMed  CAS  Google Scholar 

  22. Clifford K, Rai R, Regan L (1997) Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 12:387–389

    Article  PubMed  CAS  Google Scholar 

  23. Jauniaux E, Burton GJ (2005) Pathophysiology of histological changes in early pregnancy loss. Placenta 26:114–123

    Article  PubMed  CAS  Google Scholar 

  24. Fox H (1993) Histological classification of tissue from spontaneous abortions: a valueless exercise? Histopathology 22:599–600

    PubMed  CAS  Google Scholar 

  25. Hakvoort RA, Lisman BA, Boer K, Bleker OP, van Groningen K, van Wely M, Exalto N (2006) Histological classification of chorionic villous vascularization in early pregnancy. Hum Reprod 21:1291–1294

    Article  PubMed  CAS  Google Scholar 

  26. Morikawa M, Yamada H, Kato EH, Shimada S, Yamada T, Minakami H (2004) Embryo loss pattern is predominant in miscarriages with normal chromosome karyotype among women with repeated miscarriage. Hum Reprod 19:2644–2647

    Article  PubMed  Google Scholar 

  27. Ogasawara M, Aoki K, Okada S, Suzumori K (2000) Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 73:300–304

    Article  PubMed  CAS  Google Scholar 

  28. Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G (2001) Karyotype of the abortus in recurrent miscarriage. Fertil Steril 75:678–682

    Article  PubMed  CAS  Google Scholar 

  29. Stephenson MD, Awartini KA, Robinson WP (2002) Cytogenetic analysis of miscarriages from couples with recurring miscarriage: a case-control study. Hum Reprod 17:446–451

    Article  PubMed  CAS  Google Scholar 

  30. Braekeleer de M, Dao TN (1990) Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 5:519–528

    Google Scholar 

  31. Franssen MTM, Korevaar JC, Leschot NJ, Bossuyt PMM, Knegt AC, Gerssen-Schoorl KBJ, Wouters CH, Hansson KBM, Hochstenbach R, Madan K, van der Veen F, Goddijn M (2005) Selective chromosome analysis in couples with two or more miscarriages: case-control study. BMJ 331:137–139

    Article  PubMed  Google Scholar 

  32. Homer HA, Li TC, Cooke ID (2000) The septate uterus: a review of management and reproductive outcome. Fertil Steril 73:1–14

    Article  PubMed  CAS  Google Scholar 

  33. Salim R, Woelfer B, Backos M, Regan L, Jurkovic D (2003a) Reproducibility of three-dimension ultrasound diagnosis of congenital uterine anomalies. Ultrasound Obstet Gynecol 21:578–582

    Article  PubMed  CAS  Google Scholar 

  34. Woelfer B, Salim R, Banerjee S, Elson J, Regan L, Jurkovic D (2001) Reproductive outcome in women with congenital uterine anomalies detected by three-dimension ultrasound screening. Obstet Gynecol 98:1099–1103

    Article  PubMed  CAS  Google Scholar 

  35. Salim R, Regan L, Woelfer B, Backos M, Jurkovic D (2003b) A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum Reprod 28:162–166

    Article  Google Scholar 

  36. Gianaroli L, Gordts S, D’Angelo A, Magli MC, Brosens I, Cetera C, Campo R, Ferraretti AP (2005) Effect of inner myometrium fibroid on reproductive outcome after IVF. Reprod Biomed Online 10:473–477

    Article  PubMed  Google Scholar 

  37. Royal College of Obstetricians and Gynaecologists (1998) The management of recurrent miscarriage. Guideline 1998; Nr 17. RCOG, London

    Google Scholar 

  38. Clifford K, Rai RS, Watson H, Franks S, Regan L (1996) Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial. Br Med J 312:1508–1511

    CAS  Google Scholar 

  39. Lashen H, Fear K, Sturdee DW (2004) Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Hum Reprod 19:1644–1646

    Article  PubMed  CAS  Google Scholar 

  40. Fedorcksac P, Dale PO, Storeng R, Tanbo T, Abyholm T (2001) The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod 16:1086–1091

    Article  Google Scholar 

  41. Bellver J, Rossal LP, Bosch E, Zuniga A, Corona JT, Melendez F, Gomez E, Simon C, Remohi J, Pellicer A (2003) Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 79:1136–1140

    Article  PubMed  Google Scholar 

  42. Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F (2005a) Prospective parallel randomized, double blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:4068–4074

    Article  PubMed  CAS  Google Scholar 

  43. Palomba S, Orio F Jr, Falbo A, Russo T, Tolino A, Zullo F (2005b) Plasminogen activator inhibitor 1 and miscarriage after metformin treatment and laparoscopic ovarian drilling in patients with polycystic ovary syndrome. Fertil Steril 84:761–765

    Article  PubMed  CAS  Google Scholar 

  44. Thatcher SS, Jackson EM (2006) Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 85:1002–1009

    Article  PubMed  CAS  Google Scholar 

  45. Oates-Whitehead RM, Hass DM, Carrier JAK (2005) Progestogen for preventing miscarriage. Cochrane Database Syst Rev 4:CD003511

    Google Scholar 

  46. Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ (2005) Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 159:957–962

    Article  PubMed  Google Scholar 

  47. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA (1999) International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 42:1309–1311

    Article  PubMed  CAS  Google Scholar 

  48. Kutteh WH (1996) Antoiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 174:1584–1589

    Article  PubMed  CAS  Google Scholar 

  49. Rai RS, Cohen H, Dave M, Regan L (1997) Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphopholipid antibodies). Br Med J 314:253–257

    CAS  Google Scholar 

  50. Farquharson RG, Quenby S, Greaves M (2002) Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 100:408–413

    Article  PubMed  CAS  Google Scholar 

  51. Derksen RHWM, Khamashta MA, Branch DW (2004) Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 50:1028–1039

    Article  PubMed  CAS  Google Scholar 

  52. Empson M, Lassere M, Craig J, Scott J (2005) Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2:CD002859

    PubMed  Google Scholar 

  53. Di Nisio M, Peters LW, Middeldorp S (2005) Anticoagulants for the treatement of recurrent pregnancy loss in women without antiphospholipid syndrome. Cochrane Database Syst Rev 2:CD004734

    PubMed  Google Scholar 

  54. Rey E, Kahn SR, David M, Shrier I (2003) Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 361:901–908

    Article  PubMed  Google Scholar 

  55. Dawood F, Farquharson R, Quenby S, Toh CH (2003) Acquired activated protein C resistance may be a risk factor for recurrent fetal loss. Fertil Steril 80:649–650

    Article  PubMed  Google Scholar 

  56. Roque H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ (2004) Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 91:290–295

    PubMed  CAS  Google Scholar 

  57. Carp H, Dolizky M, Tur-Kaspa I, Inbal A (2002) Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage. Fertil Steril 78:58–62

    Article  PubMed  Google Scholar 

  58. van Dunne FM, Doggen CJ, Heemskerk M, Rosendaal FR, Helmerhorst FM (2005) Factor V Leiden mutation in relation to fecundity and miscarriage in women with venous thrombosis. Hum Reprod 20:802–806

    Article  PubMed  CAS  Google Scholar 

  59. Jivraj S, Rai R, Underwood J, Regan L (2006) Genetic thrombophilic mutations among couples with recurrent miscarriage. Hum Reprod 21:1161–1165

    Article  PubMed  CAS  Google Scholar 

  60. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GDO, Walker ID, Greaves M, Brenkel I, Regan L, Greer IA (2006) Thrombophilia in pregnancy: a systematic review. The thrombosis: risk and economic assessment of thrombophilia screening (TREATS) study. Br J Haematol 132:171–196

    Article  PubMed  CAS  Google Scholar 

  61. Nelen WLDM, Blom HK, Steegers EAP, den Heijer M, Eskes TKAB (2000) Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 74:1196–1199

    Article  PubMed  CAS  Google Scholar 

  62. Makris M (2000) Hyperhomocysteinemia and thrombosis. Clin Lab Haematol 22:133–143

    Article  PubMed  CAS  Google Scholar 

  63. George L, Mills JL, Johansson AL, Nordmark A, Olander B, Granath F, Cnattingius S (2002) Plasma folate levels and risk of spontaneous abortion. JAMA 288:1867–1873

    Article  PubMed  CAS  Google Scholar 

  64. Laird SM, Tukerman EM, Cork BA, Linjawi S, Blakemore AIF, Li TC (2003) A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Updat 9:163–174

    Article  CAS  Google Scholar 

  65. Moffett A, Regan L, Braude P (2004) Natural killer cells, miscarriage, and infertility. BMJ 329:1283–1285

    Article  PubMed  Google Scholar 

  66. Wold AS, Arici A (2005) Natural killer cells and reproductive failure. Curr Opin Obstet Gynecol 17:237–241

    Article  PubMed  Google Scholar 

  67. Rai R, Sacks G, Trew G (2005) Natural killer cells and reproductive failure, practice and prejudice. Hum Reprod 20:1123–1126

    Article  PubMed  Google Scholar 

  68. Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G (2005) Prednisolone reduces preconceptual natural killer cells in women with recurrent miscarriage. Fertil Steril 84:980–984

    Article  PubMed  CAS  Google Scholar 

  69. Kruse C, Rosgaard A, Steffensen R, Varming K, Jensenius JC, Christiansen OB (2002) Low serum level of mannan-binding lectin is a determinant for pregnancy outcome in women with recurrent spontaneous abortion. Am J Obstet Gynecol 187:1313–1320

    Article  PubMed  CAS  Google Scholar 

  70. Christiansen OB, Nielsen HS, Pedersen B (2004) Active or passive immunization in unexplained recurrent miscarriage. J Reprod Immunol 62:41–51

    Article  PubMed  CAS  Google Scholar 

  71. Christiansen OB, Nielsen HS (2005) Intravenous immunoglobulin in the prevention of recurrent miscarriage: does it work? Chem Immunol Allergy 88:117–127

    Article  PubMed  CAS  Google Scholar 

  72. Porter TF, LaCoursiere YL, Scott JR (2006) Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev

  73. Simpson JL, Mills JL, Lee J, Holmes JB, Kim H, Metzger B, Knopp R, Jovanovic-Peterson L, Aarons J, Conley M (1996) Infectious processes: an infrequent cause of first trimester spontaneous abortions. Hum Reprod 11:668–672

    PubMed  CAS  Google Scholar 

  74. Li TC, Makris M, Tomsu M, Tuckerman E, Laird S (2002) Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Updat 8:463–481

    Article  CAS  Google Scholar 

  75. Gardella JR, Hill JA (2000) Environmental toxins associated with recurrent pregnancy loss. Semin Reprod Med 18:407–424

    Article  PubMed  CAS  Google Scholar 

  76. Rumbold A, Middleton P, Crowther CA (2005) Vitamin supplementation for preventing miscarriage. Cochrane Database Syst Rev 2:CD004073

    PubMed  Google Scholar 

  77. Clark AM, Thornley B, Tomlinson L, Gattetley C, Norman RJ (1998) Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 13:1502–1505

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Niek Exalto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Exalto, N., Christiansen, O.B., Farquharson, R.G. et al. Early pregnancy failure: a review. Eur Clinics Obstet Gynaecol 2, 171–179 (2006). https://doi.org/10.1007/s11296-006-0050-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11296-006-0050-9

Keywords

Navigation