Epidemiology

Miscarriage, the most common complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation.

• 10-15% of all pregnancies miscarry.¹
• 1% of couples trying to conceive have recurrent miscarriages.
• This is much higher than the 0.34% calculated risk of three occurring consecutively by chance alone.

No underlying cause is found in many of them.

Risk factors

• Increasing maternal age affects ovarian function and the quality of available oocytes.
• There are a higher number of conceptions that are chromosomally abnormal and do not develop.
• As the number of miscarriages increases, the risk of chromosome abnormalities decreases and the risk of underlying maternal cause increases.

Aetiology

• Genetic abnormalities:
  • Fetal aneuploidy (trisomy in particular) is the most common cause of miscarriage before 10 weeks' gestation.¹
• Antiphospholipid syndrome:
  • This is the most important treatable cause of recurrent miscarriage.
  • Antiphospholipid antibodies are a family of about 20 antibodies which include lupus anticoagulant and anticardiolipin antibodies.
  • The prevalence of antiphospholipid syndrome in women with recurrent miscarriage is 15%.²
• Structural:
  • Uterine anomalies (bicornuate uterus or septa) are seen in up to 37% of cases of recurrent miscarriage.^3,4 Only 50% of pregnancies where there is a uterine structural abnormality achieve term delivery.⁴
  • Uterine fibroids are present in up to 30% of women, but the way they affect reproductive loss is unclear.
  • Cervical incompetence (late miscarriage preceded by spontaneous rupture of membranes or painless cervical dilatation), is frequently cited as a cause of midtrimester recurrent miscarriage.
• Infective:
  • Toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus (ToRCH) and listeriosis screening has been abandoned when investigating recurrent miscarriage.¹
  • There is poor evidence for bacterial vaginosis as a cause of early miscarriage secondary to endometritis.
• Endocrine:
  • The relationship between polycystic ovarian syndrome, insulin resistance and pregnancy loss is now thought to be key.⁵
  • Insulin resistance is common in women with recurrent miscarriage and has been associated with an increased rate of miscarriage.
  • Prolactin is necessary for ovulation and endometrial maturation. Hyperprolactinaemia is reported to cause recurrent miscarriage, and treatment with bromocriptine significantly reduces the rate of miscarriage.⁶
• Immune:
  • Women with recurrent miscarriage have more natural killer cells in their uterine mucosa than controls and those with the highest levels have a correspondingly high rate of miscarriage in subsequent pregnancies.⁷
  • Unfortunately, there is no association between the levels of natural killer cells in peripheral blood and in the uterine mucosa. Levels of natural killer cells in peripheral blood are not predictive of pregnancy outcome in women with unexplained recurrent miscarriage.
• Thrombophilias:
  • Three thrombophilic mutations were first identified in the mid-1990s: factor V Leiden (FVL) G1691A; factor II (prothrombin) G20210A and methylenetetrahydrofolate reductase C677T.
  • However, women with the FVL mutation can have an uncomplicated full-term pregnancy, but multiple risk factors increase the likelihood of adverse pregnancy outcomes.
• Unknown.

Investigations

• Antiphospholipid antibodies:⁸
  • The presence of these is associated with early miscarriages and maternal morbidity and is referred to as primary antiphospholipid syndrome (APS). There is requirement for two tests at least six weeks apart showing either lupus anticoagulant or anticardiolipin antibodies at significant levels.
• Pelvic ultrasound: this is used to assess uterine anatomy and morphology.
• Screening for and treatment of bacterial vaginosis is effective in some cases.

Karyotyping

• Blood karyotyping for both partners - 3-5% of couples with recurrent miscarriage have a partner with a balanced reciprocal (Robertsonian) translocation.^9,10 If this is found, the couple should be referred to a clinical geneticist for counselling. Doubts have been raised over the cost for benefit of parent karyotyping.¹¹
• Karyotyping of products of conception - probably should be used where a patient has been undergoing treatment during that pregnancy.

Management

General advice

Where no abnormality is found, reassurance that there is a 75% chance of successful future pregnancy with supportive care is often all that is required.

Pharmacological treatment

• In primary antiphospholipid syndrome (APS) patients, heparin combined with low-dose aspirin improves live birth rate to 70%.¹³ No benefit has been demonstrated for patients without APS.¹⁴
• However, even treated, there is a high risk of complications throughout pregnancy. Intravenous immunoglobulin (IVIG) with prednisolone has been used.¹⁵
• There is a body of evidence suggesting that use of metformin during pregnancy is associated with a reduction in the miscarriage rate in women with polycystic ovarian syndrome. However the RCOG DOES NOT recommend its use in pregnancy at present until further randomised prospective study results are available to provide adequate evidence of safety and efficacy of its use.¹⁶
• Cochrane review found evidence of benefit for progestogen therapy in women with a history of recurrent miscarriage. There was no statistically significant difference in rates of adverse effects.¹⁷

Surgical

Cervical cerclage: cervical incompetence is overdiagnosed as a cause of second trimester miscarriage.

• A Cochrane review failed to show a reduction in the risk of recurrent midtrimester miscarriage.¹⁸
• However, in 2 randomised controlled trials (RCTs) there was some benefit in women with three or more second trimester miscarriages or preterm deliveries.^19,20
• Cerclage carries a risk of stimulating uterine contractions.

Associations

• There is a greater proportion of women with recurrent miscarriage who have polycystic ovaries; however, this carries no predictive value for future conceptions.
• Women with recurrent miscarriage are at high risk for adverse obstetric outcomes, including fetal abnormalities, stillbirths and neonatal deaths, even when the pregnancies are ongoing.²¹

Document references

1. Rai R, Regan L; Recurrent miscarriage. Lancet. 2006 Aug 12;368(9535):601-11. [abstract]
2. Rai RS, Regan L, Clifford K, et al; Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod. 1995 Aug;10(8):2001-5. [abstract]
3. Salim R, Regan L, Woelfer B, et al; A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum Reprod. 2003 Jan;18(1):162-6. [abstract]
4. Grimbizis GF, Camus M, Tarlatzis BC, et al; Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update. 2001 Mar-Apr;7(2):161-74. [abstract]
5. Craig LB, Ke RW, Kutteh WH; Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril. 2002 Sep;78(3):487-90. [abstract]
6. Hirahara F, Andoh N, Sawai K, et al; Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil Steril. 1998 Aug;70(2):246-52. [abstract]
7. Lachapelle MH, Miron P, Hemmings R, et al; Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome. J Immunol. 1996 May 15;156(10):4027-34. [abstract]
8. Heilmann L, von Tempelhoff GF, Kuse S; The influence of antiphospholipid antibodies on the pregnancy outcome of patients with recurrent spontaneous abortion. Clin Appl Thromb Hemost. 2001 Oct;7(4):281-5. [abstract]
9. Clifford K, Rai R, Watson H, et al; An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod. 1994 Jul;9(7):1328-32. [abstract]
10. De Braekeleer M, Dao TN; Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod. 1990 Jul;5(5):519-28. [abstract]
11. Barber JC, Cockwell AE, Grant E, et al; Is karyotyping couples experiencing recurrent miscarriage worth the cost? BJOG. 2010 Jun;117(7):885-8. [abstract]
12. The investigation and treatment of couples with recurrent miscarriage, Royal College of Obstetricians and Gynaecologists (RCOG), 2003
13. Empson M, Lassere M, Craig JC, et al; Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol. 2002 Jan;99(1):135-44. [abstract]
14. Kaandorp S, Di Nisio M, Goddijn M, et al; Aspirin or anticoagulants for treating recurrent miscarriage in women without Cochrane Database Syst Rev. 2009 Jan 21;(1):CD004734. [abstract]
15. Vaquero E, Lazzarin N, Valensise H, et al; Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. Am J Reprod Immunol. 2001 Mar;45(3):174-9. [abstract]
16. Long-term consequences of polycystic ovary syndrome, Royal College of Obstetricians and Gynaecologists (RCOG), 2007
17. Haas DM, Ramsey PS; Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003511. [abstract]
18. Drakeley AJ, Roberts D, Alfirevic Z. Cervical stitch (cerclage) for preventing pregnancy loss in women. Cochrane Database Syst Rev 2003; 1:CD003253.
19. Althuisius SM, Dekker GA, van Geijn HP, et al; Cervical incompetence prevention randomized cerclage trial (CIPRACT): study design and preliminary results. Am J Obstet Gynecol. 2000 Oct;183(4):823-9. [abstract]
20. Rust OA, Atlas RO, Jones KJ, et al; A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os. Am J Obstet Gynecol. 2000 Oct;183(4):830-5. [abstract]
21. Yang CJ, Stone P, Stewart AW; The epidemiology of recurrent miscarriage: a descriptive study of 1214 prepregnant women with recurrent miscarriage. Aust N Z J Obstet Gynaecol. 2006 Aug;46(4):316-22. [abstract]

Internet and further reading

• Gynaecology services webpage, St Mary's, Paddington

Acknowledgements