Recurrent Miscarriage

Miscarriage, the commonest 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% 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 decreases² and the risk of underlying maternal cause increases.³

• Genetic abnormalities:
  • Fetal aneuploidy (trisomy in particular) is the most common cause of miscarriage before 10 weeks gestation.⁴
• Antiphospholipid syndrome:
  • This is the most important treatable cause of recurrent miscarriage.
  • Antiphospholipid antibodies are a family of about 20 antibodies that include lupus anticoagulant and anticardiolipin antibodies.
  • The prevalence of antiphospholipid syndrome in women with recurrent miscarriage is 15%.⁵
• Structural:
  • Uterine anomalies (bicornuate uterus or septa) are seen in up to 37% of cases of recurrent miscarriage.^6,7 Only 50% pregnancies where there is a uterine structural abnormality achieve term delivery.⁷
  • 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, and listeria infection screening has been abandoned when investigating recurrent miscarriage.⁸
  • 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.⁹
  • 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.¹⁰
• 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.¹¹
  • 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 1990's: Factor V (Leiden) G1691A; factor II (prothrombin) G20210A and methylene tetrahydrofolate reductase C677T.
  • However women with the factor V Leiden mutation can have an uncomplicated full-term pregnancy, but multiple risk factors increase the likelihood of adverse pregnancy outcomes.
• Unknown

• Antiphospholipid antibodies:¹²
  • The presence of these associated with early miscarriages and maternal morbidity and is referred to as primary antiphospholipid syndrome (APS). Requires 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.^13,14 If this is found the couple should be referred to a clinical geneticist for counselling.
• Karyotyping of products of conception - probably should be used where patient has been undergoing treatment during that pregnancy.

NB: The RCOG does not recommend routine screening for diabetes, inherited coagulopathies, thyroid disease, serum prolactin, or TORCH.¹⁵

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 APS patients, heparin combined with low dose aspirin improves live birth rate to 70%.¹⁶
• However, even treated there is a high risk of complications throughout pregnancy. Intravenous immunoglobulins (IVIG) with prednisolone has been used.¹⁷
• There is some evidence that use of metformin during pregnancy is associated with a reduction in the miscarriage rate in women with polycystic ovarian syndrome.

Surgical

Cervical cerclage: cervical incompetence is over-diagnosed as a cause of second trimester miscarriage.

• A Cochrane review failed to show a reduction in the risk of recurrent mid-trimester miscarriage.¹⁸
• However in 2 RCTs there was some benefit in women with three or more second trimester miscarriages or pre-term deliveries.^19,20
• Cerclage carries a risk of stimulating uterine contractions.

• 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