Infertility and spontaneous abortion  - Spontaneous abortion, habitual abortion - Miscarriage : Guidelines, reviews

Evidence-based clinical guidelines for the
investigation and treatment of couples with recurrent miscarriage

Royal College of Obstetricians and Gynaecologists. The investigation and treatment of recurrent miscarriage [Internet]. Guideline No 17. London: RCOG Press; 2003 May [cited 2009 Mar 8]. 13 p. Available from: http://www.rcog.org.uk/womens-health/clinical-guidance/investigation-and-treatment-couples-recurrent-miscarriage-green-top-

Recurrent miscarriage affects 1% of all women. This incidence is greater than that expected by chance alone, since 10-15% of all clinically recognised pregnancies end in a miscarriage and the theoretical risk of three consecutive pregnancy losses is 0.34%. Hence, only a proportion of women presenting with recurrent miscarriage will have a persistent underlying cause for their pregnancy losses.
Maternal age and previous number of miscarriages are two independent risk factors for a further miscarriage.

Genetic factors

• All couples with a history of recurrent miscarriage should have peripheral blood karyotyping performed. The finding of an abnormal parental karyotype should prompt referral to a clinical geneticist. (C)
  In approximately 3–5% of couples with recurrent miscarriage, one of the partners carries a balanced structural chromosomal anomaly (the amount of chromosomal material present is normal, but the configuration is abnormal).

• In all couples with a history of recurrent miscarriage cytogenetic analysis of the products of conception should be performed if the next pregnancy fails. (C)

Anatomical factors

• All women with recurrent miscarriage should have a pelvic ultrasound to assess uterine anatomy and morphology. (√)

Cervical weakness

• Cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and hence should only be considered in women who are likely to benefit. (B)
  The diagnosis is usually based on a history of late miscarriage, preceded by spontaneous rupture of membranes or painless cervical dilatation. Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness.

Endocrine factors

• Routine screening for occult diabetes and thyroid disease with oral glucose tolerance and thyroid function tests in asymptomatic women presenting with recurrent miscarriage is uninformative. (√)
  Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been associated with miscarriage. However, well-controlled diabetes mellitus is not a risk factor for recurrent miscarriage, nor is treated thyroid dysfunction.

• There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage. (A)

• There is insufficient evidence to evaluate the effect of human chorionic gonadotrophin (hCG) in pregnancy to prevent miscarriage. (A)

• Prepregnancy suppression of high luteinising hormone (LH) concentration among ovulatory women with recurrent miscarriage and polycystic ovaries who hypersecrete LH does not improve the live birth rate. (A)

• Polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously. (B)
  The prevalence of polycystic ovaries, identified using pelvic ultrasound criteria, is significantly higher among women with recurrent miscarriage (41%) when compared with the general population (22%). However, despite this high prevalence, polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.

• There is insufficient evidence to assess the effect of hyperprolactinaemia as a risk factor for recurrent miscarriage. (A)

Immune factors

Antithyroid antibodies

• Routine screening for thyroid antibodies in women with recurrent miscarriage is not recommended. (B)

Antiphospholipid syndrome

Primary antiphospholipid syndrome (APS) refers to the association between antiphospholipid antibodies (aPL) and adverse pregnancy outcome or vascular thrombosis. Adverse pregnancy outcomes include (a) three or more consecutive miscarriages before ten weeks of gestation, (b) one or more morphologically normal fetal deaths after the tenth week of gestation and (c) one or more preterm births before the 34th week of gestation due to severe pre-eclampsia, eclampsia or placental insufficiency. Where APS exists in chronic inflammatory disorders, such as systemic lupus erythematosus, it is referred as secondary APS.
The mechanisms by which aPL causes pregnancy morbidity include inhibition of trophoblastic function and differentiation and, in later pregnancy, thrombosis of the uteroplacental vasculature.

• To diagnose antiphospholipid syndrome (APS) it is mandatory that the patient should have two positive tests at least six weeks apart for either lupus anticoagulant or anticardiolipin (aCL) antibodies of IgG and/or IgM class present in medium or high titre. (C)
  Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage. By comparison, the prevalence of aPL in women with a low risk obstetric history is less than 2%. In women with recurrent miscarriage associated with aPL, the live birth rate in pregnancies with no pharmacological intervention may be as low as 10%.

• Currently there is no reliable evidence to show that steroids improve the live birth rate of women with recurrent miscarriage associated with aPL when compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity. (A)

• In women with a history of recurrent miscarriage and antiphospholipid antibodies (aPL), future live birth rate is significantly improved when a combination therapy of aspirin plus heparin is prescribed. (A)
  See also Treatment of antiphospholipid syndrome in pregnancy.

• Pregnancies associated with aPL treated with aspirin and heparin remain at high risk of complications during all three trimesters. (B)

Alloimmune factors

• Immunotherapy, including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes and intravenous immunoglobulin (IVIG), in women with previous unexplained recurrent miscarriage does not improve the live birth rate. (A)
  There is no clear evidence to support the hypothesis that HLA sharing between couples, the absence of maternal leucocytotoxic antibodies or the absence of maternal blocking antibodies are related to recurrent miscarriage.

Infective agents

• TORCH (toxoplasmosis, other [congenital syphilis and viruses], rubella, cytomegalovirus and herpes simplex virus) screening is unhelpful in the investigation of recurrent miscarriage. (C)
  Any severe infection that leads to bacteraemia or viraemia can cause sporadic miscarriage. For an infective agent to be implicated in the aetiology of repeated pregnancy loss, it must be capable of persisting in the genital tract. Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria infections do not fulfil these criteria and routine TORCH screening should be abandoned.

• Screening for and treatment of bacterial vaginosis in early pregnancy among high risk women with a previous history of second-trimester miscarriage or spontaneous preterm labour may reduce the risk of recurrent late loss and preterm birth. (A)

Inherited thrombophilic defects

Inherited thrombophilic defects, including activated protein C resistance (most commonly due to factor V Leiden gene mutation), deficiencies of protein C/S and antithrombin III, hyperhomocysteinaemia and prothrombin gene mutation, are established causes of systemic thrombosis.
Retrospective studies have suggested an association between inherited thrombophilic defects and fetal loss and late pregnancy complications, with a presumed mechanism being thrombosis of uteroplacental circulation.
The efficacy of thromboprophylaxis during pregnancy in women with recurrent miscarriage who have inherited thrombophilic defects, but who are otherwise asymptomatic, has not been assessed in prospective randomised controlled trials. Three uncontrolled studies have suggested that heparin therapy may improve the live birth rate for these women. In the absence of a randomised trial, the poor pregnancy outcome associated with FVL mutation, coupled with the maternal risks during pregnancy, may justify routine screening for FVL and offering thromboprophylaxis for those with FVL mutation and evidence of placental thrombosis.

Unexplained recurrent miscarriage

• Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit. (C)
  A significant proportion of cases of recurrent miscarriage remain unexplained, despite detailed investigation. These women can be reassured that the prognosis for a successful future pregnancy with supportive care alone is in the region of 75%. However, the prognosis worsens with increasing maternal age and the number of previous miscarriages. The value of psychological support in improving pregnancy outcome has not been tested in the form of a randomised controlled trial. However, data from several non-randomised studies have suggested that attendance at a dedicated early pregnancy clinic has a beneficial effect, although the mechanism is unclear.

Grades of recommendations

Good practice point

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Edited by Aldo Campana,