Key Facts

Recurrent miscarriage is the loss of three or more consecutive pregnancies. It requires a systematic approach to investigation to identify treatable causes, although in over 50% of cases no cause is found.

Epidemiology

• Affects approximately 1% of couples
• Risk of further miscarriage after 3 losses: 40% (compared to 20% background risk)
• Age-related: risk increases significantly with maternal age >35

Aetiology

• Antiphospholipid syndrome (APS): 15% of cases; most important treatable cause
• Chromosomal abnormalities: parental balanced translocation in 2-5% of couples; increased embryonic aneuploidy
• Uterine anomalies: septate uterus (most common treatable uterine cause), submucosal fibroids, Asherman syndrome
• Endocrine: poorly controlled diabetes, thyroid dysfunction, PCOS (controversial)
• Thrombophilia: inherited (Factor V Leiden, prothrombin gene mutation) - weaker association than APS
• Unexplained: >50% of cases; likely multifactorial including embryonic aneuploidy

Pathophysiology

• APS: autoantibodies activate complement, cause placental thrombosis and inflammation, impairing trophoblast invasion
• Balanced translocations: phenotypically normal parents produce unbalanced gametes leading to chromosomally abnormal embryos
• Uterine septum: poor vascularisation impairs implantation
• Cervical incompetence: painless cervical dilatation typically in second trimester

Typical History

• Three or more consecutive pregnancy losses before 24 weeks
• Losses may be first trimester (most common) or second trimester
• Pattern of loss can guide investigation (e.g. second-trimester losses suggest cervical incompetence or APS)

Associated Features

• History of thrombosis (DVT, PE, stroke) suggests APS
• Features of autoimmune disease (rash, joint pain)
• Abnormal menstrual pattern
• Previous uterine surgery (ERPC, curettage)

Red Flags

• Painless cervical dilatation in second trimester (cervical incompetence)
• History of thrombotic events (APS)
• Abnormal bleeding pattern suggesting uterine pathology
• Consanguinity (increased risk of chromosomal abnormalities)

Bedside

• BMI assessment
• Blood pressure
• Thyroid examination

Bloods

• Antiphospholipid antibodies (must be positive on 2 occasions at least 12 weeks apart):
  • Lupus anticoagulant
  • Anticardiolipin antibodies (IgG and IgM)
  • Anti-β2 glycoprotein I antibodies (IgG and IgM)
• Parental karyotyping (both partners)
• Thyroid function tests
• FBC, coagulation screen
• Inherited thrombophilia screen (controversial - RCOG suggests limited role)

Imaging

• Pelvic ultrasound: assess uterine anatomy (3D USS superior for uterine anomalies)
• MRI pelvis: gold standard for uterine anomaly classification
• Cervical length assessment: serial TVS if cervical incompetence suspected

Special Tests

• Hysteroscopy: direct visualisation and treatment of intrauterine pathology (septum, adhesions, polyps, fibroids)
• Karyotyping of products of conception (if available from the miscarriage)

Non-pharmacological

• Supportive care: tender loving care in a dedicated early pregnancy clinic improves outcomes (70-75% live birth rate in unexplained recurrent miscarriage)
• Lifestyle modification: stop smoking, reduce alcohol, limit caffeine to <200mg/day, optimise BMI
• Psychological support and counselling

Pharmacological

• Antiphospholipid syndrome: aspirin 75mg OD from positive pregnancy test PLUS LMWH (e.g. enoxaparin 40mg OD) from positive pregnancy test until 6 weeks postpartum; improves live birth rate to ~70%
• Progesterone: micronised progesterone 400mg PV BD from positive pregnancy test to 12 weeks (PRISM trial showed benefit in subgroup with ≥3 prior miscarriages)
• Thyroid replacement: optimise TSH to <2.5 mU/L in first trimester
• Pre-conception folic acid: 400mcg OD (5mg if previous NTD)

Surgical/Interventional

• Hysteroscopic septum resection: for uterine septum (improves outcomes though RCT evidence limited)
• Cervical cerclage: McDonald or Shirodkar suture at 12-14 weeks for cervical incompetence; rescue cerclage if cervical dilatation <4cm
• Myomectomy: for submucosal fibroids distorting the cavity

Referral Criteria

• Refer to specialist recurrent miscarriage clinic after 3 consecutive losses (some clinicians investigate after 2 if age >35)
• Haematology referral for APS management
• Genetics referral if parental translocation identified
• Fertility specialist if concurrent subfertility

• With no identifiable cause and supportive care: 75% live birth rate in next pregnancy
• With APS treated with aspirin and LMWH: 70% live birth rate (vs 40% untreated)
• Parental balanced translocation: 60% chance of healthy pregnancy (genetic counselling essential)
• Cervical cerclage: reduces preterm birth by 25% in those with proven cervical incompetence
• Risk of miscarriage increases with number of prior losses and maternal age

Antiphospholipid Syndrome Diagnostic Criteria (Revised Sapporo/Sydney)

PRISM Trial Summary