What is the appropriate workup for a 35-year-old woman with recurrent (three or more consecutive) first-trimester miscarriages?

Workup for Recurrent First-Trimester Miscarriages

Recurrent miscarriage is defined as three or more consecutive pregnancy losses before 24 weeks of gestation, affecting approximately 1% of women of reproductive age. 1, 2

Definition and When to Evaluate

• Definition: Three or more consecutive first-trimester miscarriages 2
• Clinical Discretion: Evaluation may be considered after two first-trimester miscarriages if pathological rather than sporadic nature is suspected 2

Recommended Diagnostic Workup

1. Genetic Testing

• Cytogenetic analysis of pregnancy tissue from the third and subsequent miscarriage(s) 2
• Parental peripheral blood karyotyping if:
  • Pregnancy tissue shows unbalanced structural chromosomal abnormality
  • No pregnancy tissue is available for testing 2

2. Anatomical Assessment

• 3D ultrasound to assess for congenital uterine anomalies 2
  • Uterine septum is associated with recurrent miscarriage and may require resection 2

3. Thrombophilia Testing

• Acquired thrombophilia: Test for lupus anticoagulant and anticardiolipin antibodies (antiphospholipid syndrome) 2
• Inherited thrombophilia: Consider testing for Factor V Leiden, prothrombin gene mutation, and protein S deficiency in women with second-trimester losses 2
  • Routine testing for protein C, antithrombin deficiency, and MTHFR mutation is NOT recommended 2

4. Endocrine Evaluation

• Thyroid function tests and assessment for thyroid peroxidase (TPO) antibodies 2
• Fasting blood glucose to rule out diabetes 3

5. Tests NOT Routinely Recommended

• Immunological screening (HLA, cytokine, natural killer cell tests) 2
• Infection screening 2
• Sperm DNA testing 2

Management Based on Findings

1. Antiphospholipid Syndrome

• Aspirin and heparin from positive test until at least 34 weeks of gestation 2

2. Uterine Septum

• Surgical resection should be considered 2

3. Unexplained Recurrent Miscarriage

• Supportive care in a dedicated recurrent miscarriage clinic 2
• Progesterone supplementation (400 mg micronized vaginal progesterone twice daily) for women who present with bleeding in early pregnancy until 16 weeks of gestation 2
• Do NOT use aspirin and/or heparin for unexplained recurrent miscarriage 2, 4

4. Lifestyle Modifications

• Maintain BMI between 19-25 kg/m²
• Smoking cessation
• Limit alcohol consumption
• Limit caffeine to less than 200 mg/day 2

Prognosis

Despite recurrent miscarriages, the prognosis is generally favorable:

• 77% of women with recurrent miscarriage have a subsequent pregnancy
• 63% of these pregnancies result in live birth 5
• Factors associated with reduced likelihood of successful pregnancy include:
  • Advanced maternal age (≥40 years)
  • Smoking
  • Parental balanced translocations 5

Common Pitfalls to Avoid

1. Unnecessary testing: Avoid non-evidence-based tests that add cost without changing management
2. Inappropriate treatment: Do not prescribe aspirin or heparin for unexplained recurrent miscarriage
3. Delayed evaluation: Consider evaluation after two losses if risk factors are present
4. Overlooking psychological impact: Ensure supportive care is provided alongside medical management

Remember that approximately 60% of recurrent miscarriages remain unexplained even after comprehensive evaluation 5, but the prognosis for future successful pregnancy is still favorable with appropriate management and supportive care.