How should I investigate a patient with recurrent pregnancy loss (≥2 consecutive miscarriages before 20 weeks gestation)?

Investigation of Recurrent Pregnancy Loss (RPL)

Begin the diagnostic workup after two consecutive clinically recognized pregnancy losses before 20 weeks' gestation, as evaluation at this threshold identifies the same prevalence of treatable causes as waiting for three losses. 1, 2

Essential Laboratory Testing (All Patients with ≥2 Losses)

Antiphospholipid Antibody Screening (Highest Priority)

• Screen all patients for antiphospholipid antibodies (APLAs) because this is the single most treatable cause of RPL with Grade 1A evidence for improving live-birth rates and reducing maternal morbidity/mortality. 1, 3
• Test for lupus anticoagulant, anticardiolipin antibodies (IgG and IgM), and anti-β2-glycoprotein I antibodies 1
• Repeat positive tests at 12 weeks to confirm persistent positivity required for diagnosis 3

Parental Chromosomal Analysis

• Perform karyotyping on both partners to identify balanced translocations, inversions, or other chromosomal rearrangements that account for 5-7% of RPL cases 1, 4
• This percentage increases when family history of RPL is present, making testing even more critical in these cases 3
• Balanced translocations are the most common abnormality detected (92.9% of structural abnormalities) 4

Thyroid Function Assessment

• Measure TSH and free T4 to identify and correct thyroid dysfunction before attempting conception 1, 3
• Optimize thyroid function and monitor throughout subsequent pregnancies 5

Metabolic and Endocrine Screening

• Assess for polycystic ovary syndrome (PCOS), which is linked to higher miscarriage rates 1, 3
• Measure anti-Müllerian hormone (AMH); severely diminished ovarian reserve (AMH <0.7 ng/mL) may increase miscarriage risk, especially in women <35 years 1, 3

Anatomical Assessment

Imaging Protocol

• Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 1, 5
• Follow with saline-infusion sonohysterography (SIS) for detailed evaluation; structural abnormalities are identified in up to 38% of RPL patients 1
• Three-dimensional SIS provides 100% accuracy for classifying uterine anomalies compared with hysteroscopy 1, 5
• The prevalence of uterine abnormalities is equivalent in women with two versus three or more losses (OR 1.00,95% CI 0.79-1.27) 2

Male Partner Evaluation (Mandatory)

Evaluate the male partner in all couples with ≥2 losses; male factors are recognized contributors to RPL. 1, 3

Specific Male Testing

• Perform karyotype testing to detect chromosomal abnormalities 1, 3
• Consider sperm DNA fragmentation testing, as elevated fragmentation is increasingly linked to RPL 1, 3

Special Genetic Considerations

Recurrent Hydatidiform Moles

• For recurrent complete hydatidiform moles, test for NLRP7 and KHDC3L mutations (autosomal-recessive familial condition) 1, 3
• Patients with confirmed mutations should be offered ovum donation rather than conventional IVF due to very low success with autologous oocytes 1, 3

Products of Conception Analysis

• Test products of conception when available to determine if chromosomal errors are contributing (account for 50-60% of early losses) 3, 6
• Chromosomal analysis detects major abnormalities in 31.9% of abortion materials 4

Tests NOT Routinely Recommended

Thrombophilia Screening

• Do NOT screen routinely for inherited thrombophilias (factor V Leiden, prothrombin G20210A, protein C/S deficiency) in RPL workup 1, 3
• Exception: Consider testing only if personal or strong family history of venous thromboembolism exists 3
• Viscoelastic testing (TEG/ROTEM) is NOT correlated with thrombophilic defects and provides no evidence of a pro-thrombotic state in unexplained RPL 1, 3, 5

Important Clinical Pitfalls to Avoid

• Count anembryonic (blighted-ovum) pregnancies when calculating RPL for workup, as they meet diagnostic criteria for confirmed early pregnancy loss 5
• Do NOT assume a sporadic cause when family history exists; inherited chromosomal rearrangements rise from 3.6% to 5-7% with documented family history 1, 3
• Do NOT omit male partner assessment; male chromosomal abnormalities and sperm DNA fragmentation are recognized contributors 1, 3
• Do NOT use anticoagulation therapy in women with inherited thrombophilias alone (without APS or VTE history), as evidence does not support this practice 3

Algorithmic Approach Summary

1. First-line mandatory testing: APLA panel, parental karyotypes (both partners), TSH/free T4, TVUS 1, 3
2. Second-line imaging: Saline-infusion sonohysterography if TVUS shows abnormality or is inconclusive 1, 5
3. Metabolic assessment: PCOS screening, AMH level, consider fasting glucose 1, 3
4. Male evaluation: Karyotype and sperm DNA fragmentation 1, 3
5. Special scenarios only: NLRP7/KHDC3L testing for recurrent molar pregnancies; products of conception analysis when available 1, 3
6. Avoid: Routine thrombophilia panels, viscoelastic testing 1, 3, 5

The prognosis for couples with RPL is generally good, with up to 70% chance of successful subsequent pregnancy even when no cause is identified 7, 6, though likelihood depends on maternal age and number of previous losses 6.