What is the most likely cause of recurrent early miscarriage in a 33-year-old woman with three prior early pregnancy losses: antiphospholipid syndrome, cervical insufficiency, or chromosomal abnormalities?

Most Likely Cause of Recurrent Early Miscarriage

In a 33-year-old woman with three consecutive early pregnancy losses (all before 10 weeks), chromosomal abnormalities are the most likely cause, accounting for 50-60% of early losses, but antiphospholipid syndrome must be ruled out first as it is the most treatable cause with proven benefit for future pregnancies.

Diagnostic Priority Algorithm

First-Line Testing (Most Critical)

Screen for antiphospholipid antibodies immediately in all patients with ≥3 early miscarriages before 10 weeks, as antiphospholipid syndrome (APS) affects 7-25% of recurrent pregnancy loss cases and is the only cause with proven effective treatment 1, 2, 3.

• Test for lupus anticoagulant and anticardiolipin antibodies, as these are the only sufficiently standardized assays for routine use 2, 3
• APS is associated with placental thrombosis and infarction, acting directly on trophoblastic cells 3
• Women meeting laboratory criteria for APS should receive unfractionated heparin or LMWH plus low-dose aspirin throughout pregnancy, which improves live-birth rates (Grade 1A evidence) 1, 2

Second-Line Testing

Perform parental karyotyping on both partners to identify chromosomal rearrangements 1, 4.

• Parental chromosomal abnormalities (balanced translocations or inversions) are found in 4-6% of couples with recurrent miscarriage 2, 5
• When available, test products of conception, as chromosomal errors account for 50-60% of early losses 1, 6, 5
• Numerical chromosomal abnormalities (86% of genetic causes) have low recurrence risk, but structural abnormalities (6%) may be inherited from a parent 5

Additional Evaluation

• Transvaginal ultrasound to screen for uterine cavity abnormalities 1, 7
• Thyroid function tests (TSH, free T4) as thyroid dysfunction contributes to pregnancy loss 1
• Assess for PCOS, which is associated with higher pregnancy loss rates 1, 8
• Evaluate male partner with karyotype and consider sperm DNA fragmentation testing 1, 8

Why Each Answer Choice Ranks Differently

A. Antiphospholipid Syndrome (Most Treatable, Must Rule Out)

This is the most important diagnosis to establish because it has proven treatment with aspirin plus heparin that significantly improves outcomes 1, 2.

• Affects 7-25% of recurrent spontaneous abortion cases 3
• Critical pitfall: Failure to test for APS means missing the only cause with evidence-based treatment that prevents future losses 1
• Testing is straightforward with standardized assays for lupus anticoagulant and anticardiolipin antibodies 2, 3

B. Cervical Incompetence (Wrong Timing)

Cervical incompetence does NOT cause first-trimester losses - it manifests as painless cervical dilation in the second trimester (typically 16-24 weeks) 8.

• This patient's losses are all early (at 6 weeks currently, with history of early losses) 8
• Cervical insufficiency causes unexplained second-trimester loss in the absence of placental abruption 1
• This diagnosis is excluded by the timing of losses alone

C. Chromosomal Abnormalities (Most Common Overall)

While chromosomal abnormalities account for 50-60% of early losses, most are sporadic numerical abnormalities with low recurrence risk 1, 6, 5.

• Fetal chromosome abnormalities cause about 50% of first-trimester pregnancy losses 5
• 86% are numerical abnormalities (aneuploidy) with low recurrence risk 5
• Only 6% are structural abnormalities that may indicate parental balanced translocation (4-6% of couples with recurrent loss) 2, 5
• Key distinction: Random chromosomal errors are the most common cause of individual early losses, but parental chromosomal rearrangements are less common than APS in recurrent loss 2, 4

Clinical Management Approach

The correct diagnostic sequence is:

1. Test for APS first (lupus anticoagulant and anticardiolipin antibodies) because it is treatable 1, 2
2. Perform parental karyotyping on both partners to identify balanced translocations 1, 4
3. Test products of conception when available to determine if sporadic chromosomal errors are contributing 1, 6
4. Screen for anatomic, endocrine, and male factors as outlined above 1, 8

Common Pitfalls to Avoid

• Do not assume chromosomal abnormalities without testing for APS first - you will miss the only treatable cause with proven benefit 1, 2
• Do not attribute early losses to cervical incompetence - the timing is wrong for this diagnosis 8
• Do not use LMWH for recurrent pregnancy loss outside of confirmed APS - there is no evidence supporting this 1, 7
• Do not omit male partner evaluation - male chromosomal abnormalities and sperm DNA fragmentation contribute to recurrent loss 1, 8

Up to 75% of recurrent pregnancy loss cases remain idiopathic even after complete evaluation 4, but these couples should be reassured they have a good prognosis for future pregnancies with appropriate emotional support 2.