What is the recommended evaluation and workup for a woman and her partner with recurrent miscarriage and a family history of recurrent miscarriage?

Workup for Recurrent Miscarriage with Family History

Women with recurrent pregnancy losses (≥2 miscarriages) and a family history of recurrent miscarriage require genetic counseling and parental karyotyping of both partners, as chromosomal rearrangements account for 5-7% of recurrent pregnancy losses and may cluster in families. 1

Essential Investigations for Both Partners

Genetic Evaluation

• Perform karyotype testing on both partners to identify balanced translocations, inversions, or other chromosomal rearrangements that can be inherited and cause recurrent losses 1, 2, 3
• Refer to genetics/genetic counseling for any couple with recurrent pregnancy losses and family history, as this represents a specific indication for genetic consultation 1
• Test products of conception from miscarriages when available, as chromosomal errors account for 50-60% of early losses 2, 3
• For patients with recurrent complete hydatidiform moles specifically, test for NLRP7 and KHDC3L gene mutations, as these cause familial recurrent hydatidiform mole and may run in families 1, 2, 4

Male Partner Evaluation

• Evaluate the male partner in all couples with ≥2 pregnancy losses, including complete reproductive history and karyotype testing 1, 2, 3, 4
• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 2, 3, 4

Female Partner Evaluation

Immunologic Testing:

• Screen for antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) in all patients with recurrent early pregnancy loss (≥3 miscarriages before 10 weeks) 2, 3, 5, 6, 7

Anatomic Assessment:

• Begin with transvaginal ultrasound as initial screening for uterine cavity abnormalities 2, 3, 4
• Proceed to sonohysterography for superior assessment of Müllerian anomalies, intrauterine synechiae, or other structural abnormalities 2, 3, 4

Endocrine Evaluation:

• Measure thyroid function tests (TSH, free T4), as thyroid dysfunction contributes to pregnancy loss and requires optimization before conception 2, 3, 4, 5
• Evaluate for polycystic ovary syndrome (PCOS), which is associated with higher rates of pregnancy loss 2, 3, 4, 8
• Assess ovarian reserve (AMH levels), as severely diminished ovarian reserve may be associated with increased miscarriage risk 2, 3, 4

Critical Management Based on Findings

If Parental Chromosomal Rearrangements Identified:

• Provide genetic counseling regarding options including preimplantation genetic testing, prenatal diagnosis, donor gametes, or adoption 2, 3, 6
• Discuss the unpredictable intrafamilial variability in expression and 50% recurrence risk if one partner carries a balanced translocation 1

If NLRP7 or KHDC3L Mutations Found:

• Recommend ovum donation rather than conventional IVF, as women with familial recurrent hydatidiform mole are unlikely to achieve normal pregnancy except through ovum donation from an unaffected individual 1, 2, 3

If Antiphospholipid Syndrome Confirmed:

• Treat with unfractionated heparin or low-molecular-weight heparin plus low-dose aspirin in subsequent pregnancies 2, 3, 5

Common Pitfalls to Avoid

Do not assume sporadic causes when family history is present - the presence of family history significantly increases the likelihood of inherited chromosomal rearrangements from 3.6% in general recurrent miscarriage populations to 5-7% when specifically evaluated 1, 8

Do not skip male partner evaluation - chromosomal abnormalities and sperm DNA fragmentation in the male partner contribute to recurrent losses and require assessment 1, 2, 3, 4

Do not use low-molecular-weight heparin outside of confirmed antiphospholipid syndrome - there is no evidence supporting LMWH for prevention of recurrent pregnancy loss as sole indication 2, 4

Lifestyle Modifications

• Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs 2, 3, 4
• Optimize nutrition and maintain healthy weight before attempting conception 2, 3, 4
• Regular physical activity within guidelines is safe and may benefit insulin resistance and obesity, which increase miscarriage risk 2, 3, 4

Management of Subsequent Pregnancies

• Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected 2, 3, 4
• Provide regular prenatal visits with serial ultrasound monitoring throughout pregnancy 2, 3, 4
• Screen for gestational diabetes and monitor endocrine conditions 2, 3, 4