Evaluation and Management of Recurrent Pregnancy Loss
Definition and When to Initiate Workup
Begin a comprehensive evaluation after two or more clinically recognized pregnancy losses (confirmed by ultrasound or hCG), including anembryonic pregnancies, as these meet diagnostic criteria for recurrent pregnancy loss. 1, 2, 3, 4
The threshold of two losses (rather than three) is now standard because evidence shows identifiable causes can be detected earlier, and psychological burden warrants prompt investigation. 5, 4
Initial Diagnostic Evaluation
Essential Testing for All Patients
Screen for antiphospholipid antibodies (APLAs) in all women with recurrent early pregnancy loss (≥2 miscarriages), as this is the most treatable cause with proven mortality/morbidity benefit. 6, 1
Perform parental karyotyping on both partners to identify balanced translocations, inversions, or chromosomal rearrangements that account for 5-7% of cases. 1, 2
Evaluate the male partner in all couples with ≥2 losses, including karyotype testing and consideration of sperm DNA fragmentation testing, as male chromosomal abnormalities and sperm DNA damage contribute to recurrent loss. 1, 2
Obtain transvaginal ultrasound (TVUS) initially, then proceed to sonohysterography (SIS) for superior assessment of uterine cavity abnormalities; three-dimensional SIS shows 100% accuracy compared to hysteroscopy. 1, 2
Measure thyroid function tests (TSH, free T4) as thyroid dysfunction is a modifiable contributor requiring optimization before conception. 1, 2
Test products of conception when available to determine if chromosomal errors (which account for 50-60% of early losses) are contributing. 1
Additional Targeted Testing
Assess for polycystic ovary syndrome (PCOS), which associates with higher pregnancy loss rates. 1, 2
Measure ovarian reserve (AMH levels), as severely diminished ovarian reserve (AMH <0.7 ng/ml) may increase miscarriage risk, particularly in women under 35 years. 6
For patients with recurrent complete hydatidiform moles, test for NLRP7 and KHDC3L gene mutations, as these cause familial recurrent hydatidiform mole. 1, 2
What NOT to Test
Do NOT routinely screen for inherited thrombophilias in women with recurrent pregnancy loss, as there is no evidence supporting antithrombotic prophylaxis for inherited thrombophilia alone. 6
Do NOT perform viscoelastic testing (TEG/ROTEM), as it shows no correlation with thrombophilic defects and no evidence of prothrombotic state in unexplained recurrent pregnancy loss. 6, 2
Evidence-Based Treatment Strategies
For Identified Antiphospholipid Syndrome
Treat women who meet laboratory criteria for APLA syndrome with unfractionated heparin or LMWH plus low-dose aspirin throughout pregnancy. 6, 1, 5
This is the only intervention with Grade 1A evidence for improving live birth rates and reducing morbidity/mortality in recurrent pregnancy loss. 6
For Inherited Thrombophilias
For women with homozygous factor V Leiden or prothrombin 20210A mutation AND positive family history for VTE: Use antepartum prophylaxis with prophylactic- or intermediate-dose LMWH and postpartum prophylaxis for 6 weeks. 6, 2
For women with inherited thrombophilia but NO prior VTE and NO family history: Use clinical vigilance only; do NOT use antithrombotic prophylaxis. 6
Critical Caveat on Anticoagulation
For women with two or more miscarriages but WITHOUT APLA or thrombophilia, do NOT use antithrombotic prophylaxis (Grade 1B recommendation against). 6, 1
There is no evidence supporting LMWH for prevention of recurrent pregnancy loss outside of confirmed antiphospholipid syndrome. 1
For Chromosomal Abnormalities
Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing, prenatal diagnostic testing, donor gametes, or adoption. 1
Women with confirmed NLRP7 or KHDC3L mutations should be offered ovum donation rather than conventional IVF, as the likelihood of achieving normal pregnancy with autologous oocytes is extremely low. 1, 2
For Uterine Abnormalities
Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence. 1, 4
History-indicated cerclage should be reserved for individuals with classic historical features of cervical insufficiency or unexplained second-trimester loss in the absence of placental abruption. 1
For Pre-eclampsia Risk
For women considered at risk for pre-eclampsia, use low-dose aspirin throughout pregnancy starting from the second trimester. 6
Lifestyle Modifications with Proven Impact
Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors. 1, 2, 5
Encourage regular physical activity within guidelines, which is safe and may benefit insulin resistance and obesity—both increase miscarriage risk. 1, 2
Optimize nutrition and maintain healthy weight before attempting conception. 1, 2
Management of Subsequent Pregnancies
Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected. 1, 2
Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy. 1, 2
Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss. 1, 2
Monitor for and promptly treat any endocrine conditions, such as thyroid dysfunction. 1, 2
Consider vaginal progesterone supplementation in patients experiencing vaginal bleeding during the first trimester. 4
Prognosis and Psychological Support
Most couples with recurrent pregnancy loss, including those without identifiable risk factors, are expected to achieve a live birth within 5 years from initial evaluation. 4
Clinicians should be sensitive to the psychological toll of multiple pregnancy losses and provide compassionate, supportive care across all stages, as the emotional burden is significant even when prognosis is favorable. 7, 4
Common Pitfalls to Avoid
Do not assume a sporadic cause when family history is present; the prevalence of inherited chromosomal rearrangements rises from 3.6% to 5-7% when family history exists. 1
Do not omit male partner assessment; male factors are recognized contributors requiring investigation. 1, 2
Do not use anticoagulation empirically in unexplained recurrent pregnancy loss without confirmed APLA syndrome, as this increases maternal risk without proven benefit. 6, 1
Do count anembryonic pregnancies when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria. 1, 2, 3