What is the recommended evaluation and management for a woman with recurrent pregnancy loss (two or more consecutive miscarriages)?

Evaluation and Management of Recurrent Pregnancy Loss

For women with two or more consecutive miscarriages, screen for antiphospholipid antibodies (APLAs) and perform parental karyotyping on both partners; do NOT routinely use antithrombotic prophylaxis unless antiphospholipid syndrome is confirmed. 1, 2

Initial Diagnostic Workup

Essential Laboratory Testing

• Screen all women with ≥2 miscarriages for antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), as this represents the most treatable cause with proven benefit for live birth rates 3, 2, 4

• Perform karyotyping on both partners to identify chromosomal rearrangements (balanced translocations, inversions), which account for 5-7% of recurrent losses and are inherited in families 3, 2, 4

• Measure thyroid function tests (TSH and free T4) because thyroid dysfunction directly contributes to pregnancy loss and must be optimized before conception 3, 2, 4

• Test products of conception when available to determine if chromosomal errors (which cause 50-60% of early losses) are contributing 3, 2

• Assess for polycystic ovary syndrome (PCOS), which is associated with higher pregnancy loss rates 3, 2, 4

• Measure ovarian reserve using AMH levels, as severely diminished reserve (AMH <0.7 ng/mL) may increase miscarriage risk, particularly in women under 35 3, 2

Anatomical Evaluation

• Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 3, 2, 4

• Proceed to sonohysterography (SIS) for superior assessment of the uterine cavity, as three-dimensional SIS shows 100% accuracy in classifying uterine anomalies compared with hysteroscopy 2, 4

• Structural uterine abnormalities are identified in up to 38% of women with recurrent miscarriage 4

Male Partner Evaluation

• Evaluate the male partner in ALL couples with ≥2 pregnancy losses, including karyotype testing to identify chromosomal abnormalities 3, 2, 4

• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 3, 2, 4

Special Genetic Testing

• For women with recurrent complete hydatidiform moles, test for mutations in NLRP7 and KHDC3L genes, as these cause familial recurrent hydatidiform mole 3, 2, 4

What NOT to Test or Treat

Critical Caveats to Avoid Harm

• Do NOT routinely screen for inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency) in women with recurrent pregnancy loss, as evidence does not support antithrombotic prophylaxis for these conditions alone 1, 3, 4

• For women with ≥2 miscarriages but WITHOUT antiphospholipid syndrome or thrombophilia, do NOT use antithrombotic prophylaxis (Grade 1B recommendation against treatment) 1, 2

• Do NOT use viscoelastic testing (TEG/ROTEM), as it shows no correlation with thrombophilic defects and provides no evidence of a pro-thrombotic state in unexplained recurrent loss 3

• There is NO evidence supporting LMWH for prevention of recurrent pregnancy loss outside of confirmed antiphospholipid syndrome 3

Treatment Based on Identified Causes

Antiphospholipid Syndrome (Proven Benefit)

• For women who meet laboratory criteria for antiphospholipid syndrome, treat with unfractionated heparin or LMWH plus low-dose aspirin throughout pregnancy (Grade 1B recommendation) 1, 3, 2, 4

• This regimen improves live-birth rates and reduces maternal morbidity and mortality 3

Thrombophilia Management (VTE Prevention Only)

• For women with homozygous factor V Leiden or prothrombin 20210A mutation AND positive family history for VTE, provide antepartum prophylaxis with prophylactic- or intermediate-dose LMWH and continue for 6 weeks postpartum 1, 2, 4

• For pregnant women with all other thrombophilias and no prior VTE who do not have a positive family history for VTE, use antepartum and postpartum clinical vigilance rather than pharmacologic prophylaxis (Grade 2C) 1, 2

Genetic Abnormalities

• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing, prenatal diagnostic testing, donor gametes, or adoption 3, 2

• Women with confirmed NLRP7 or KHDC3L mutations should be offered ovum donation rather than conventional IVF, as the likelihood of achieving a normal pregnancy with autologous oocytes is extremely low 3, 2

Structural Abnormalities

• Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence 3, 5

• History-indicated cerclage should be reserved for individuals with classic features of cervical insufficiency or unexplained second-trimester loss (not for early first-trimester losses) 3, 4

Lifestyle Modifications

• Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors 3, 2, 4

• Regular physical activity within guidelines is safe and may actually benefit insulin resistance and obesity, which increase miscarriage risk 3, 2, 4

• Optimize nutrition and maintain healthy weight before attempting conception 3, 2, 4

Management of Subsequent Pregnancies

• Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected 3, 2, 4

• Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy 3, 2, 4

• Screen for gestational diabetes, as glucose intolerance may contribute to pregnancy loss 3, 2, 4

• For women at risk for pre-eclampsia, administer low-dose aspirin throughout pregnancy starting in the second trimester (Grade 1B) 1, 3, 2

• Vaginal progesterone supplementation may be considered in patients experiencing vaginal bleeding during the first trimester 5

Prognosis and Psychological Support

• Most people with recurrent pregnancy loss, including those without identifiable risk factors, are expected to achieve a live birth within 5 years from the initial evaluation 5

• Clinicians should be sensitive to the psychological needs of individuals with this condition and provide compassionate and supportive care across all stages 5, 6

• Tender loving care and health advice are interventions that do not require more randomized controlled trials and should be provided to all couples 7

Important Clinical Pitfall

Anembryonic pregnancies should be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria 3, 2