How should recurrent pregnancy loss (two or more consecutive miscarriages) be evaluated and managed?

Evaluation and Management of Recurrent Pregnancy Loss

For women with two or more consecutive miscarriages, begin with screening for antiphospholipid antibodies, parental karyotyping of both partners, thyroid function tests, and transvaginal ultrasound to evaluate the uterine cavity—these represent the highest-yield diagnostic tests with proven treatment options. 1, 2

Diagnostic Workup Algorithm

First-Line Essential Testing

Screen all patients with ≥2 consecutive pregnancy losses for the following:

• Antiphospholipid antibodies (APLAs) – This is the single most important treatable cause of recurrent pregnancy loss and should be tested in all patients, with the American College of Chest Physicians providing Grade 1B evidence for screening women with ≥3 early miscarriages (before 10 weeks). 1, 2, 3

• Parental karyotyping on both partners – Chromosomal rearrangements account for 50-60% of early losses, and identifying balanced translocations or inversions in either partner is critical, as these can be transmitted to offspring. 1, 2, 3

• Thyroid function tests (TSH and free T4) – Thyroid dysfunction directly contributes to pregnancy loss and must be optimized before attempting conception. 1, 2, 3

• Transvaginal ultrasound (TVUS) as initial uterine screening – Begin with TVUS to identify structural uterine abnormalities, which are present in up to 38% of women with recurrent miscarriage. 1, 3

  • If abnormalities are suspected, proceed to sonohysterography (SIS), which provides superior assessment of the uterine cavity with 100% accuracy in classifying uterine anomalies compared to hysteroscopy. 1, 2

• Polycystic ovary syndrome (PCOS) evaluation – PCOS is associated with higher pregnancy loss rates and should be assessed clinically and biochemically. 1, 2, 3

• Ovarian reserve testing (AMH levels) – Severely diminished ovarian reserve (AMH <0.7 ng/mL) may increase miscarriage risk, particularly in women under 35 years old. 1, 2, 3

Male Partner Evaluation

The male partner must be evaluated in all couples with ≥2 pregnancy losses:

• Karyotype testing to identify chromosomal abnormalities that contribute to recurrent loss. 1, 2, 3

• Sperm DNA fragmentation testing should be considered, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss. 1, 2, 3

Specialized Testing in Specific Scenarios

• For recurrent complete hydatidiform moles: Test for pathogenic variants in NLRP7 and KHDC3L genes, which cause familial recurrent hydatidiform mole. 1, 3

• Products of conception testing when tissue is available to determine if chromosomal errors are contributing. 1

What NOT to Test

Critical caveat: 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

• Viscoelastic testing (TEG/ROTEM) should be avoided as it shows no correlation with thrombophilic defects and provides no evidence of a pro-thrombotic state in unexplained recurrent loss. 1

Treatment Based on Identified Causes

Antiphospholipid Syndrome

For women meeting laboratory criteria for APLA syndrome, treat with unfractionated heparin or low-molecular-weight heparin (LMWH) plus low-dose aspirin throughout pregnancy. This regimen improves live-birth rates and reduces maternal morbidity/mortality (Grade 1A evidence). 1, 2, 3

Genetic Abnormalities

• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing (PGT-A), prenatal diagnostic testing, donor gametes, or adoption. 1, 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. 1, 2

Thrombophilia Management (Limited Indications)

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

• For all other inherited thrombophilias without prior VTE and without family history of VTE: Use clinical vigilance only—do NOT use antithrombotic prophylaxis. 1, 2

Structural Abnormalities

• Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence. 1

• 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

Critical "Do NOT Treat" Recommendation

For women with ≥2 miscarriages but without confirmed APLA syndrome or specific thrombophilia indications, do NOT use antithrombotic prophylaxis (including LMWH). This is a Grade 1B recommendation against treatment from the American College of Chest Physicians. 1, 2

Lifestyle Modifications

• Smoking cessation, alcohol avoidance, and elimination of recreational drugs are modifiable risk factors that must be addressed. 1, 2, 3

• Regular physical activity within established guidelines is safe and may actually benefit insulin resistance and obesity, which increase miscarriage risk. 1, 2, 3

• Optimize nutrition and maintain healthy weight before attempting conception. 1, 2, 3

Management of Subsequent Pregnancies

• Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected. 1, 2, 3

• Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy. 1, 2, 3

• Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss. 1, 2, 3

• Monitor and promptly treat endocrine conditions, particularly thyroid dysfunction. 1, 2

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

Important Clinical Pitfalls

• Anembryonic pregnancies should be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria. 1, 2

• Do not assume a sporadic cause when family history is present—the prevalence of inherited chromosomal rearrangements rises from approximately 3.6% to 5-7% when family history is specifically evaluated. 1

• Do not omit male partner assessment—male chromosomal abnormalities and sperm DNA fragmentation are recognized contributors to recurrent loss. 1, 2, 3

• Even after thorough evaluation, up to 75% of recurrent pregnancy loss cases remain unexplained, but approximately 70% of women with recurrent miscarriage ultimately succeed in having a baby. 4, 5, 6