What is the best approach to manage a woman with a history of recurrent pregnancy loss, defined as two or more consecutive pregnancy losses?

Management of Recurrent Pregnancy Loss

For women with recurrent pregnancy loss (≥2 consecutive losses), initiate a systematic evaluation including parental karyotyping, antiphospholipid antibody screening, anatomical assessment via transvaginal ultrasound with sonohysterography, thyroid function testing, and male partner evaluation with consideration for karyotype and sperm DNA fragmentation testing. 1, 2, 3

Initial Diagnostic Workup

Genetic Evaluation

• Perform parental karyotyping on both partners to identify chromosomal rearrangements that could cause recurrent losses 3
• Test products of conception when available to determine if chromosomal errors (which account for 50-60% of early losses) are contributing 2
• For patients with recurrent complete hydatidiform moles specifically, consider genetic testing for mutations in NLRP7 and KHDC3L genes, as these cause familial recurrent hydatidiform mole (an autosomal recessive condition) 1, 2, 3

Immunologic Testing

• Screen for antiphospholipid antibodies (APLAs) in all patients with recurrent early pregnancy loss (≥3 miscarriages before 10 weeks) 3
• This is the only thrombophilia worth testing routinely 3

Anatomical Assessment

• Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 1, 2, 3
• Proceed to sonohysterography (SIS) for superior assessment of the uterine cavity, as three-dimensional SIS has shown 100% accuracy in classification of uterine anomalies when compared with hysteroscopy 2
• Hysterosalpingography (HSG) serves as an alternative imaging modality if SIS is unavailable 1, 3
• Look specifically for Müllerian anomalies, intrauterine synechiae, and cervical incompetence 1

Endocrine Evaluation

• Measure thyroid function tests (TSH, free T4) as thyroid dysfunction contributes to pregnancy loss and requires optimization before conception 3
• Evaluate for polycystic ovary syndrome (PCOS), which is associated with higher rates of pregnancy loss 1, 2, 3
• Assess ovarian reserve (AMH levels), as severely diminished ovarian reserve may be associated with increased miscarriage risk 1

Male Partner Evaluation

• Evaluate the male partner in ALL couples with ≥2 pregnancy losses - this is now a guideline recommendation 1, 2, 3
• Perform karyotype testing to identify chromosomal abnormalities 3
• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 1, 3

What NOT to Test

Do NOT routinely screen for inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency) in women with recurrent pregnancy loss 3

The only exception: women with homozygous factor V Leiden or prothrombin 20210A mutation AND a positive family history for VTE should receive antepartum prophylaxis with LMWH, but this is for VTE prevention, not pregnancy loss prevention 1, 3

Treatment Based on Identified Causes

Antiphospholipid Syndrome

• For women who meet laboratory criteria for APLA syndrome, treat with unfractionated heparin or LMWH plus low-dose aspirin 3, 4, 5
• This is the only treatment with proven efficacy in properly controlled trials 5

Genetic Abnormalities

• Patients with recurrent anembryonic pregnancies due to NLRP7 and KHDC3L gene mutations may benefit from ovum donation rather than conventional IVF 2
• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing 3

Anatomical 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 6

Endocrine Dysfunction

• Optimize thyroid function before attempting conception and monitor regularly during pregnancy 2, 3
• Manage PCOS appropriately 1, 2
• For women with 22q11.2 deletion syndrome, provide calcium and vitamin D supplementation 2

Lifestyle Modifications

• Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs - these are modifiable risk factors 2, 3
• Regular physical activity within guidelines is safe and unlikely to increase pregnancy loss risk; it may actually benefit insulin resistance and obesity, which increase miscarriage risk 1, 2, 3
• Optimize nutrition and maintain healthy weight before attempting conception 3

Management of Subsequent Pregnancies

Early Pregnancy Monitoring

• 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

Ongoing Surveillance

• Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss 2, 3
• Monitor for and promptly treat any endocrine conditions, such as thyroid dysfunction 2

Important Caveats

Unproven Therapies

• There is NO evidence supporting the use of LMWH for the sole indication of prevention of recurrent pregnancy loss (outside of confirmed antiphospholipid syndrome) 1
• Sildenafil and activity restriction are not recommended 1

Prognosis for Unexplained Cases

Even after complete evaluation, the cause remains uncertain in over 50% of cases 5. These patients should understand that subsequent pregnancies have up to a 70% chance of success without treatment 5, though prognosis depends on maternal age and number of previous losses 7. The likelihood of successful pregnancy is generally good overall 7.

Definition Clarification

Anembryonic pregnancies (previously termed "blighted ovum") should be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria 2