What is the management approach for a patient with Recurrent Pregnancy Loss (RPL)?

Management of Recurrent Pregnancy Loss

Begin a comprehensive diagnostic evaluation after 2 clinically recognized first-trimester pregnancy losses, and implement a systematic, evidence-based approach targeting identifiable causes while providing supportive care for unexplained cases. 1, 2, 3

Initial Diagnostic Workup

Genetic and Chromosomal Testing

• Perform parental karyotyping on both partners to identify chromosomal rearrangements (translocations, inversions) that could cause recurrent losses 1, 2
• Test products of conception when available, as chromosomal errors account for 50-60% of early losses 1
• For patients with recurrent complete hydatidiform moles specifically, order genetic testing for NLRP7 and KHDC3L gene mutations, which cause familial recurrent hydatidiform mole (an autosomal recessive condition) 1, 2, 4

Immunologic Evaluation

• Screen all patients for antiphospholipid antibodies (APLAs) including lupus anticoagulant and anti-cardiolipin antibodies 1, 2
• Do NOT routinely screen for inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency) as these are not evidence-based causes of RPL 2
• The only exception: women with homozygous factor V Leiden or prothrombin 20210A mutation AND positive family history for VTE should receive antepartum LMWH prophylaxis—but this is for VTE prevention, not pregnancy loss prevention 2, 4

Anatomical Assessment

• Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 1, 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 to hysteroscopy 1, 4
• Hysterosalpingography (HSG) serves as an alternative imaging modality 2

Endocrine and Metabolic Testing

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

Male Partner Evaluation

• Evaluate the male partner in ALL couples with ≥2 pregnancy losses—this is now a guideline recommendation 5, 1, 2
• Perform karyotype testing on the male partner to identify chromosomal abnormalities 5, 1, 2
• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 5, 1, 2

Treatment Based on Identified Causes

Antiphospholipid Syndrome

• For women meeting laboratory criteria for APLA syndrome, treat with unfractionated heparin or LMWH plus low-dose aspirin 1, 2
• This is the only anticoagulation indication with proven efficacy in RPL 6

Genetic Abnormalities

• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing 1
• Patients with recurrent anembryonic pregnancies due to NLRP7 and KHDC3L gene mutations may benefit from ovum donation rather than conventional IVF 1, 4

Anatomical Abnormalities

• Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence 1, 3
• 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

Myeloproliferative Neoplasms (Special Population)

• In low-risk essential thrombocythemia (ET) patients, aspirin therapy alone may be sufficient 5
• High-risk ET or polycythemia vera patients require cytoreductive therapy with pegylated interferon-alpha (45 mcg subcutaneously weekly) plus aspirin throughout pregnancy 5
• Consider interferon-alpha even in low-risk patients with history of recurrent fetal loss, prominent splenomegaly, or suboptimal hematocrit control 5

Lifestyle Modifications

• Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs—these are modifiable risk factors 1, 2, 4
• Regular physical activity within guidelines is safe and may actually benefit insulin resistance and obesity, which increase miscarriage risk 1, 2, 4
• Optimize nutrition and maintain healthy weight before attempting conception 1, 2

Management of Subsequent Pregnancies

Early Pregnancy Monitoring

• Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected 1, 2, 4
• Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy 1, 2, 4

Ongoing Surveillance

• Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss 1, 2, 4
• Monitor for and promptly treat any endocrine conditions, particularly thyroid dysfunction 1, 4
• Consider vaginal progesterone supplementation in patients experiencing first-trimester vaginal bleeding 3

Critical Caveats and Common Pitfalls

What NOT to Do

• There is NO evidence supporting LMWH for prevention of recurrent pregnancy loss outside of confirmed antiphospholipid syndrome 1
• Do not routinely screen for inherited thrombophilias as they are not established causes of RPL 2
• Avoid hydroxyurea and warfarin in women contemplating pregnancy as they are teratogenic 5

Important Definitions

• Anembryonic pregnancies SHOULD be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria (gestational sac ≥25 mm without an embryo) 4
• RPL is now defined as ≥2 consecutive pregnancy losses, not the traditional 3 losses 3

Prognosis and Counseling

• Most people with RPL, including those without identifiable risk factors, are expected to achieve a live birth within 5 years from initial evaluation 3
• Even with unexplained RPL, subsequent pregnancies have up to 70% chance of success without treatment 6
• Provide compassionate psychological support, as multiple pregnancy losses have significant emotional impact on affected couples 3, 7