Recurrent Pregnancy Loss (RPL)

Definition

Etiology

1. Genetic Factors (most common cause of first-trimester loss)

• Fetal aneuploidy - the single most common cause of sporadic miscarriage. As the number of losses increases, the proportion with a chromosomally abnormal conceptus decreases (from ~78% with 1 loss to ~18% with 7+ losses), meaning other etiologies become proportionally more important.
• Parental chromosomal abnormalities - found in 3-5% of RPL couples vs. 0.2-0.7% of the general population. The most common is a balanced translocation (reciprocal 60%, Robertsonian 40%).
• Polyploidy and uniparental disomy - detectable by SNP array but may be missed by standard G-banding or aCGH.

2. Anatomic Abnormalities (~15% of RPL)

• Septate uterus - most common anomaly associated with RPL and most amenable to surgical correction (hysteroscopic metroplasty)
• Bicornuate, unicornuate, and didelphic uteri
• Acquired defects: submucosal fibroids, intrauterine adhesions (Asherman syndrome), endometrial polyps

3. Antiphospholipid Syndrome (APS) - most treatable cause

• Clinical criteria: 1+ pregnancy loss at ≥10 weeks, 3+ losses before 10 weeks, or thrombosis
• Laboratory criteria (must be positive on 2 occasions ≥12 weeks apart):
  • Lupus anticoagulant (LA)
  • Anticardiolipin antibodies (aCL) IgG/IgM
  • Anti-β2-glycoprotein I (aβ2GPI) IgG/IgM

4. Endocrine Abnormalities

5. Thrombophilias (Inherited)

• Factor V Leiden, Prothrombin gene mutation (G20210A), MTHFR mutations, Protein C/S deficiency, Antithrombin III deficiency
• Evidence for routine screening is weak - inherited thrombophilias have a less established link to early RPL than to late fetal loss. ASRM does not recommend routine thrombophilia screening beyond APS.

6. Immunologic Factors

• Cellular immunity: Altered NK cell function and Th1/Th2 imbalance have been proposed. A 2023 meta-analysis (PMID 37236061) confirmed elevated peripheral NK cell cytotoxicity in recurrent miscarriage.
• Leukocyte immunization, IVIG, and paternal lymphocyte immunotherapy remain unproven and experimental.

7. Male Factors

• Sperm DNA fragmentation and chromosomal abnormalities in sperm contribute to embryo aneuploidy and RPL.

8. Other/Environmental Factors

• Obesity (BMI >25-30 independently increases risk)
• Smoking, alcohol, caffeine (>200 mg/day)
• Advanced maternal age (due to increased aneuploidy)
• Uterine blood flow abnormalities

9. Unexplained RPL

Evaluation

History

• Number, timing (trimester), and characteristics of each loss
• Subfertility, menstrual pattern, DES exposure, infections
• Personal/family history of thrombosis, autoimmune disease
• Medications, environmental/substance exposures
• Consanguinity

Physical Examination

• BMI, signs of PCOS (hirsutism, acanthosis nigricans)
• Thyroid palpation
• Galactorrhea
• Pelvic exam (anatomy, estrogenization)

Recommended Laboratory and Imaging Tests

Tests NOT routinely recommended

• ANA, celiac markers, other autoantibodies
• Ovarian reserve testing (AMH, FSH/E2) - not part of ASRM standard RPL work-up, though it may guide prognosis
• Routine thrombophilia panel beyond APS

Management

Genetic Abnormalities

• Parental balanced translocation: Genetic counseling; IVF with preimplantation genetic testing for structural rearrangements (PGT-SR) can improve live birth rates. A 2025 meta-analysis (PMID 39151684) found PGT for aneuploidy in unexplained RPL does not clearly improve live birth rates over expectant management in unselected patients.
• Karyotype products of conception from subsequent losses to determine whether it is a "random" aneuploid event (somewhat reassuring) or euploid (indicating another etiology).

Anatomic Correction

• Septate uterus: Hysteroscopic metroplasty is first-line; live birth rates improve significantly.
• Submucosal fibroids / polyps: Hysteroscopic removal.
• Intrauterine adhesions: Hysteroscopic lysis.

APS Treatment

• Low-dose aspirin (75-81 mg/day) + unfractionated or low-molecular-weight heparin throughout pregnancy - this is the only treatment for RPL with strong evidence of benefit. Live birth rates improve from ~10-20% (no treatment) to 70-80%.

Endocrine Treatment

• Hypothyroidism / subclinical hypothyroidism: Levothyroxine to maintain TSH <2.5 mIU/mL in first trimester.
• Hyperprolactinemia: Bromocriptine or cabergoline to normalize levels.
• PCOS/insulin resistance: Metformin may be considered; evidence insufficient for routine use.
• Strict glycemic control in women with diabetes.

Progesterone Supplementation

• Vaginal progesterone is widely used in clinical practice. The PROMISE trial showed no benefit in unexplained RPL; however, the PRISM trial (n>4000) suggested possible benefit in women with early pregnancy bleeding. Current consensus: reasonable to use in clinical practice but not strongly evidence-based for unexplained RPL.

Psychological Support

• Strong evidence that dedicated support programs with early ultrasound monitoring (the "tender loving care" model) significantly improve live birth rates in unexplained RPL - independent of any specific treatment.
• Close monitoring with serial beta-hCG and ultrasound in subsequent pregnancy.

Interventions of Unproven/No Benefit

• Leukocyte immunization therapy
• Paternal lymphocyte immunization
• IVIG alone
• Routine anticoagulation for inherited thrombophilias without thrombotic history

Prognosis

• After 3 losses: ~55-75% chance of next live birth (age-dependent)
• After 5 losses: ~40-55%
• Prognosis worsens significantly with advanced maternal age and increasing number of losses

Recent Guidelines (2024-2025)

• Australasian ACCEPT 2024 (PMID 38934293) - two-part guideline covering investigation and management
• SOGC Guideline No. 464, 2025 (PMID 41176277) - Canadian practice guideline updated
• APS in pregnancy, 2025 (PMID 40128683) - comprehensive review confirming aspirin + LMWH as standard of care