Recurrent Pregnancy Loss (RPL)

Definition

Prognosis

Etiology

1. Genetic Factors (~3–5%)

• Parental balanced structural chromosomal rearrangements are found in 3–5% of RPL couples vs. 0.2–0.7% in the general population
• Types: balanced reciprocal translocations (most common), Robertsonian translocations, chromosomal inversions, insertions, mosaicism
• Robertsonian translocations: fusion of long arms of group D (chromosomes 13, 14, 15) and group G (chromosomes 21, 22) chromosomes; total chromosome number = 45; ~2/3 of gametes will be unbalanced
• Reciprocal translocations: exchange of material between two chromosomes with no net gain/loss; ~half of gametes are abnormal
• De novo fetal aneuploidy accounts for ≥60% of early pregnancy losses overall; however, as the number of losses increases, the proportion with a chromosomally abnormal fetus decreases — by 7+ losses, ~80% of failed pregnancies have a normal embryonic karyotype
• Best parental test: metaphase G-banding karyotype (microarrays cannot detect balanced rearrangements)

2. Anatomic Abnormalities (~10–12%)

• Uterine anomalies: septate uterus (most common correctable anomaly), bicornuate, unicornuate, arcuate, and didelphic uteri
• Acquired defects: submucosal fibroids, intrauterine adhesions (Asherman syndrome), endometrial polyps, cervical incompetence
• Evaluation: hysterosalpingography (HSG), 3D ultrasound, sonohysterography, or hysteroscopy
• Uterine septum resection is associated with improved pregnancy outcomes

3. Antiphospholipid Syndrome (APS) (~15%)

• The only immunologic cause with an established treatment
• Diagnosis requires ≥1 clinical criterion (≥3 unexplained losses, or ≥1 loss after 10 weeks, or ≥1 premature birth <34 weeks due to placental disease) plus ≥1 laboratory criterion on two occasions ≥12 weeks apart:
  • Lupus anticoagulant
  • Anticardiolipin antibodies (IgG or IgM), medium-to-high titer
  • Anti-β2 glycoprotein I antibodies
• Treatment: low-dose aspirin + low-molecular-weight heparin (LMWH) — shown to improve live birth rates

4. Endocrine Abnormalities

• Poorly controlled diabetes mellitus and thyroid disease (hypothyroidism, hyperthyroidism) — optimize before conception
• Polycystic ovary syndrome (PCOS): associated with increased miscarriage risk, possibly related to hyperandrogenemia, insulin resistance, elevated LH
• Hyperprolactinemia: associated with ovulatory dysfunction and altered HPO axis; treatment with bromocriptine or cabergoline may reduce miscarriage rates
• Luteal phase defect: controversial — low progesterone or inadequate endometrial preparation; progesterone supplementation is widely used but evidence is inconsistent

5. Thrombophilias

• Inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency, antithrombin deficiency) have been associated with late pregnancy loss and fetal growth restriction
• For first-trimester RPL, the evidence linking inherited thrombophilias is weak and inconsistent — routine screening is not supported by current evidence for most patients
• Exception: APS (see above)

6. Immunologic Factors

• Cellular immunity: NK cell abnormalities in endometrial tissue have been reported; significance remains unclear
• Alloimmune mechanisms: thought to involve failure of maternal tolerance to paternal antigens
• Outside of APS, no immunologic testing or treatment has proven benefit in randomized trials

7. Maternal Infection

• Association with RPL is controversial and poorly explored
• Potential organisms: Listeria, Toxoplasma, rubella, herpes simplex, Mycoplasma, Ureaplasma
• No specific infectious workup is recommended unless clinical features suggest active infection

8. Male Factors

• Elevated sperm DNA fragmentation has been associated with RPL; clinical utility of testing remains under investigation

9. Environmental & Lifestyle Factors

• Smoking, alcohol use, caffeine, obesity, and occupational exposures have been linked to increased miscarriage risk
• Tobacco and alcohol are modifiable risk factors; cessation is advised

Evaluation

Recommended Testing

Tests with Unproven Utility (Not Routinely Recommended)

• Routine thrombophilia screening (factor V Leiden, prothrombin mutation, etc.) for first-trimester RPL
• NK cell testing
• HLA testing / leukocyte immunization
• Anti-thyroid antibody screening (controversial)

Management

Based on Identified Etiology

Controversial/Investigational Treatments

• IVF with PGT-A (preimplantation genetic testing for aneuploidy): may reduce miscarriage per transfer but does not improve cumulative live birth rates; evidence insufficient for routine recommendation
• Immunosuppression (prednisolone, IVIG): not supported by RCT evidence for unexplained RPL
• Leukocyte immunization (LIT): largest trial (REMIS study) did not show benefit; not recommended
• Anticoagulation (LMWH) for inherited thrombophilias without APS: not proven to reduce miscarriage in trials

Supportive Care (for all patients)

• Close monitoring with serial β-hCG and early ultrasound in subsequent pregnancy
• Psychological support — RPL carries significant emotional burden; rates of anxiety, depression, and grief are high
• Reassurance: prognosis is generally good even without a specific diagnosis

Key Takeaways

1. Sporadic loss is common (15–25%); RPL (≥3 losses) affects ~1% of women
2. Evaluation is appropriate after 2 consecutive losses
3. ~50% of RPL is unexplained even after full workup
4. The most important treatable cause is APS — treat with aspirin + heparin
5. Fetal aneuploidy explains most sporadic losses, but its role decreases as the number of recurrent losses increases
6. Parental balanced translocations found in 3–5% → refer for genetic counseling
7. Most patients will ultimately achieve a live birth — prognosis should be conveyed positively