Recurrent Pregnancy Loss (RPL)

Recurrent pregnancy loss (RPL) is defined as three or more clinically recognized pregnancy losses before the 20th week of gestation. The condition affects approximately 1 in 300 pregnancies.

For women with a history of recurrent miscarriages, the risk of future pregnancy loss increases with each subsequent miscarriage:

• 24% after two miscarriages
• 30% after three miscarriages
• 40–50% after four miscarriages

What Causes Recurrent Pregnancy Loss?

Several factors contribute to RPL, including:

1. Genetic Factors (3.5%–5%)

• Chromosomal abnormalities
• Genetic mutations
• Multifactorial genetic disorders

2. Anatomical Abnormalities (12%–16%)

• Congenital uterine anomalies:
  • Müllerian anomalies (improper fusion of Müllerian ducts)
  • Uterine septum
  • Intrauterine exposure to DES (Diethylstilbestrol)
  • Uterine vascular abnormalities
  • Cervical insufficiency
• Acquired uterine abnormalities:
  • Uterine fibroids
  • Intrauterine adhesions (Asherman’s syndrome)
  • Endometriosis

3. Endocrine Factors (17%–20%)

• Luteal phase defect
• Polycystic ovary syndrome (PCOS)
• LH disorders
• Androgen imbalances
• Diabetes
• Thyroid dysfunction
• Prolactin disorders

4. Infectious Factors (0.5%–5%)

• Bacterial, viral, parasitic, fungal infections
• Zoonotic infections

5. Immunological Factors (20%–50%)

• Cellular immune factors:
  • Deficiencies in suppressor cells or immune-modulating factors
  • Altered expression of major histocompatibility complex (MHC) antigens
  • Dysregulation of immune cell responses
• Humoral immune factors:
  • Antiphospholipid antibodies
  • Anti-thyroid antibodies
  • Anti-sperm antibodies
  • Anti-trophoblast antibodies

6. Thrombophilia (Blood Clotting Disorders)

• Inherited thrombophilia:
  • Factor V Leiden
  • Prothrombin G20210A mutation
  • MTHFR C677T mutation
• Acquired thrombophilia:
  • Antiphospholipid syndrome (APS)

7. Other Factors (10%)

• Altered endometrial receptivity (e.g., integrins, adhesion molecules)
• Environmental factors (toxins, alcohol, drugs, smoking, caffeine)
• Systemic diseases (cardiac, renal, hematological disorders)
• Intense physical activity
• Asynchronous fertilization

Diagnostic Tests for Recurrent Pregnancy Loss

• Clinical examination
• Ultrasound & 3D ultrasound – detects congenital uterine abnormalities
• Hysterosalpingography (HSG) – further assessment of uterine structure
• Hysteroscopy/Laparoscopy – surgical evaluation if needed
• Laboratory Tests:
  • Karyotyping (both partners)
  • TSH & prolactin levels
  • Vitamin D levels
  • Blood sugar testing
  • Anticardiolipin antibodies & lupus anticoagulant
  • Complete blood count (CBC) & platelet levels
  • Thrombophilia screening (Factor V Leiden, Prothrombin mutation, MTHFR mutation, homocysteine levels, protein S, protein C, and antithrombin III, especially in cases with personal or family history of deep vein thrombosis)

Treatment Approach for Recurrent Pregnancy Loss

The goal of treatment is to identify and address the underlying causes of recurrent miscarriages.

1. Genetic Factors

• Preimplantation Genetic Testing (PGT) – screens embryos for chromosomal abnormalities before implantation
• Use of donor sperm or donor eggs (if a genetic issue is identified in one of the partners)

2. Anatomical Abnormalities

• Hysteroscopic surgery – for uterine fibroids, adhesions, or septum removal
• Laparoscopic or surgical removal of fibroids or endometriomas
• Cervical cerclage – for cervical insufficiency

3. Endocrine Factors

• Ovulation induction to improve egg quality
• Insulin-sensitizing medications (for PCOS patients)
• Glucose control for diabetes
• Thyroid hormone replacement (for hypothyroidism)

4. Infections

• Antibiotic treatment for identified infections

5. Immunological Factors

• Intravenous immunoglobulin (IVIG): Used in some cases, particularly antiphospholipid syndrome (APS)
• Progesterone therapy: Supports implantation and modulates immune responses
• Prednisolone (steroids): Suppresses immune reactions, especially in APS cases

6. Thrombophilia Management

• Low-dose aspirin (160 mg/day) + Low Molecular Weight Heparin (LMWH):
  • Prophylactic doses (40 mg/day enoxaparin or 5000 IU/day dalteparin) for women without thrombosis history
  • Therapeutic doses (40–80 mg twice daily enoxaparin or 5000–10000 IU twice daily dalteparin) for women with thrombosis history or multiple thrombophilic mutations
• Folic acid supplementation (0.4–1 mg/day) for hyperhomocysteinemia

Key Takeaways

• Recurrent pregnancy loss has multiple causes (genetic, anatomical, hormonal, immunological, or environmental).
• Early diagnosis & targeted treatment improve the chances of a successful pregnancy.
• Couples experiencing RPL should seek specialized fertility advice to determine the best course of action.