What are the causes and treatments of recurrent pregnancy loss?

Causes of Multiple Miscarriages

Recurrent pregnancy loss (RPL) is caused by genetic abnormalities, uterine anomalies, antiphospholipid syndrome, hormonal disorders, thrombophilias, and other factors, with approximately half of cases remaining unexplained despite thorough evaluation. 1, 2

Definition and Prevalence

• Recurrent pregnancy loss affects approximately 2-5% of couples trying to conceive 2, 3
• Defined as the loss of two or more clinically recognized pregnancies before 20-24 weeks of gestation 1, 3
• While some guidelines previously required three losses for diagnosis, evaluation after two losses is now recommended 1

Established Causes

Genetic Factors

• Parental chromosomal abnormalities/rearrangements are directly associated with RPL 4
• Embryonic chromosomal errors account for a significant percentage of early pregnancy losses 3
• Some patients with recurrent complete hydatidiform moles have an autosomal recessive condition called familial recurrent hydatidiform mole (FRHM) with mutations in NLRP7 and KHDC3L genes 5

Anatomical Factors

• Uterine anomalies are established causes of recurrent pregnancy loss 1, 2
• Surgical correction may be considered for patients with identified uterine anomalies 1
• Structural defects can interfere with proper implantation and placental development 2

Antiphospholipid Syndrome (APS)

• Antiphospholipid syndrome is a well-established cause of RPL 1, 2
• Testing should include lupus anticoagulant and anticardiolipin antibodies 4
• Treatment with anticoagulant therapy and low-dose aspirin is recommended for patients with RPL who have been diagnosed with APS 1

Endocrine and Metabolic Disorders

• Hormonal abnormalities can contribute to recurrent pregnancy loss 2
• Vaginal progesterone supplementation may be considered in patients experiencing vaginal bleeding during the first trimester 1
• Diminished ovarian reserve may be associated with increased miscarriage risk, particularly with severely reduced AMH levels (<0.7 ng/ml) 5

Thrombophilias

• Certain thrombophilias may increase risk of pregnancy loss 6
• Women with homozygous factor V Leiden or prothrombin 20210A mutation with positive family history for VTE should receive antepartum prophylaxis with prophylactic or intermediate-dose LMWH 6
• Blood coagulation protein/platelet defects have been associated with recurrent fetal loss 7

Controversial or Less Established Causes

• Chronic endometritis 2
• Inherited thrombophilias (beyond those mentioned above) 2
• Luteal phase deficiency 2
• High sperm DNA fragmentation levels 2
• Immunologic disorders beyond APS 3
• Endometrial dysfunction 3

Evaluation Approach

Recommended Basic Investigations

• Obstetric and family history 4
• Assessment of age, BMI, and exposure to toxins 4
• Complete blood count 4
• Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) 4
• Parental karyotype 4
• Pelvic ultrasound and/or hysterosalpingogram to assess uterine anatomy 4

Additional Targeted Testing

• Thrombophilia testing in selected cases 6
• Genetic testing when indicated by history 1
• Endocrine evaluation based on clinical presentation 1

Treatment Options

Evidence-Based Treatments

• Surgical correction of uterine anomalies when appropriate 1, 2
• Aspirin and heparin for antiphospholipid syndrome 1, 2
• Low-dose (81 mg/day) aspirin preconception followed by postconception low-dose (5000 units q 12 h) heparin for thrombotic defects 7

Empiric Treatments for Unexplained RPL

• Progesterone supplementation for first-trimester bleeding 1
• Supportive care and psychological support 4, 3
• Health advice and lifestyle modifications 4

Prognosis

• The long-term prognosis for couples with RPL is generally good 2, 3
• Most couples (including those with unexplained RPL) eventually achieve a healthy live birth 1, 2
• Likelihood of successful pregnancy depends on maternal age and number of previous losses 3
• Most people with RPL are expected to achieve a live birth within 5 years from initial evaluation 1

Important Considerations

• Multiple pregnancy losses can have significant psychological impact on affected couples 2, 3
• Compassionate and supportive care is essential across all stages 1
• Evaluation and management of additional comorbidities should be guided by the patient's history rather than solely based on the diagnosis of RPL 1
• Many proposed therapies for unexplained RPL lack strong evidence and should be used cautiously 4