What are the causes of recurrent pregnancy loss in a female patient of reproductive age with a history of multiple miscarriages?

Causes of Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL), defined as three or more consecutive pregnancy losses before 24 weeks gestation, is caused by genetic abnormalities (up to 60% of cases), antiphospholipid syndrome, uterine structural defects, endocrine disorders, and male factor contributions, though up to 75% of cases remain unexplained despite thorough evaluation. 1, 2, 3

Established Genetic Causes

Chromosomal abnormalities are the most common identifiable cause of RPL:

• Fetal chromosomal defects account for 50-60% of early miscarriages and are non-modifiable 4, 5
• Parental chromosomal rearrangements (translocations, inversions) should be identified through karyotyping of both partners 1
• Recurrent complete hydatidiform moles may indicate mutations in NLRP7 and KHDC3L genes, causing familial recurrent hydatidiform mole (FRHM), an autosomal recessive condition requiring genetic counseling 1, 5, 6

Autoimmune and Thrombotic Causes

Antiphospholipid antibody syndrome (APLA) is the primary autoimmune cause requiring treatment:

• Screen for lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA) in all patients with three or more miscarriages before 10 weeks 1, 7
• APLA causes thrombosis in maternal circulation leading to fetal loss 7
• Treatment with unfractionated heparin or LMWH plus low-dose aspirin is recommended for confirmed APLA syndrome 1

Do NOT routinely screen for inherited thrombophilias (factor V Leiden, prothrombin G20210A, protein C/S deficiency) as they are not established causes of RPL 1, 6. 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 1, 6.

Anatomical/Structural Causes

Uterine cavity abnormalities interfere with implantation and cause 14-38% of RPL cases:

• Congenital uterine anomalies (Müllerian anomalies) affect up to 38% of women with recurrent miscarriage 4, 6
• Intrauterine synechiae (adhesions) from prior infection or surgery 4, 6
• Cervical incompetence 4
• Evaluation approach: Start with transvaginal ultrasound (TVUS), then sonohysterography (SIS) for superior cavity assessment, or hysterosalpingography (HSG) as an alternative 1, 5, 6

Endocrine and Metabolic Causes

Hormonal dysfunction contributes significantly to RPL:

• Thyroid dysfunction requires TSH and free T4 testing with optimization before conception 1, 6
• Polycystic ovary syndrome (PCOS) is associated with higher pregnancy loss rates and should be evaluated 1, 6
• Insulin resistance and obesity increase miscarriage risk 4, 6
• Diminished ovarian reserve with severely reduced AMH levels may increase miscarriage risk 6

Male Factor Contributions

Male partner evaluation is now mandatory in couples with two or more pregnancy losses:

• Perform karyotype testing to identify chromosomal abnormalities 1, 6
• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with RPL 1, 6
• Abnormal male partner karyotype is an established contributing factor 6

Unexplained Causes

Idiopathic RPL represents the majority of cases:

• Up to 75% of RPL cases remain unexplained despite thorough evaluation 2, 8
• The long-term prognosis is generally good, with most couples eventually achieving a healthy live birth 8, 3
• Regular physical activity within guidelines is safe and may actually benefit insulin resistance and obesity, which increase miscarriage risk 4, 1, 6

Critical Pitfalls to Avoid

• Do not over-test for thrombophilias: Routine inherited thrombophilia screening is not indicated and wastes resources 1
• Do not use LMWH for prevention of recurrent fetal growth restriction: There is no evidence supporting this indication 6
• Do not count biochemical pregnancies only: RPL definition requires clinically recognized pregnancies (confirmed by ultrasound or hCG), including anembryonic pregnancies 5
• Do not neglect male partner evaluation: This is now a guideline recommendation after two or more losses 1, 6

Modifiable Risk Factors

Lifestyle modifications should be addressed in all patients:

• Smoking cessation, alcohol avoidance, and elimination of recreational drugs are essential modifiable risk factors 1, 5
• Optimize nutrition and maintain healthy weight before attempting conception 1
• Regular physical activity is safe and unlikely to increase pregnancy loss risk 4, 1, 6