Recurrent Pregnancy Loss (RPL)

Summary

Recurrent pregnancy loss (RPL) is a complex and multifactorial condition affecting 1–2% of women of reproductive age, with significant emotional and psychological impact. Despite advances in understanding its etiologies—including genetic, anatomical, endocrine, immunological, and thrombotic factors—over half of cases remain unexplained. Comprehensive evaluation, targeted management of identifiable causes, and multidisciplinary care are essential to improving outcomes. Importantly, with appropriate support and treatment, many women with RPL are able to achieve a successful live birth.

Definition and Epidemiology

Recurrent pregnancy loss (RPL), also referred to as recurrent miscarriage or habitual abortion, is classically defined as three or more consecutive pregnancy losses before 20–24 weeks of gestation. The Royal College of Obstetricians and Gynaecologists (RCOG) defines it as three or more miscarriages before 24 weeks, while in clinical practice, some guidelines begin evaluation after two losses.
RPL affects approximately 1–2% of women of reproductive age, with a significant psychological impact requiring both medical and emotional support.

Etiology

RPL is a multifactorial condition, with identified causes in only 40–50% of cases. In more than half of affected women, no clear etiology is found.

1. Genetic Factors

• Embryonic chromosomal abnormalities: account for up to 30–57% of miscarriages, most commonly due to trisomies.

• Parental chromosomal rearrangements: present in 2–5% of couples, usually balanced reciprocal or Robertsonian translocations, leading to unbalanced conceptions.

2. Antiphospholipid Syndrome (APS)

• APS is present in up to 15% of women with RPL.

• Without treatment, live birth rates may be as low as 10%.

• Defined by recurrent pregnancy failure or vascular thrombosis in the presence of persistent antiphospholipid antibodies.

3. Endocrine and Metabolic Disorders

• Diabetes mellitus and thyroid disease (if uncontrolled) increase miscarriage risk.

• Polycystic ovarian syndrome (PCOS) is associated with RPL, possibly due to insulin resistance and hyperandrogenism.

• Progesterone deficiency, hyperprolactinemia, and other hormonal disturbances may contribute.

4. Anatomical Abnormalities

• Congenital uterine malformations: septate, bicornuate, or arcuate uterus.

• Acquired lesions: intrauterine adhesions (Asherman’s syndrome), submucosal fibroids, endometriosis, or pelvic tumors.

• Cervical incompetence: a major cause of second-trimester pregnancy loss, often presenting with painless cervical dilatation or premature rupture of membranes.

5. Thrombophilias

• Inherited thrombophilias (Factor V Leiden, prothrombin gene mutation, protein C or S deficiency, antithrombin III deficiency) are linked more strongly with second-trimester losses due to placental thrombosis.

6. Infective Causes

• Rarely implicated in RPL, although bacterial vaginosis in early pregnancy is associated with later miscarriage.

• Severe systemic infections causing bacteraemia or viraemia may contribute to sporadic but not recurrent miscarriage.

7. Other Maternal Factors

• Chronic hypertension, uncontrolled diabetes, malnutrition, autoimmune diseases (e.g., SLE).

• Lifestyle factors: advanced maternal or paternal age, smoking, alcohol use, and high caffeine intake may increase risk.

Risk Factors

• Maternal age: miscarriage risk rises from 11% at age 20 to >50% after age 40, and over 90% above 45.

• Number of prior miscarriages: risk increases with each successive loss (up to 40% after three consecutive miscarriages).

• Parental age, abnormal BMI, smoking, alcohol, and stress may further contribute.

Clinical Evaluation and Investigations

All women with RPL should undergo a comprehensive assessment, including:

History and Examination

• Detailed medical, obstetric, and family history.

• Physical and pelvic examination.

Laboratory Investigations

• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein I).

• Thrombophilia screen (Factor V Leiden, prothrombin mutation, protein C/S, antithrombin III).

• Endocrine testing: thyroid function, HbA1c, prolactin, luteal phase hormones.

• Cytogenetic analysis: products of conception and parental karyotyping when indicated.

Imaging

• Pelvic ultrasound for uterine structure.

• 3D ultrasound, hysteroscopy, or laparoscopy for suspected anomalies.

• Cervical surveillance via ultrasound in women with suspected cervical weakness.

Management

Management of RPL is cause-specific, with emphasis on supportive care:

Genetic Abnormalities

• Referral to a clinical geneticist and genetic counselling.

• Options: natural conception, IVF with preimplantation genetic testing, gamete donation, or adoption.
  
  

Antiphospholipid Syndrome

• Low-dose aspirin plus heparin significantly improves live birth rates.

• No role for empirical anticoagulation in women without APS.

Endocrine and Metabolic Causes

• Optimize diabetes and thyroid function prior to conception.

• Address PCOS-related risks through weight management and insulin-sensitizing therapy if indicated.

Anatomical Causes

• Surgical correction of uterine anomalies (e.g., septum resection) may be beneficial.

• Cervical cerclage is indicated in select women with documented cervical insufficiency.

Thrombophilias

• Women with recurrent losses and inherited thrombophilia may benefit from anticoagulation in pregnancy.
  
  

Unexplained RPL

• More than 50% of cases remain idiopathic.

• Management focuses on close monitoring, supportive care, and psychological support.

Prognosis

• Even without treatment, many women with RPL ultimately achieve a successful live birth.

• Prognosis depends on maternal age, underlying cause, and number of prior miscarriages.