Recurrent Pregnancy Loss: Definition, Epidemiology, Causes, Diagnosis, and Treatment

Recurrent pregnancy loss (RPL) refers to repeated spontaneous miscarriages. According to current ESHRE guidelines, RPL is defined as two or more consecutive miscarriages; ASRM also uses the criterion of "≥2" clinically confirmed losses. Previously, RPL was defined as three or more consecutive losses, but recent studies indicate that investigation is justified after two consecutive losses. Approximately 10–15% of clinical pregnancies end in miscarriage, with RPL occurring in ~1–3% of couples trying to conceive. Among women with one previous miscarriage, the chance of carrying the next pregnancy to term is 80–90%, with the likelihood of a second loss estimated at 12–20% (and ~29% after two losses). Risk factors for RPL include advancing maternal age (loss rates increase from ≈11% at 20–24 years to >50% after 40), previous miscarriages, and certain medical conditions. A clear cause of RPL is identified in only about half of patients, with the remainder classified as idiopathic losses.

Main Causes of RPL

RPL is a multifactorial condition. The main categories of causes include genetic abnormalities, uterine structural anomalies, endocrine disorders, immunological factors, infectious agents, and thrombophilias. Below is their classification.

Category	Examples/Description
Genetic	Chromosomal abnormalities: embryonic (aneuploidies – trisomies, monosomies, etc.) and parental (balanced translocations, inversions). Approximately 50% of sporadic early miscarriages are caused by embryonic chromosomal defects; parental karyotype abnormalities are found in about 1–3% of RPL cases.
Anatomical	Uterine developmental anomalies: septum, bicornuate uterus, unicornuate uterus, etc. (a common cause – up to 7–28% in women with RPL compared to 4–7% in the general population). Acquired anomalies: intrauterine adhesions (synechiae), polyps, fibroids, or prior surgeries/inflammatory processes that deform the uterine cavity.
Endocrine	Thyroid dysfunction (hypothyroidism, autoimmune thyroiditis). Polycystic ovary syndrome (PCOS) with insulin resistance. Other hypo/hyperhormonal conditions (hyperprolactinemia, diabetes).
Immunological	Antiphospholipid syndrome (antiphospholipid antibodies: lupus anticoagulant, anti-cardiolipin antibodies, β2-glycoprotein-I) – a proven cause of RPL. Other autoimmune conditions (thyroiditis, systemic lupus erythematosus, etc.) may contribute to miscarriage.
Infectious	Chronic endometrial or genital tract infections (e.g., bacterial endometritis microorganisms, certain viral or bacterial infections) – their role is suspected, but data are conflicting. Researchers estimate infections as a cause in only 0.5–5% of RPL cases.
Thrombophilias	Hereditary (Factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency, homocystinuria, etc.) and acquired (APS) coagulation disorders. APS is clearly associated with RPL; the significance of hereditary thrombophilias is less clear.

Diagnostic Methods

According to international guidelines (ESHRE, ASRM), the evaluation of couples with RPL should be comprehensive. Initially, a detailed history is collected (number of losses, gestational age, live births, comorbidities, lifestyle factors, etc.).

• Genetic evaluation: Parental karyotyping (to detect translocations) and, where possible, analysis of genetic material (products of conception) using array-CGH. ESHRE recommends array-CGH for embryonic tissue due to reduced maternal cell contamination.
• Uterine ultrasound diagnostics: Transvaginal 3D ultrasound is the method of choice with high sensitivity and specificity. If 3D ultrasound is unavailable, sonohysterography or hysterosalpingography can be used. Hysteroscopy/hydrosalpingography can clarify and remove intrauterine formations (synechiae, polyps).
• Endocrine tests: Measurement of TSH and anti-thyroid peroxidase antibodies (TPO-Ab) – all women with RPL should be screened for subclinical hypothyroidism. Glycemic control (HbA1c, fasting glucose) is assessed for possible diabetes or prediabetes. Prolactin testing is recommended by ESHRE only in the presence of hyperprolactinemia symptoms (oligomenorrhea, galactorrhea); routine testing is not advised.
• Immunological evaluation: All women with two or more pregnancy losses should be screened for antiphospholipid antibodies – lupus anticoagulant and anti-cardiolipin antibodies (IgG/IgM); β2-glycoprotein-I is tested if suspicion arises. Other immunological tests (HLA typing, NK cells, cytokines, ANA, etc.) are not used in routine practice due to insufficient evidence of their relevance.
• Thrombophilia assessment: Hereditary mutations (FV Leiden, FII20210A, etc.) are not recommended for routine testing without additional indications – their association with RPL is questionable. However, APS screening automatically covers "acquired thrombophilia."
• Infection screening: General screenings (e.g., TORCH complex) are not routinely indicated; chronic endometritis is often detected via hysteroscopy/biopsy based on clinical indications (e.g., heavy discharge).

Treatment

The treatment approach depends on the identified cause:

• Genetic factors: If a parental chromosomal abnormality is detected, consultation with a clinical geneticist is recommended. For couples with balanced translocations, preimplantation genetic testing (PGT-SR) within IVF is advised: embryos are screened for chromosomal abnormalities before transfer, and only normal ones are implanted. However, studies show that the natural chance of delivering a healthy child is higher (~50–74%) than with PGT and IVF (~30–35%), so the decision for PGT is individualized.
• Anatomical anomalies: If a uterine septum is diagnosed, hysteroscopic metroplasty (septum resection) is the method of choice. Removal of symptomatic polyps or submucosal fibroids may improve pregnancy conditions, though evidence for reducing loss risk is limited. In cases of confirmed cervical incompetence (isthmic-cervical insufficiency), cervical cerclage is considered, especially with a history of spontaneous second-trimester deliveries and a short cervical canal on ultrasound.
• Endocrine and metabolic disorders: Identified conditions are treated: hypothyroidism is managed with levothyroxine (often targeting TSH >2.5 mIU/L during pregnancy planning). PCOS-related insulin resistance is corrected. Women with prediabetes/diabetes should optimize glycemic control (balanced diet, medications as indicated).
• Immunological factors and thrombophilias: For confirmed APS, anticoagulant therapy is mandatory. Low-dose acetylsalicylic acid (ASA, 75–100 mg/day) is typically prescribed before conception, followed by low-molecular-weight heparin (or unfractionated heparin) after pregnancy confirmation. Meta-analyses show that combining heparin with ASA increases live birth rates in women with APS compared to ASA alone. For hereditary thrombophilias (FVL, FII G20210A, etc.), ESHRE does not recommend routine antiplatelet/anticoagulant therapy due to insufficient evidence of benefit in RPL.
• Assisted reproductive technologies (ART): In the absence of an obvious RPL cause, the direct role of IVF is not proven. However, for couples with prolonged unsuccessful attempts to conceive (or with a genetic factor), IVF with PGT-A/PGT-SR may be considered to select euploid embryos. ESHRE recognizes PGT as the primary therapeutic method for genetic causes of miscarriage, though the chance of delivering a child through natural conception is higher than with any form of PGT/IVF.

Prevention and Multidisciplinary Approach

RPL prevention focuses on optimizing the couple’s health and addressing risk factors. Couples are advised to quit smoking and limit alcohol, as these habits can negatively impact the chances of delivering a child. Maintaining a normal body weight (addressing overweight or obesity) and engaging in moderate physical activity (avoiding excessive exercise) are recommended. Pregnancy planning should include folic acid deficiency prevention and chromosomal abnormality screening (subsequent screening tests based on maternal age). Maternal age is particularly significant: the risk of loss is lowest between 20–35 years, with early or late reproduction carrying higher risks.

Managing couples with RPL requires a multidisciplinary approach. Ideally, care is coordinated at a specialized RPL center involving an obstetrician-gynecologist, geneticist, endocrinologist, immunologist (as needed), and a psychologist or psychotherapist. Psychological support is crucial, as repeated losses can cause significant stress, anxiety, and depression. Healthcare providers should collaboratively develop an individualized plan for monitoring subsequent pregnancies (early diagnosis, correction of identified abnormalities) and ensure regular consultations.

Conclusions

Current international research and statistics support the above approaches. According to a 2023 review, about 5% of women experience ≥2 miscarriages, with over 50% of RPL cases remaining without a clear etiology. Updated ESHRE (2023) and ASRM (2012) clinical guidelines detail diagnostic algorithms and therapeutic recommendations for each cause category. Understanding this information by both clinicians and patients enables the development of an optimal evaluation and treatment plan, increasing the chances of successful pregnancy management and the birth of a healthy child.

Conclusions: RPL is a multifactorial syndrome. The key to success lies in timely diagnosis of causes, etiology-based treatment, and a holistic approach to the couple. Even in the absence of a precise cause, successful management often involves monitoring hormonal status, correcting identified uterine abnormalities, supporting implantation, and creating a "favorable" environment for future pregnancy.

Sources: Updated international guidelines and scientific reviews on reproductive medicine: eshre.eu, researchgate.net, mdpi.com.