Recurrent pregnancy losses

Recurrent Pregnancy Loss (RPL) is defined as the spontaneous loss of two or more consecutive clinically confirmed pregnancies [ESHRE 2022]. A single pregnancy loss is considered an isolated event. Spontaneous abortion occurs in up to 90% of cases during early pregnancy (before 12 weeks). Pregnancy loss occurring before the 22nd week is classified as a late miscarriage. Preterm birth refers to delivery occurring between the 22nd and 37th weeks of gestation, whereas delivery after the 37th week is considered full-term Causes of Recurrent Pregnancy Loss: Embryonic pathology (life-incompatible anatomical anomalies, genetic mutations, and chromosomal abnormalities) Maternal pathology. Male factor. In up to 50% of cases, the underlying cause of RPL remains unidentified (idiopathic RPL)

Maternal Factors in Recurrent Pregnancy Loss Anatomical Factors: Congenital uterine malformations. All women with RPL should have an assessment of the uterine anatomy. If a Müllerian uterine malformation is diagnosed, further investigations (including investigation of the kidneys and urinary tract) should be considered. Acquired uterine malformations (submucous myomas, endometrial polyps and uterine adhesions) have been found prevalent in women that suffered pregnancy loss, but the clinical relevance is unclear Endocrine factors: Polycystic ovary syndrome. Lutein deficiency (inadequate progesterone secretion by the corpus luteum) Hyperprolactinemia (elevated blood prolactin levels) Uncontrolled diabetes mellitus Thyroid dysfunction. Thyroid screening (TSH and TPO antibodies) is recommended in women with RPL. Abnormal TSH levels should be followed up by T4 testing in women with RPL. Endometriosis (recent studies indicate progesterone resistance in endometriosis patients) Disruptions in maternal-fetal microcirculation and the development of systemic thrombosis have been identified as major contributors to RPL. Thrombophilia and Recurrent Pregnancy Loss Thrombophilia is a hereditary or acquired condition that predisposes women with RPL to venous thromboembolism (i.e., venous thrombosis and pulmonary embolism). Acquired Thrombophilia The most common form of acquired thrombophilia is antiphospholipid syndrome (APS), a systemic autoimmune disorder characterized by specific clinical and laboratory findings. In APS, pregnancy loss is primarily due to thrombosis within the maternal-fetal circulatory system. Diagnosis of antiphospholipid syndrome requires the assessment of antiphospholipid antibodies, including: • Lupus anticoagulant (LA) • Anticardiolipin antibodies (ACA IgG/IgM) • Anti-beta2-glycoprotein antibodies (aβ2GPI)

Genetic thrombophilia is an inherited pathological condition that predisposes to the development of thrombosis, which is manifested by obstetric complications. Hereditary thrombophilia is considered a possible cause of recurrent miscarriage and late pregnancy complications with a probable mechanism of thrombosis development in the uterine-placental circulation. It has been considered that hypercoagulable state of pregnancy and the likelihood of developing thrombosis in the maternal and fetal circulatory system are often due to polymorphism of various genes of thrombophilia. In the early stages of pregnancy, including in the preimplantation period, development of pregnancy loss is facilitated due to the disruption of blood flow in the endometrial blood vessels through implantation disorders, and in the late term promotes development of complications such as preeclampsia (PE), preterm labor (PTL), and preterm placental abruption. According to evidence-based medicine, specific genetic thrombophilias are associated with an increased risk of thromboembolic and obstetric complications, including: Antithrombin III deficiency, Protein C and Protein S deficiency, Prothrombin (F2) G20210A mutation, Factor V Leiden mutation, PAI-1 (-675 5G/4G) polymorphism, MTHFR C677T and MTHFR A1298C polymorphisms. Current guidelines from RCOG, ASRM, and ESHRE recommend screening for thrombophilia gene mutations only in women with RPL who also have a personal or family history of thrombosis. In cases of acquired and/or hereditary thrombophilia, aspirin and low-molecular-weight heparin (LMWH) are commonly considered for treatment. Hyperhomocysteinemia and Pregnancy Loss Recent studies suggest that hyperhomocysteinemia (elevated homocysteine levels in the blood) may contribute to pregnancy loss. Infectious Causes of Pregnancy Loss Any acute infection characterized by bacteremia, viremia, and/or high fever may precipitate pregnancy loss. Notable infections include Influenza, Rubella, Syphilis, Listeriosis, Chlamydia and other bacterial and viral infections Male Factor in Recurrent Pregnancy Loss Recent research has established a correlation between male reproductive health and pregnancy loss. Conditions such as: • Varicocele • Sperm DNA fragmentation Additionally, imbalances in seminal fluid composition may influence maternal immune responses to pregnancy. Moreover, balanced structural chromosomal aberrations in the father can result in unbalanced transmission to the fetus, leading to pregnancy loss. Risk Factors for Recurrent Pregnancy Loss • Advanced parental age: The risk of spontaneous abortion increases when the mother is over 35 years old, and the father is over 40 years old. • Lifestyle factors: Tobacco use, alcohol, caffeine, and drug consumption are dose-dependent risk factors for pregnancy loss. • Obesity: Both maternal and paternal obesity are recognized as risk factors. • Stress is associated with RPL, but couples should be informed that there is no evidence that stress is a direct cause of pregnancy loss. Management and Prevention of Recurrent Pregnancy Loss Women with a history of recurrent pregnancy loss should not attempt conception until a definitive cause is identified and appropriately addressed. Comprehensive counseling and psychological support are crucial for couples experiencing recurrent pregnancy loss. Management of affected couples should be led by specialists using personalized medicine approaches within specialized medical institutions. It is essential to acknowledge that the challenge of pregnancy loss escalates with increasing spontaneous abortion rates. Timely diagnosis is fundamental to effective, targeted, and evidence-based treatment.

Author: Elene AsanidzeAssociate Professor, Obstetrician-Gynecologist, Doctor of Medicine