Efficacy of Progesterone and Low Molecular Weight Heparin in Recurrent Pregnancy Loss

This prospective, single-centre, open-label, randomized Phase III superiority trial will enroll approximately 268 women aged 18-40 years with at least two consecutive unexplained miscarriages and a singleton intrauterine pregnancy confirmed by ultrasound at 5-7 weeks of gestation. Participants will be randomly assigned in a 1:1 ratio to standard antenatal care without active pharmacological treatment for recurrent pregnancy loss or to vaginal micronized progesterone plus subcutaneous enoxaparin. The primary outcome is live birth at or beyond 24+0 weeks of gestation. Study follow-up continues through six weeks postpartum. Delivery and postpartum outcomes will be obtained remotely using a structured participant-completed questionnaire. An optional exploratory translational sub-study involving one maternal blood sample at 10-12 weeks requires separate informed consent.

Inclusion Criteria 1. Women aged 18-40 years. 2. History of at least two consecutive unexplained miscarriages. 3. Confirmed pregnancy at 5-7 weeks of gestation, with a singleton intrauterine pregnancy confirmed by ultrasound before randomization. 4. Willingness to comply with study procedures and, if assigned to the intervention arm, to use vaginal progesterone and administer daily subcutaneous enoxaparin injections; ability to provide written informed consent. 5. No medical contraindication to progesterone or low-molecular-weight heparin. Exclusion Criteria 1. Documented antiphospholipid syndrome or any current anticoagulant requirement. 2. Clinically significant thyroid disease requiring treatment adjustment. 3. Anatomical abnormalities (such as significant uterine malformations or large fibroids) conclusively linked to recurrent pregnancy loss. 4. Known hypersensitivity to enoxaparin or heparins, or prior heparin-induced thrombocytopenia. 5. Use of systemic steroids beyond standard pregnancy doses for other immunological or inflammatory conditions. 6. Severe renal insufficiency (estimated glomerular filtration rate below 30 mL/min), advanced liver disease, or other clinically significant systemic autoimmune disease (such as systemic lupus erythematosus or rheumatoid arthritis) that may affect pregnancy or study compliance. 7. Inability or unwillingness to comply with study requirements (for example, language barriers or severe psychiatric conditions). 8. Known parental chromosomal abnormalities. 9. Multiple pregnancy. 10. Current use of progesterone or other progestogen therapy for luteal support at screening or randomization, including luteal support after assisted reproductive technology, such as in vitro fertilization or frozen embryo transfer.