The Mechanisms of Recurrent Pregnancy Loss - PowerPoint Presentation

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The Mechanisms of Recurrent Pregnancy Loss

Maggie Donovan, PA-S2

University of South Dakota Physician Assistant Studies Program

Recurrent pregnancy loss (RPL) is an important issue in reproductive health and is commonly defined as two or more clinically recognized failed pregnancies before 20 weeks of gestation. Recurrent pregnancy loss has been found to affect 1%-5% of couples trying to conceive and the mechanism of nearly 50% of cases of RPL remains unknown. Generally accepted mechanisms of RPL include uterine abnormalities, immunologic factors such as antiphospholipid antibody syndrome, and genetic abnormalities. Some hypothesized mechanisms that remain controversial are endocrine factors, inherited thrombophilia disorders, paternal sperm abnormalities, infections, environmental, and psychological factors. This review evaluates past and current research to assess which mechanisms are empirically supported as underlying causes of recurrent pregnancy loss.

Early pregnancy loss is the spontaneous loss of a fetus prior to 20 weeks gestation and occurs in 10-25% of clinically recognized pregnancies. Recurrent pregnancy loss is two or more clinically recognized failed pregnancies before 20 weeks gestation. The American College of Obstetricians and Gynecologists recommend a thorough physical exam and testing after a couple experiences three recurrent pregnancy losses. American Society for Reproductive Medicine estimates that less than 5% of individuals experience two consecutive pregnancy losses and approximately 1% experience 3 or more losses. The American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) are two organizations that provide the framework for classifying RPL, identifying mechanisms or RPL, and help establish clinical management strategies based on evidence-based literature.

A computer-based literature search was conducted using both the University of South Dakota and Augustana University library databases (PubMed, Wiley Online Library, CINAHL Complete, ScienceDirect, Cochrane Library, DynaMed Plus, and ClinicalKey). Search terms included “recurrent pregnancy loss,” “recurrent miscarriage,” “recurrent spontaneous abortion,” “mechanisms of recurrent pregnancy loss,” ”treatment of recurrent pregnancy loss,” “endocrine causes of RPL,” “genetic causes of RPL,” “uterine anomalies and RPL,” and “etiology of RPL.” Sixty articles were analyzed to identify information on RPL and of the sixty articles reviewed 29 were cited in this review. Articles included in this review focused on the mechanisms and underlying causes of recurrent pregnancy loss or recurrent miscarriage. Articles that provided contradicting research on the etiology behind RPL were also included for comparison. Articles were excluded if the primary focus of the article deviated from that of recurrent pregnancy loss or recurrent miscarriage.

Anatomic Uterine Abnormalities Acquired Abnormalities (adhesions, myomas, and endometrial polyps) interfere with vascularization of the endometrium and abnormal formation of the placenta Congenital Abnormalities are due to abnormal development of the Mullerian ducts. Can have a septate uterus or bicornate uterus which divide the uterine cavity and can interfere with implantation and inadequate formation of the placenta.Antiphospholipid Antibody Syndrome Immunologic disorder in which immune system produces autoantibodies that bind to phospholipids throughout the systemic circulation and increase risk for thrombosis. Must have one clinical criterion and one laboratory criterion for diagnosis. Clinical Criteria – One or more causes of venous or arterial thrombosis, 3 or more consecutive losses <10 weeks gestation, unexplained pregnancy loss >10 weeks gestation, premature birth <34 weeks gestation due to placental insufficiency or pre-eclampsia Lab Criteria – Anti-beta2 glycoprotein Ab, Lupus Anticoagulant, or Anti-cardiolipin Ab in plasma on 2+ occasions 12 weeks apart Antiphospholipid Antibodies may altar the vascular endothelium resulting in venous, or arterial thromboses interrupting the blood supply to the fetus. Antiphospholipid Antibodies can alter implantation of the developing embryo by disrupting differentiation of trophoblast cells Antiphospholipid Antibodies have been shown to alter the secretion of human placental chorionic gonadotropin (hCG)Genetic Factors The earlier in gestation a pregnancy loss occurs the more likely there is a genetic abnormality. Common genetic issues associated with RPL are aneuploidy (most common), structural chromosome abnormalities, single-gene disorders, and mosaicism. Genetic abnormalities detected via karyotyping and chromosomal microarray of the products of conceptionEndocrine Factors Hypothyroid: Thyroid hormones are important for fetal development. Studies have suggested that alterations of thyroid hormones are associated with alterations in fertilization and development of the embryo, fetal death, and preterm delivery. Insulin Resistance: The exact mechanism of insulin resistance and RPL remains unknown. Insulin resistance has been linked to metabolic and endocrine abnormalities leading to high rates of pregnancy loss in individuals with PCOS. ASRM and ESHRE recommend screening for thyroid abnormalities and uncontrolled diabetes in individuals with RPL.Inherited Thrombophilia Genetic condition with increased risk of developing venous thromboembolism due to a dysfunction in the coagulation cascade (ex: Factor V Leiden) Substantial contradicting evidence so the ASRM and ESHRE only recommend screening for those who have family history or a past medical history of venous thromboembolisms Aspirin and LMWH potential treatment option during pregnancy Sperm/Paternal Factors There may be a potential association between the rates of sperm DNA fragmentation and RPL. Some studies have demonstrated abnormal morphological structure of sperm in couples with RPL but there is contradicting evidence to indicate routine screening as a potential cause.Infectious, Environmental, and Psychological Factors Infection, environmental, and psychological factors remain some of the most controversial mechanisms of RPL due to the multifactorial nature of RPL. Infectious: Mycoplasma hominus, chlamydia, Listeria monocytogenes, herpes virus, Ureaplasma urealyticum Environmental: Cigarette smoking, alcohol consumption, obesity, cocaine use, and caffeine consumption. Psychological: Depression, anxiety, anger, and feelings of guild and grief

The American College of Obstetricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) recommend a thorough physical exam and testing after a couple experiences three recurrent pregnancy lossesRecommended Tests Antiphospholipid Antibodies: 1. Anti-Beta2 glycoprotein Ab 2. Anti-cardiolipin Ab 3. Lupus anticoagulant. Thyroid Stimulating Hormone Reflux to Free T4 Thyroid Peroxidase Antibody Hemoglobin A1C Saline infused sonohysterography KaryotypeExamples to treat underlying cause Heparin for Antiphospholipid Antibody Syndrome Levothyroxine for hypothyroid Metformin or Insulin to stabilize diabetes mellitus Myomectomy for uterine fibroids Genetic counseling and information on preimplantation genetic testing

Recurrent pregnancy loss is estimated to affect up to 5% of clinical recognized pregnancies and of the theorized RPL causes, the potential mechanisms remain highly diverse. Most cases of recurrent pregnancy loss may be difficult to diagnose and are often multifactorial. While substantial literature exists on the potential mechanisms of RPL and the successful therapeutic approaches available, nearly 50% of all cases of RPL remain unknown. As current and future providers, it is important that as we are evaluating our patients, we remember the multifactorial nature of RPL and the supported recommended tests to be ordered. As providers it is imperative that we use our clinical judgement to provide psychological support in addition to a full RPL workup based on the guidelines set forth by ACOG, ASRM, and ESHRE with the hopes to identify potential treatable mechanisms of recurrent pregnancy loss.

Abstract

Conclusion

Suggested Work-up of RPL

Proposed Mechanisms of RPL

Methods & Materials

Introduction

El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives.

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