1. RECURRENT PREGNANCY LOSS Rukset Attar, MD, PhD Obstetrics and Gynecology Department

2. Early pregnancy loss is defined as Early pregnancy loss is defined as the termination of pregnancy before 20 weeks' gestation or the termination of pregnancy before 20 weeks' gestation or with a fetal weight of <500 g with a fetal weight of <500 g Most investigators agree that both ectopic and molar pregnancies should not be included in the definition Most investigators agree that both ectopic and molar pregnancies should not be included in the definition

3. Terms Used to Describe Pregnancy Loss Chemical pregnancy loss Loss of a biochemically evident pregnancy Early pregnancy loss Abortion of the first trimester, loss of a histologically recognized pregnancy, or a loss based on ultrasonographic findings Spontaneous abortions (SAB) Pregnancy loss before 20 weeks' gestation, as based on last menstrual period

4. Terms Used to Describe Pregnancy Loss Habitual or recurrent abortion 2 or more consecutive SABs Stillbirth Pregnancy loss after 20 weeks' gestation (Neonatal loss is the death of a liveborn fetus.)

5. Incidence 10-15% true rate of early pregnancy loss is close to 50% because of the high number of chemical pregnancies that are not recognized in the 2-4 weeks after conception

6. Etiology The most common causes of recurrent miscarriages are as follows: Genetic causes Aneuploidy Somatic Sex chromosome Mendelian disorders Multifactorial disorders Parental chromosomal abnormalities (translocations) Chromosomal inversions

7. Etiology Immunologic causes Autoimmune causes Alloimmune causes Anatomic causes Uterine Müllerian anomalies Uterine septum (the anomaly most commonly associated with pregnancy loss) Hemiuterus (unicornuate uterus) Bicornuate uterus

8. Etiology Diethylstilbestrol-linked condition Diethylstilbestrol-linked condition Acquired defects (eg, Asherman syndrome) Acquired defects (eg, Asherman syndrome) Incompetent cervix Incompetent cervix Leiomyomas Leiomyomas Uterine polyps Uterine polyps

9. Etiology Infectious causes Environmental causes (Smoking, excessive alcohol consumption, caffeine) Endocrine factors (Diabetes mellitus, Antithyroid antibodies, Luteal phase deficiency)Luteal phase deficiency Hematologic disorder

10. Etiology The gestational age at the time of the SAB can provide clues about the cause The gestational age at the time of the SAB can provide clues about the cause nearly 70% of SABs in the first 12 weeks are due to chromosomal anomalies nearly 70% of SABs in the first 12 weeks are due to chromosomal anomalies losses due to antiphospholipid syndrome (APS) and cervical incompetence tend to occur after the first trimester. losses due to antiphospholipid syndrome (APS) and cervical incompetence tend to occur after the first trimester.

11. Immunological Factors Autoimmune factors include various autoantibodies such as Autoimmune factors include various autoantibodies such as anti-phospholipid antibodies (APA) anti-phospholipid antibodies (APA) antinuclear antibodies (ANA) antinuclear antibodies (ANA) anti-thyroid antibodies (ATA) anti-thyroid antibodies (ATA) Antiphospholipid antibodies (APA) are antibodies directed against negatively charged phospholipid molecules constituting parts of the membranes of the cell surfaces and cell organelles Antiphospholipid antibodies (APA) are antibodies directed against negatively charged phospholipid molecules constituting parts of the membranes of the cell surfaces and cell organelles Almost all of the fetal demises in women with SLE are related to APAs. Almost all of the fetal demises in women with SLE are related to APAs.

12. Antiphospholipid Syndrome was originally defined as the association between antiphospholipid antibodies and either recurrent miscarriage, thrombosis, or thrombocytopenia was originally defined as the association between antiphospholipid antibodies and either recurrent miscarriage, thrombosis, or thrombocytopenia is the most important treatable cause of recurrent miscarriage is the most important treatable cause of recurrent miscarriage Anti phospholipid antibodies are a family of about 20 anti bodies that are directed against phospholipid binding plasma proteins. Anti phospholipid antibodies are a family of about 20 anti bodies that are directed against phospholipid binding plasma proteins. The common antiphospholipid antibodies The common antiphospholipid antibodies (APAs) lupus anticoagulant (LAC) (APAs) lupus anticoagulant (LAC) anticardiolipin (ACA) anticardiolipin (ACA) anti-b2 glycoprotein I (b2GPI) anti-b2 glycoprotein I (b2GPI) antiannexin V antiannexin V

13. Antiphospholipid Syndrome Clinical features Clinical features venous or arterial thrombosis, venous or arterial thrombosis, unexplained fetal deaths after 10 weeks, unexplained fetal deaths after 10 weeks, delivery at or before 34 weeks as a result of severe pregnancy-induced hypertension (PIH) or delivery at or before 34 weeks as a result of severe pregnancy-induced hypertension (PIH) or recurrent pregnancy loss (RPL) before 10 weeks recurrent pregnancy loss (RPL) before 10 weeks One of the clinical features in combination with a positive laboratory result of antibodies to cardiolipin (CL) or a positive lupus anticoagulant (LAC) on two occasions at least 6 (12) weeks apart are parameters for diagnosis of the antiphospholipid antibody syndrome (APS) (Wilson et al., 2001). One of the clinical features in combination with a positive laboratory result of antibodies to cardiolipin (CL) or a positive lupus anticoagulant (LAC) on two occasions at least 6 (12) weeks apart are parameters for diagnosis of the antiphospholipid antibody syndrome (APS) (Wilson et al., 2001).

14. Treatment options include the following: Treatment options include the following: Subcutaneous heparin Subcutaneous heparin Low-dose aspirin Low-dose aspirin Prednisone Prednisone Immunoglobulins Immunoglobulins Combinations of these therapies Combinations of these therapies Several well-controlled studies showed that subcutaneous heparin (5000 U) given twice a day with low-dose aspirin 81 mg/d increases fetal survival rates from 50% to 80% among women who have had at least 2 losses and who have unequivocally positive results for APLA. Several well-controlled studies showed that subcutaneous heparin (5000 U) given twice a day with low-dose aspirin 81 mg/d increases fetal survival rates from 50% to 80% among women who have had at least 2 losses and who have unequivocally positive results for APLA.

15. Infectious Causes infection is viewed as a rare cause of recurrent miscarriage. infection is viewed as a rare cause of recurrent miscarriage. A recent review failed to show sufficient evidence for the notion that any type of infection can be identified as a causal factor for recurrent miscarriage. A recent review failed to show sufficient evidence for the notion that any type of infection can be identified as a causal factor for recurrent miscarriage. Most patients with a history of recurrent miscarriage do not benefit from an extensive infection workup Most patients with a history of recurrent miscarriage do not benefit from an extensive infection workup

16. Infectious Causes Listeria Monocytogenes Listeria Monocytogenes Listeria Monocytogenes Listeria Monocytogenes Chlamydial Genitourinary Infections Chlamydial Genitourinary Infections Chlamydial Genitourinary Infections Chlamydial Genitourinary Infections Ureaplasma Infection Ureaplasma Infection Ureaplasma Infection Ureaplasma Infection Mycoplasma Infections Mycoplasma Infections Mycoplasma Infections Mycoplasma Infections Bacterial Vaginosis Bacterial Vaginosis Bacterial Vaginosis Bacterial Vaginosis Cytomegalovirus Cytomegalovirus Cytomegalovirus Rubella Rubella Rubella Herpes Simplex Herpes Simplex Herpes Simplex Herpes Simplex HIV Disease HIV Disease HIV Disease HIV Disease Parvovirus B19 Infection Parvovirus B19 Infection Parvovirus B19 Infection Parvovirus B19 Infection Toxoplasmosis Toxoplasmosis Toxoplasmosis Treponematosis (Endemic Syphilis) Treponematosis (Endemic Syphilis) Treponematosis (Endemic Syphilis) Treponematosis (Endemic Syphilis) Lyme Disease Lyme Disease Lyme Disease Lyme Disease Malaria Malaria Malaria

17. Summary Genetic causes Genetic causes Perform karyotype of parents with family or personal history of genetic abnormalities. Perform karyotype of parents with family or personal history of genetic abnormalities. Perform karyotype of the abortus in recurrent cases. Perform karyotype of the abortus in recurrent cases. Provide genetic counseling for families with recurrent loss or familial history of genetic disease. Provide genetic counseling for families with recurrent loss or familial history of genetic disease. In patients with a high risk for recurrent, chromosomally abnormal conceptus, discuss the options of adoption, gamete donation, and PGD. In patients with a high risk for recurrent, chromosomally abnormal conceptus, discuss the options of adoption, gamete donation, and PGD. Immunologic causes Immunologic causes Perform APLA testing if indicated. Perform APLA testing if indicated. If APLA levels are elevated, counseling with a hematologist and a specialist in maternal fetal medicine is recommended. If APLA levels are elevated, counseling with a hematologist and a specialist in maternal fetal medicine is recommended. Aspirin and heparin therapy may be given to patients who are diagnosed with APS. Aspirin and heparin therapy may be given to patients who are diagnosed with APS.

18. Anatomic causes Anatomic causes Imaging may include HSG, hysteroscopy, ultrasonography, and/or MRI. Imaging may include HSG, hysteroscopy, ultrasonography, and/or MRI. Surgical correction may be required. Surgical correction may be required. Infectious causes Infectious causes Cervical cultures should be obtained during the evaluation of infertility. Cervical cultures should be obtained during the evaluation of infertility. Empiric antibiotics should be given before invasive testing, such as HSG. Empiric antibiotics should be given before invasive testing, such as HSG. Environmental causes - Encourage life-style changes and counseling for preventable exposures. Environmental causes - Encourage life-style changes and counseling for preventable exposures. Endocrine factors - Perform thyroid-stimulating hormone (TSH) screening in symptomatic patients. Endocrine factors - Perform thyroid-stimulating hormone (TSH) screening in symptomatic patients. Thrombophilic disorders - Aspirin and heparin therapy may be given for proven diagnoses. Thrombophilic disorders - Aspirin and heparin therapy may be given for proven diagnoses.