The Diagnostic Evaluation and Treatment of Recurrent Pregnancy Loss Ashim Kumar, M.D. Reproductive Endocrinology and Infertility Clinical Assistant Professor, UCLA School of Medicine Fertility & Surgical Associates of California, Encino & Thousand Oaks, CA

Luteal Support Progesterone +/- Estradiol Start after ovulation or egg retrieval Continue until 10 weeks gestational age

Early Pregnancy Reassurance Ultrasounds Pelvic rest as needed As Indicated Monitor TSH Monitor BP

Prenatal Testing Screening Diagnostic 1st Trimester – Nuchal Fold + Serum 2nd Trimester – Triple/Quadruple Screen Diagnostic 1st Trimester – Chorionic Villus Sampling 2nd Trimester – Amniocentesis

Recurrent Pregnancy Loss SAB: involuntary loss of pregnancy before 20wk GA RPL: Three or more pregnancy losses in the first trimester Indications to evaluate after 2 or more consecutive losses: + FCA in prior loss Normal Karyotype on prior loss Female > 35yr Infertility Emotional Support is critical

Risk of RPL in Young Women # of Prior SAB’s % Risk of SAB in Next Pregnancy h/o prior liveborn 12% 1 24% 2 26% 3 32% 4 6 53% No liveborn 2 or more 40-45%

Early Pregnancy Loss Clinically unrecognized (less than 8wk GA) 30-60% of all pregnancies end in SAB At least ½ are early losses (go unnoticed) ~75% of embryos with chromosomal abnormalities 90% are numerical (aneuploidy/polyploidy) Rest are structural or mosaicism 2/3 of the remaining 25% with normal karyotype exhibit gross structural abnormalities

Etiology Uterine Defect (~30%) Thrombophilia Genetic General Endocrine Congenital Acquired Thrombophilia Immunologic (~3-5%) Genetic Meiotic Nondisjunction Balanced Translocation (5%) General Endocrine

Uterine Defect Congenital Acquired Septum Bicornuate / Unicornuate T-Shaped Uterus Acquired Submucosal Leiomyoma Endometrial Polyp Synechia Adenomyosis

Uterine Evaluation Ultrasound Sonohysterogram (saline ultrasound) Hysterosalpingogram MRI Hysteroscopy

Bicornuate or Septate

Endometrial Polyp

Thrombophilias Congenital Immunologic - Antiphospholipid Syndrome Factor V Leiden Mutation Protein C / Protein S Deficiency Prothrombin Gene Mutation Methylenetetrahydrofolate Reductase (MTHFR) – homocysteine Antithrombin III Immunologic - Antiphospholipid Syndrome Anticardiolipin Antibodies Lupus Anticoagulant

Virchow’s Triad Stasis (Decrease flow in placental vessels) Damaged Vasculature Hypercoagulable State Cancer Pregnancy (Elevated Estradiol leads to increased hepatic production of clotting factors) Congenital Immunologic

Genetic Meiotic Nondisjunction Balanced Translocation (5% of couples) Risk of miscarriage increases with advancing reproductive age Balanced Translocation (5% of couples) Robertsonian Reciprocal Others Mosaicism Inversion Chromosomally abnormal sperm do not play a role in RPL

Meiotic Nondisjunction

Age and Miscarriage Risk <30 yr- 7-15 % 30-34 yr- 8-21% 35-39 yr- 17-28% ≥40 yr- 34-52%

Risk of Chromosomal Abnormality in Newborns by Maternal Age Maternal Fetal Medicine: Practice and Principles. Creasey and Resnick 1994

Preimplantation Genetic Diagnosis

Preimplantation Genetic Diagnosis

Preimplantation Genetic Diagnosis

Robertsonian Translocation

Reciprocal Translocation

General Endocrine Diabetes (Fasting Glucose) Thyroid Disease (TSH) Hyperprolactinemia (Prolactin) Polycystic Ovary Syndrome Luteal Phase Deficiency (Supplement Everyone)

Treatment Provide Emotional Support Uterus Hypercoagulable State Resect lesion Hypercoagulable State Heparin Aspirin Folate Genetic PGD General Endocrine Correct hormonal imbalance

What Does Not Work Alloimmune Disorders Genetic Hypercoagulable State Testing HLA testing Mixed lymphocyte culture Natural killer cell assay Treatment Paternal leukocyte immunization Intravenous immunoglobulins (IVIG) Genetic PGD Hypercoagulable State Glucocorticoids Uterus Metroplasty

Conclusion The likelihood of successful delivery is very high. The challenge is to do it an a cost-effective fashion while being sensitive to the emotional sequelae.