Recurrent Loss 2009

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Mark Perloe, MD, GRS 404-843-2229 www.IVF.com discusses recurrent pregnancy loss, evaluation and treatment.

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  • 11/04/09
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  • 11/04/09 Figure 1. Decline in the Number of Oocytes from Birth to Menopause. Data provided in Panel A are adapted from Faddy et al.1 The images in Panel B -- which shows histologic specimens of oocytes (arrows) taken from patients at birth, at the age of 25 years, and at the age of 50 years -- are adapted from Erickson8 and are reprinted with the permission of the publisher.
  • 11/04/09 Figure. Fertility and Miscarriage Rates as a Function of Maternal Age. Adapted from Menken et al.1 and Anderson et al.2
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  • 11/04/09 Figure 1. The Process of IVF. The ovaries are stimulated by daily injections of gonadotropins to optimize follicular development, which is monitored by means of transvaginal ultrasonography. Ultrasonography of an unstimulated ovary shows a small antral follicle (Panel A, arrow). The same ovary has multiple growing follicles after gonadotropin stimulation. One follicle is shown with measurements in two dimensions (Panel B). After ovarian stimulation, eggs are retrieved by means of ultrasound-guided transvaginal aspiration of follicular fluid (Panel C). A mature human egg is recovered from the aspirated fluid (Panel D). Recovered eggs are often fertilized in vitro by culturing eggs with many motile sperm (Panel E); in this image, multiple sperm are attached to the egg's zona pellucida (arrows point to three of the sperm). Eggs can also be fertilized by means of intracytoplasmic sperm injection, a technique in which a single sperm is injected into the egg with the use of a thin glass pipette (Panel F). This technique was developed to facilitate fertilization in cases of male-factor infertility but is now used in a majority of IVF cycles. Multiple embryos are cultured, often for 3 days (an eight-cell embryo, shown in Panel G) or 5 days (a blastocyst embryo, shown in Panel H, with the inner cell mass indicated by the arrow) before selected embryos are transferred back to the uterus (Panel I). Good-quality, excess embryos are often cryopreserved.
  • 11/04/09 Figure. Embryos and Blastocysts during Assisted Reproduction (x20). Panel A shows two embryos in the pronuclear stage, approximately 18 hours after insemination. Panel B shows two eight-cell embryos three days after insemination. Panel C shows a blastocyst five days after insemination. Panel D shows a blastocyst hatching from the zona pellucida six days after insemination.
  • 11/04/09 Figure 3. Biopsy and Preimplantation Genetic Diagnosis of a 3-Day-Old (Eight-Cell) Embryo. One or two blastomeres are removed from the embryo, as shown in Panel A, for preimplantation genetic diagnosis. Fluorescence in situ hybridization (FISH) is used to identify and count individual chromosomes. Panel B shows a blastomere with trisomy 21 detected by means of FISH (red probe). With current techniques, up to 10 chromosomes in a single cell can be evaluated, although techniques that allow more comprehensive evaluation are being developed.
  • 11/04/09 In Vitro Fertilization and Preimplantation Genetic Haplotyping. Embryos are created with the use of in vitro fertilization. On the third day after fertilization, a single cell is removed from each embryo for genetic testing. After whole-genome amplification, the DNA is tested for the presence of a large series of specific short-tandem-repeat loci closely linked to the mutation causing the susceptibility. This testing will reveal contamination by extraneous DNA and provide sufficient information for a diagnosis to be made with the use of genetic-linkage analysis, even without precise knowledge of the mutation sequence. Up to two mutation-free embryos are considered for transfer back to the uterus.
  • 11/04/09 Figure 1. Analysis by Comparative Genomic Hybridization of a Blastomere Obtained by Biopsy of a Six-to-Eight-Cell Embryo. Comparative genomic hybridization simultaneously evaluates all chromosomes from a single cell for aneuploidy. Selected results from chromosome 10, which is euploid, and chromosome 21, which is aneuploid, are shown in the boxes. See figure 2 of Wilton et al.9 for an explanation of the chromosomal diagram.
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  • 11/04/09 Figure 1. Blastocyst Apposition and Adhesion. The diagram shows a preimplantation-stage blastocyst (approximately six to seven days after conception) and the processes thought to be necessary for uterine receptivity and blastocyst apposition and adhesion. COX-2 denotes cyclooxygenase-2, EGF epidermal growth factor, and LIF leukemia inhibiting factor.
  • 11/04/09 Figure 2. Blastocyst Implantation. The diagram shows an invading blastocyst (about 9 to 10 days after conception) and the processes necessary for trophoblast invasion.
  • 11/04/09 Figure 3. Maintenance of Early Pregnancy. The diagram shows an implanted embryo (approximately 14 days after conception) and the processes necessary for the maintenance of an early pregnancy. VEGF denotes vascular endothelial growth factor, and hCG human chorionic gonadotropin.
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  • Recurrent Loss 2009

    1. 1. Recurrent Pregnancy Loss Mark Perloe, M.D. Georgia Reproductive Specialists Atlanta, Georgia
    2. 2. Learning Objectives <ul><li>Identify possible causes of early pregnancy loss </li></ul><ul><li>Outline basic evaluation for recurrent pregnancy loss (RPL) </li></ul><ul><li>Review current treatment approaches for these patients </li></ul>
    3. 3. Definition <ul><li>Classical: 3 or more consecutive pregnancy losses before 20 weeks gestation </li></ul><ul><li>Expanded: 2 or more consecutive losses </li></ul><ul><ul><li>Risk of further loss similar for 2 versus 3 consecutive losses </li></ul></ul><ul><ul><li>Initiation of evaluation appropriate after 2 losses based on patient age and desire </li></ul></ul>Hill Curr Prob Obstet Gynecol Fertil 1994;37:693-704
    4. 4. Recurrent Loss Epidemiology <ul><li>5% of couples attempting pregnancy have 2 or more consecutive losses </li></ul><ul><li>1% have 3 or more consecutive losses </li></ul><ul><li>Most clinicians consider RPL even if losses are not consecutive </li></ul>Lee Semin Reprod Med 2000;18(4):433-40
    5. 5. SPAB Epidemiology <ul><li>34% pregnancy loss in prospective cohort of healthy women </li></ul><ul><ul><li>22% unrecognized - detected by assay only </li></ul></ul><ul><ul><li>12 % clinically recognized </li></ul></ul><ul><li>Obstetrical history predictive </li></ul><ul><ul><li>prior success: 4-6 % chance of loss </li></ul></ul><ul><ul><li>prior loss: 19-24%chance of loss </li></ul></ul>Wilcox NEJM 1988;319:189-194
    6. 6. SPAB or RPL? <ul><li>A single SAB, unless a successful pregnancy intervenes, increases the risk for the next pregnancy </li></ul><ul><li>Distinction between “sporadic” and “recurrent” loss blurred </li></ul><ul><li>Effect of maternal age: SAB risk approaches 50% by age 40 for both aneuploid and euploid losses </li></ul>Cramer Semin Reprod Med 2000;18(4):331-9
    7. 7. Miscarriage Recurrence Risk Warburton D, Fraser FC: Am J Human Genet 16:1, 1964 Outcome Prior Losses Recurrence Risk % Liveborn 0 12 1 24 2 26 3 32 4 26 No Live Births 1 19 2 35 3 47 4 54
    8. 8. PCOS & Pregnancy Loss <ul><li>Pregnancy loss ↑ with PCOS </li></ul><ul><li>Franks S, Ann Int Med 93, Jacobs HS BRJOBGYN 93 </li></ul><ul><li>GnRH-a ↓ miscarriage in PCOS women </li></ul><ul><li>Homburg R, et al: Fertil Steril 59:527, 1993 </li></ul><ul><li>RSA patients with ↑ LH, DHEAS or T more likely to miscarry </li></ul><ul><li>Tulpalla M, et al: BrJOBGYN 100:348, 1993 </li></ul><ul><li>GnRH-a ↓ miscarriages in RSA patients with PCOS compared to clomid (10% vs 55%) </li></ul><ul><ul><li>Johnson P, et al: BMJ 300:154, 1990 </li></ul></ul>
    9. 9. Metformin Reduces Pregnancy Loss in PCOS <ul><li>Retrospective study of PCOS women who became pregnant </li></ul><ul><ul><li>Group 1: metformin during pregnancy (n=101) </li></ul></ul><ul><ul><li>Group 2: control (n=31) </li></ul></ul><ul><li>Early loss rate 12.9% vs 41.9% (p=0.001) </li></ul><ul><li>Prior SPAB: 15.7% vs 58.3% (p=0.005) </li></ul><ul><li>Jakubowicz DJ, et al: abstract P2-427, Endocrine Society, 2001 </li></ul>
    10. 10. Etiology Anatomic Factors <ul><li>10-15% recurrent 1 st trimester losses have congenital anomaly </li></ul><ul><li>Variations of the double uterus the most common </li></ul><ul><li>Septate loss rates 25-90% - usually amenable to resection </li></ul><ul><li>Bicornuate loss rates 40% - uncertain benefit of surgery </li></ul>Propst & Hill Semin Reprod Med 2000;18(4):341-50
    11. 11. Etiology Anatomic Factors <ul><li>Unicornuate uteri 50% loss </li></ul><ul><li>Uterus didelphys 40% loss </li></ul><ul><li>DES exposure - many have abnormal uterine structure </li></ul><ul><li>Cervical incompetence </li></ul><ul><li>Intrauterine synechiae </li></ul>
    12. 12. Etiology Anatomic Factors <ul><li>Unclear relationship between uterine leiomyomata and RPL </li></ul><ul><ul><li>Large submucosal fibroids distort the cavity or occupy a large subendometrial area </li></ul></ul><ul><ul><li>? Mechanism(s) - mechanical constriction or inadequate placentation resulting from poorly vascularized endometrium </li></ul></ul>
    13. 13. Acquired Uterine Defects
    14. 14. Etiology Infection <ul><li>No infectious agent has been proven to cause recurrent pregnancy loss </li></ul><ul><ul><li>? Colonization with Ureaplasma urealyticum leading to empiric antibiotics </li></ul></ul><ul><li>Certain infections have been associated with spontaneous loss </li></ul><ul><ul><li>Toxoplasma gondii , rubella, HSV, CMV, measles, coxsackie </li></ul></ul>Lee Semin Reprod Med 2000;18(4):433-40
    15. 15. Etiology Genetic Factors <ul><li>Trisomy (50%) </li></ul><ul><ul><li>#16 all lethal 1/3 of all trisomies </li></ul></ul><ul><ul><li>#21 Down Syndrome usually due to meiotic non-disjunction 80% maternatal </li></ul></ul><ul><li>Monsomy X (20%) </li></ul><ul><ul><li>45X Turner Syndrome most common </li></ul></ul><ul><li>Triploidy (15%) </li></ul><ul><ul><li>90% from father </li></ul></ul><ul><li>Tetraploidy (5%) </li></ul><ul><li>Mosaicism (2%) </li></ul>% Chromosomal Abnormal by Gestational Age % abnormal Gestational age 60 12 45 16 12 20 6 24 ~1 40
    16. 16. Etiology Genetic Factors <ul><li>Parental abnormalities in 3-5% of couples with recurrent loss </li></ul><ul><li>Balanced translocation most common </li></ul><ul><ul><li>Reciprocal (60%) or Robertsonian (40%) </li></ul></ul><ul><ul><li>25-50% risk of pregnancy loss </li></ul></ul><ul><ul><li>May eventually produce normal offspring </li></ul></ul>
    17. 17. Etiology Genetic Factors
    18. 18. Etiology Genetic Factors <ul><li>Homologous Robertsonian translocation </li></ul><ul><ul><li>1/2500 couples </li></ul></ul><ul><ul><li>precludes successful reproduction </li></ul></ul><ul><li>Heterozygous may lead to partial monosomy or trisomy; “milder” phenotypical expression </li></ul>Ward Semin Reprod Med 2000;18(4):425-32
    19. 20. Etiology Genetic Factors <ul><li>Speculation about single gene mutations </li></ul><ul><ul><li>Blastocyst formation </li></ul></ul><ul><ul><li>Implantation </li></ul></ul><ul><ul><li>Morphogenesis of vital organs </li></ul></ul>
    20. 21. Etiology Genetic Factors <ul><li>Skewed X inactivation </li></ul><ul><ul><li>Preferential inactivation(>90%) of one of the X alleles </li></ul></ul><ul><ul><li>May be lethal to a male offspring </li></ul></ul><ul><ul><li>May result in X-autosome translocations </li></ul></ul><ul><ul><li>Trisomy mosaicism in the germline </li></ul></ul>
    21. 22. Etiology Genetic Factors <ul><li>Advanced maternal age </li></ul><ul><ul><li>Impact on risk for pregnancy loss cannot be over-emphasized </li></ul></ul><ul><ul><li>Increased rates of maternally-derived trisomies </li></ul></ul><ul><ul><li>Probable “natural selection” of better quality oocytes earlier in reproductive life </li></ul></ul><ul><ul><li>Oocytes recruited later in life more likely to be abnormal or experience meiotic error </li></ul></ul>
    22. 23. Lobo, R. A. N Engl J Med 2005;353:64-73 Decline in the Number of Oocytes from Birth to Menopause
    23. 24. Heffner, L. J. N Engl J Med 2004;351:1927-1929 Fertility and Miscarriage Rates as a Function of Maternal Age
    24. 25. Etiology Thrombophilia <ul><li>Pregnancy is a hypercoagulable state </li></ul><ul><li>Women with heritable or acquired thrombophilic disorders have significantly increased risks of pregnancy loss </li></ul>Kutteh Semin Reprod Med 2006;24(1):54-65
    25. 26. Etiology Thrombophilia Venous <ul><li>Most common inherited: </li></ul><ul><ul><li>Heterozygous Factor V Leiden (G1691A) </li></ul></ul><ul><ul><li>Factor II-prothrombin mutation (G20210A) </li></ul></ul><ul><ul><li>Hyperhomocysteinemia (MTHFR C677T and A1298C) </li></ul></ul>
    26. 27. Etiology Thrombophilia Venous <ul><li>Most common acquired: </li></ul><ul><ul><li>Anti-phospholipid antibodies (APAs) </li></ul></ul><ul><ul><li>Activated Protein C resistance </li></ul></ul><ul><ul><li>Hyperhomocysteinemia (MTHFR C677T and A1298C) </li></ul></ul><ul><li>Other possible abnormalities </li></ul><ul><ul><li>Anti-thrombin deficiency </li></ul></ul><ul><ul><li>Protein C or S deficiency </li></ul></ul><ul><ul><li>Elevated Factor VIII </li></ul></ul>
    27. 28. Etiology Thrombophilia Arterial <ul><li>Hyperhomocysteinemia </li></ul><ul><li>APAs </li></ul><ul><li>Lupus anticoagulant </li></ul>
    28. 29. Etiology Thrombophilia <ul><li>Factor V Leiden </li></ul><ul><ul><li>Abnormal factor V resistant to anticoagulant effects of activated protein C </li></ul></ul><ul><ul><li>Majority of patients resistant to activated protein C will be heterozygous for Factor V Leiden </li></ul></ul><ul><ul><li>Present in 3-8% of the White population </li></ul></ul><ul><ul><li>Rare in Blacks, Asians, Native Americans </li></ul></ul>
    29. 30. Etiology Thrombophilia <ul><li>Factor V Leiden </li></ul><ul><ul><li>Autosomal dominant </li></ul></ul><ul><ul><li>Acquired activated protein C resistance in pregnancy, OCP use and in presence of APAs </li></ul></ul><ul><ul><li>Heterozygotes: 7X increase lifetime risk thrombosis; 15X increase during pregnancy or OCP use </li></ul></ul><ul><ul><li>Homozygotes: 50-100X increase lifetime risk thrombosis </li></ul></ul>
    30. 31. Etiology Thrombophilia <ul><li>Prothrombin G20210A Mutation </li></ul><ul><ul><li>Higher plasma prothrombin concentrations, augmented thrombin generation </li></ul></ul><ul><ul><li>Heterozygotes: 2-3% Whites </li></ul></ul><ul><ul><li>Conflicting prevalence studies among RPL </li></ul></ul><ul><ul><li>Recent critical review suggests an association </li></ul></ul>
    31. 32. Etiology Thrombophilia <ul><li>Hyperhomocysteinemia polymorphisms </li></ul><ul><ul><li>C677T thermolabile MTHFR </li></ul></ul><ul><ul><ul><li>Heterozygous 10-20% Whites </li></ul></ul></ul><ul><ul><ul><ul><li>Normal or slightly elevated homocysteine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increased homocysteine when combined with B vitamin deficiencies </li></ul></ul></ul></ul><ul><ul><ul><li>Homozygous 10% Whites </li></ul></ul></ul><ul><ul><ul><ul><li>Significantly increased homocysteine </li></ul></ul></ul></ul>
    32. 33. Etiology Thrombophilia <ul><li>Hyperhomocysteinemia polymorphisms </li></ul><ul><ul><li>A1298C often occurs with thermolabile C677T </li></ul></ul><ul><ul><ul><li>33% frequency in Dutch population </li></ul></ul></ul><ul><ul><ul><li>Combined heterozygosity results in hyperhomocysteinemia and decreased plasma folate levels </li></ul></ul></ul>
    33. 34. Etiology Thrombophilia <ul><li>Hyperhomocysteinemia polymorphisms </li></ul><ul><ul><li>Significant association between hyperhomocysteinemia and RPL </li></ul></ul><ul><ul><li>? Mechanism: interference in embryonic development through defective chorionic villous vascularization </li></ul></ul><ul><ul><li>Known association with later pregnancy-related complications </li></ul></ul>
    34. 35. Etiology Thrombophilia <ul><li>Anti-thrombin Deficiency </li></ul><ul><ul><li>Physiologic inhibitor of coagulation </li></ul></ul><ul><ul><ul><li>Type I: quantitative; decreased antigen and function; caused by gene deletions, nucleotide changes </li></ul></ul></ul><ul><ul><ul><li>Type II: qualitative; normal antigen levels, decreased function; caused by point mutations with single amino acid changes leading to a dysfunctional protein </li></ul></ul></ul>
    35. 36. Etiology Thrombophilia <ul><li>Anti-thrombin Deficiency </li></ul><ul><ul><li>Autosomal dominant </li></ul></ul><ul><ul><li>Prevalence Type I heterozygous carriers: 1/2000 – 1/5000 </li></ul></ul><ul><ul><li>Prevalence Type II heterozygous carriers: 3/1000 </li></ul></ul><ul><ul><li>Most thrombogenic of inherited thrombophilia: 20-50% lifetime risk </li></ul></ul><ul><ul><li>Associated increased risk stillbirth and fetal loss </li></ul></ul>
    36. 37. Etiology Thrombophilia <ul><li>Protein C Deficiency </li></ul><ul><ul><li>Down-regulates coagulation cascade; deficiencies lead to unregulated fibrin formation </li></ul></ul><ul><ul><li>Autosomal dominant: > 160 mutations </li></ul></ul><ul><ul><li>Type I: quantitative </li></ul></ul><ul><ul><li>Type II: decreased function </li></ul></ul><ul><ul><li>Associated with 2 nd trimester losses </li></ul></ul>
    37. 38. Etiology Thrombophilia <ul><li>Protein S Deficiency </li></ul><ul><ul><li>Principal cofactor of activated Protein C; mimics C deficiency: questionable association with pregnancy loss </li></ul></ul><ul><ul><li>Autosomal dominant: > 160 mutations: prevalence 0.15-0.8% general population; acquired forms in multiple disease states </li></ul></ul><ul><ul><li>Type I: quantitative </li></ul></ul><ul><ul><li>Type II: decreased function </li></ul></ul><ul><ul><li>Type III: low free protein, normal antigen, reduced activity </li></ul></ul>
    38. 39. Etiology Luteal Phase Defect <ul><li>Luteal phase defect is a controversial cause of RPL </li></ul><ul><ul><li>Studies proving LPD as a cause of RPL lacking </li></ul></ul><ul><ul><li>No convincing studies showing LPD treatment improves pregnancy outcome </li></ul></ul><ul><ul><li>Lee Semin Reprod Med 2000;18(4):433-40 </li></ul></ul><ul><ul><li>80% of women with low midluteal progesterone proceed to term </li></ul></ul><ul><ul><li>20% of fertile women have abnormal endometrial biopsies </li></ul></ul><ul><ul><li>P4 drops after meals & standing </li></ul></ul>
    39. 40. Etiology Endocrine Factors <ul><li>Poorly controlled diabetes </li></ul><ul><li>Overt hyperthyroidism </li></ul><ul><li>Overt hypothyroidism </li></ul><ul><li>No evidence that asymptomatic systemic endocrinologic or metabolic disorders are a cause of RPL </li></ul>
    40. 41. Etiology Autoimmune Factors <ul><li>Certain autoimmune diseases are associated with pregnancy loss </li></ul><ul><ul><li>Systemic lupus erythematosis </li></ul></ul><ul><ul><ul><li>1 st trimester loss: 10% risk </li></ul></ul></ul><ul><ul><ul><li>2 nd and 3 rd trimester loss: 6% </li></ul></ul></ul><ul><ul><li>Anti-phospholipid syndrome </li></ul></ul><ul><ul><ul><li>2 nd trimester loss: 38% </li></ul></ul></ul>Fausett & Branch Semin Reprod Med 2000;18(4):379-392
    41. 42. Etiology Autoimmune Factors <ul><li>Anti-phospholipid antibodies (aPL) </li></ul><ul><ul><li>autoantibodies recognizing various combinations of phospholipids, phospholipid-binding proteins, or both </li></ul></ul><ul><li>Anti-phospholipid syndrome (APS) - clinical association between aPL and syndrome of hypercoagulability </li></ul>Levine NEJM 2002;346:752-63
    42. 43. Etiology Autoimmune Factors <ul><li>APS diagnostic criteria: </li></ul><ul><ul><li>Clinical features </li></ul></ul><ul><ul><ul><li>Vascular thrombosis or </li></ul></ul></ul><ul><ul><ul><li>Loss of fetus at or after 10 weeks or </li></ul></ul></ul><ul><ul><ul><li>Preterm delivery at or before 34 weeks or </li></ul></ul></ul><ul><ul><ul><li>3 or more consecutive SAB before 10 weeks </li></ul></ul></ul>
    43. 44. Etiology Autoimmune Factors <ul><li>APS diagnostic criteria: </li></ul><ul><ul><li>Laboratory features </li></ul></ul><ul><ul><ul><li>Anti-cardiolipin (aCL) antibodies: IgG or IgM at moderate or high levels on 2 or more occasions at least 6 weeks apart </li></ul></ul></ul><ul><ul><ul><li>Lupus anticoagulant (LA) antibodies: detected on 2 or more occasions at least 6 weeks apart </li></ul></ul></ul>
    44. 45. Etiology Autoimmune Factors <ul><li>Other anti-phospholipid antibodies </li></ul><ul><ul><li>Anti-phosphatidylserine: nearly always associated with APS, highly correlated to cardiolipin binding </li></ul></ul><ul><ul><li>Other antibodies have less correlation </li></ul></ul><ul><ul><ul><li>No consistency among reported studies </li></ul></ul></ul><ul><ul><ul><li>No independence from aCL </li></ul></ul></ul>Fausett Semin Reprod Med 2000;18(4):379-92
    45. 46. Etiology Autoimmune Factors <ul><li>Low levels of aPL are not associated with RPL </li></ul><ul><li>Assays for non-aCL aPL are not standardized </li></ul><ul><li>Studies thus far are contradictory </li></ul>
    46. 47. Etiology Autoimmune Factors <ul><li>Other auto-antibodies NOT associated with RPL </li></ul><ul><ul><li>Anti-nuclear antibodies may be more common among women with RPL but their presence or absence do not predict subsequent pregnancy outcome </li></ul></ul>
    47. 48. Etiology Autoimmune Factors <ul><li>Other auto-antibodies NOT associated with RPL </li></ul><ul><ul><li>Anti-thyrogobulin and anti-thyroid peroxidase are markers of increased risk for pregnancy loss if identified early in pregnancy </li></ul></ul><ul><ul><li>Some small studies suggest a slight association in RPL; other larger studies do not </li></ul></ul><ul><ul><li>Subsequent pregnancy outcomes not affected </li></ul></ul>
    48. 49. Etiology Alloimmune Factors <ul><li>Immune response to non-self components of pregnancy </li></ul><ul><ul><li>Cytotoxic antibodies </li></ul></ul><ul><ul><li>Absence of maternal blocking antibodies </li></ul></ul><ul><ul><li>Inappropriate sharing of HLA </li></ul></ul><ul><ul><li>Disturbances in natural killer cell function and distribution </li></ul></ul>Porter Semin Reprod Med 2000;18(4):393-400
    49. 50. Etiology Alloimmune Factors <ul><li>Cytotoxic antibodies </li></ul><ul><ul><li>Maternal response to paternal antigens </li></ul></ul><ul><ul><li>Present in normal pregnancies </li></ul></ul><ul><ul><li>More common in fertile couples than those with RPL </li></ul></ul><ul><ul><li>No bearing on subsequent pregnancy outcome </li></ul></ul>
    50. 51. Etiology Alloimmune Factors <ul><li>Blocking antibodies </li></ul><ul><ul><li>Theory: maternal anti-fetal antibodies block maternal cell-mediated response; if absent, then fetal rejection occurs </li></ul></ul>
    51. 52. Etiology Alloimmune Factors <ul><li>Blocking antibodies </li></ul><ul><ul><li>Not present in normal pregnancies, yet are often present in RPL </li></ul></ul><ul><ul><li>Detected by the non-specific mixed lymphocyte response assay </li></ul></ul>
    52. 53. Etiology Alloimmune Factors <ul><li>Blocking antibodies </li></ul><ul><ul><li>Animal model: B-cell deficient (agammaglobulinemic) mice have normal pregnancy outcomes </li></ul></ul><ul><ul><li>Human agammaglobulinemics have successful pregnancies </li></ul></ul><ul><ul><li>Presence or absence not predictive of subsequent outcome </li></ul></ul>
    53. 54. Etiology Alloimmune Factors <ul><li>Parental HLA sharing </li></ul><ul><ul><li>Theory: if parents are antigenically similar, mother is less likely to develop blocking antibodies </li></ul></ul><ul><ul><li>Studies contradictory: some show increased sharing in HLA-B and HLA-DR loci </li></ul></ul><ul><ul><li>Most show no associations </li></ul></ul>
    54. 55. Etiology Alloimmune Factors <ul><li>Natural killer cells </li></ul><ul><ul><li>Theory: CD56+ NK-like cells secrete a transforming growth factor-  -like substance crucial to the maintenance of pregnancy </li></ul></ul><ul><ul><li>Present in endometria and early gestational decidua of women with RPL </li></ul></ul>
    55. 56. Etiology Alloimmune Factors <ul><li>Natural killer cells </li></ul><ul><ul><li>Murine models show activation of NK cells increases the rate of abortion; depletion of NK cells has opposite effect </li></ul></ul><ul><ul><li>Human studies show no association of testing and successful pregnancy </li></ul></ul>
    56. 57. Etiology Alloimmune Factors <ul><li>T helper (Th1) immunodystrophism </li></ul><ul><ul><li>Theory: aberrant or inappropriate Th1 stimulation may result in overproduction of cytokines that have deleterious effect on conceptus </li></ul></ul><ul><ul><li>Dichotomous Th1 versus Th2 cytokine profile associated with human pregnancy loss and success </li></ul></ul>Hill Semin Reprod Med 2000;18(4):401-405
    57. 58. Etiology Male Factor <ul><li>No significant difference in semen parameters among men whose partners have RPL compared to WHO standards and men fathering successful pregnancies </li></ul><ul><li>No difference in incidence of anti-sperm antibodies </li></ul><ul><li>Aside from cytogenetic abnormalities, male factor contribution to RPL unknown </li></ul><ul><li>Hill ASRM 2002 Course 6 p.56 </li></ul><ul><li>DNA Fragmentation may result in early embryo loss </li></ul><ul><li>Hum Reprod. 2006 Nov;21(11):2876-81; Check JH: Arch Androl. 2005 Mar-Apr;51(2):121-4 </li></ul>
    58. 59. Etiology Male Factor <ul><li>RPL males have higher incidence of sperm aneuploidy: </li></ul><ul><ul><li>Oligoasthenoteratospermia 35-74% </li></ul></ul><ul><ul><li>Fertile donor sperm 4-7% </li></ul></ul>
    59. 60. Etiology - Environmental Factors <ul><li>Confirmed association </li></ul><ul><ul><li>Ionizing irradiation </li></ul></ul><ul><ul><li>Organic solvents </li></ul></ul><ul><ul><li>Alcohol </li></ul></ul><ul><ul><li>Mercury </li></ul></ul><ul><ul><li>Lead </li></ul></ul>Gardella & Hill Semin Reprod Med 2000;18(4):407-424 <ul><li>Suspected association </li></ul><ul><ul><li>Caffeine (> 300 mg/day) </li></ul></ul><ul><ul><li>Hyperthermia/fever </li></ul></ul><ul><ul><li>Cigarette smoking </li></ul></ul><ul><li>Unknown association </li></ul><ul><ul><li>Pesticides </li></ul></ul>
    60. 61. Etiology - Environmental Factors <ul><li>Diagnostic x-rays </li></ul><ul><li>Air travel </li></ul><ul><li>Microwave ovens </li></ul><ul><li>Diagnostic ultrasounds </li></ul><ul><li>Electromagnetic fields </li></ul><ul><li>Video display terminals </li></ul><ul><li>Aspartame </li></ul><ul><li>Chocolate </li></ul><ul><li>Drinking water </li></ul><ul><li>BGH </li></ul><ul><li>Phytoestrogens </li></ul><ul><li>Phthalates </li></ul><ul><li>Herbicides </li></ul><ul><li>Hair dyes </li></ul><ul><li>Nail polish </li></ul><ul><li>Saccharin </li></ul>
    61. 62. Etiology - Idiopathic <ul><li>More than 50% of couples with RPL have no explanation despite extensive evaluation(s) </li></ul><ul><li>Informative and sympathetic counseling appears to play an important role </li></ul><ul><ul><li>70% live birth rates reported in couples with unexplained RPL who undertake an untreated subsequent pregnancy </li></ul></ul>Lee Semin Reprod Med 2000;18(4):433-40
    62. 63. Evaluation <ul><li>History </li></ul><ul><ul><li>Pattern and trimester of pregnancy losses and whether a live embryo or fetus was present </li></ul></ul><ul><ul><li>Exposure to environmental,toxins or drugs </li></ul></ul><ul><ul><li>Known gynecological or obstetrical infections </li></ul></ul><ul><ul><li>Features associated with APS </li></ul></ul>
    63. 64. Evaluation <ul><li>History </li></ul><ul><ul><li>Family history of RPL or syndrome associated with embryonic or fetal loss </li></ul></ul><ul><ul><li>Previous diagnostic tests and treatments </li></ul></ul>
    64. 65. Evaluation <ul><li>Physical </li></ul><ul><ul><li>General physical exam </li></ul></ul><ul><ul><li>Pelvic exam </li></ul></ul>
    65. 66. Evaluation <ul><li>Tests </li></ul><ul><ul><li>Saline Sonogram or hysteroscopy </li></ul></ul><ul><ul><li>Hysterosalpingogram </li></ul></ul><ul><ul><li>?? Luteal phase endometrial biopsy; repeat in next cycle if abnormal </li></ul></ul><ul><ul><li>Placental FISH analysis </li></ul></ul><ul><ul><li>Parental karyotypes </li></ul></ul><ul><ul><li>Lupus anticoagulant </li></ul></ul><ul><ul><li>Anticardiolipin antibodies IgG and IgM </li></ul></ul>
    66. 68. Evaluation <ul><li>Tests </li></ul><ul><ul><li>Antiphosphatidylserine antibody IgG and IgM </li></ul></ul><ul><ul><li>Platelet count </li></ul></ul><ul><ul><li>Thrombophilia mutations and functional assays </li></ul></ul><ul><ul><li>Thyroid stimulating hormone </li></ul></ul>
    67. 69. Evaluation <ul><li>Tests NOT useful </li></ul><ul><ul><li>Other anti-phospholipid antibodies </li></ul></ul><ul><ul><li>ANA </li></ul></ul><ul><ul><li>Maternal anti-paternal leukocyte antibodies </li></ul></ul><ul><ul><li>Mixed lymphocyte maternal-paternal cell cultures </li></ul></ul><ul><ul><li>HLA genotyping </li></ul></ul><ul><ul><li>Mouse embryotoxicity assays </li></ul></ul><ul><ul><li>Immunophenotype panels (CD56, CD16) </li></ul></ul>Hill ASRM 2002 Course 6 p.58-59
    68. 70. Treatment - Thrombophilia <ul><li>For heritable or acquired thrombophilia: heparin anticoagulation </li></ul><ul><li>For bonafide APS, multiple studies support use of heparin and aspirin </li></ul>
    69. 71. Treatment - APS <ul><li>Aspirin 81 mg po/day </li></ul><ul><li>Subcutaneous heparin 10K-20K units/day divided doses </li></ul><ul><li>Alternative: low-molecular-weight heparin 2500-5000 units/day single dose </li></ul><ul><li>Calcium supplementation </li></ul>
    70. 72. Treatment - Thrombophilia <ul><li>For elevated homocysteinemia without thrombosis history </li></ul><ul><ul><li>Supplementation with Vitamin B6, B12 and folic acid </li></ul></ul><ul><li>Heparin anticoagulation for history of thrombosis or homozygous MTHFR mutation or pregnancy outcomes unresponsive to vitamin supplementation </li></ul>
    71. 73. Empiric Treatment <ul><li>Use of aspirin alone attractive because of ease of use and relative safety profile, barring contraindication to low-dose aspirin use </li></ul><ul><li>Supporting data lacking </li></ul>
    72. 74. Treatment - Immunotherapy <ul><li>“ Blocking antibody” hypothesis </li></ul><ul><ul><li>Paternal leukocyte immunization or desensitization </li></ul></ul><ul><ul><ul><li>Efficacy disproven </li></ul></ul></ul><ul><ul><ul><li>May increase risk of loss </li></ul></ul></ul><ul><ul><ul><li>Potential adverse effects: transfusion reaction, immunization, infection, IUGR, GVH, thrombocytopenia </li></ul></ul></ul>
    73. 75. Treatment - Immunotherapy <ul><li>“ Blocking antibody” hypothesis </li></ul><ul><ul><li>Intravenous immunoglobulin </li></ul></ul><ul><ul><ul><li>Studies and meta-analyses show no benefit </li></ul></ul></ul><ul><ul><ul><li>Extremely expensive $7-14,000 </li></ul></ul></ul><ul><ul><ul><li>Side effects: headache, hypotension, nausea </li></ul></ul></ul><ul><ul><ul><li>Potential anaphylaxis in IgA deficient patients </li></ul></ul></ul><ul><ul><ul><li>Potential for prion disease transmission due to large pool of donors </li></ul></ul></ul>
    74. 76. Treatment - Immunotherapy <ul><li>Progesterone called “nature’s immunosuppressant” due to inhibition of immune cells at maternal-fetal interface </li></ul><ul><li>No verification yet through RCT </li></ul><ul><li>Safe and inexpensive </li></ul><ul><li>Dose: 100 mg BID vaginal suppositories, beginning 3 days after ovulation </li></ul>
    75. 77. Supportive Treatment <ul><li>60-90% chance of pregnancy success with supportive care and ... </li></ul><ul><ul><li>Timed intercourse for genetic and idiopathic RPL </li></ul></ul><ul><ul><li>Surgery for selected anatomic factors </li></ul></ul><ul><ul><li>P 4 and/or ovulation induction for LPD </li></ul></ul>
    76. 78. Supportive Treatment <ul><li>60-90% chance of pregnancy success with supportive care and ... </li></ul><ul><ul><li>Immunosuppresive P 4 for presumed alloimmune factors </li></ul></ul><ul><ul><li>Thyroid replacement for hypothyroidism </li></ul></ul><ul><ul><li>Appropriate anticoagulation for APS/thrombophilias </li></ul></ul>
    77. 79. Management: Genetic Losses <ul><li>Consider Preimplantation Genetic Diagnosis (PGD) </li></ul><ul><ul><li>IVF </li></ul></ul><ul><ul><li>Day 3 blastomere biopsy (single cell) </li></ul></ul><ul><ul><li>FISH for most common aneuploidies or single gene defect (if probe available) </li></ul></ul><ul><ul><li>Blastocyst biopsy on day 5 allows detection of entire genome </li></ul></ul>
    78. 80. Van Voorhis B. N Engl J Med 2007;356:379-386 The Process of IVF
    79. 81. Rebar, R. W. et al. N Engl J Med 2004;350:1603-1604 Embryos and Blastocysts during Assisted Reproduction (x20)
    80. 82. Van Voorhis B. N Engl J Med 2007;356:379-386 Biopsy and Preimplantation Genetic Diagnosis of a 3-Day-Old (Eight-Cell) Embryo
    81. 83. Embryo Evaluation “omics” <ul><li>GENomics </li></ul><ul><ul><li>FISH – day 3 </li></ul></ul><ul><ul><li>Array CGH – day 5 </li></ul></ul><ul><ul><li>SNPs </li></ul></ul><ul><li>TRANSCIPT omics </li></ul><ul><ul><li>Gene transcription </li></ul></ul><ul><li>PROTEomics </li></ul><ul><ul><li>Proteins </li></ul></ul><ul><ul><li>Secretomics </li></ul></ul><ul><li>METABOLomics </li></ul><ul><ul><li>Metabolites </li></ul></ul><ul><ul><li>Amino Acids </li></ul></ul>
    82. 84. Braude P. N Engl J Med 2006;355:541-543 In Vitro Fertilization and Preimplantation Genetic Haplotyping
    83. 85. Elias S. N Engl J Med 2001;345:1569-1571 Analysis by Comparative Genomic Hybridization of a Blastomere Obtained by Biopsy of a Six-to-Eight-Cell Embryo
    84. 86. Management: Genetic Losses <ul><li>Drawbacks </li></ul><ul><ul><li>Expense </li></ul></ul><ul><ul><li>Possibility of no transfer </li></ul></ul><ul><ul><li>10-25% mosaicism and potential for misidentification </li></ul></ul><ul><ul><li>No large scale studies supporting benefit </li></ul></ul>
    85. 87. Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Blastocyst Apposition and Adhesion
    86. 88. Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Blastocyst Implantation
    87. 89. Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Maintenance of Early Pregnancy
    88. 90. Summary <ul><li>Early pregnancy loss is a frustrating entity for both patients and providers </li></ul><ul><li>Possibility of successful pregnancy outcome high, depending on maternal age and number of prior losses </li></ul><ul><li>Understanding the potential underlying mechanisms of loss along with empathetic supportive care decreases emotional stress and facilitates cost-effective evaluation and therapy </li></ul>

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