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Recurrent Pregnancy Loss Mark Perloe, M.D. Georgia Reproductive Specialists Atlanta, Georgia
Learning Objectives ,[object Object],[object Object],[object Object]
Definition ,[object Object],[object Object],[object Object],[object Object],Hill  Curr Prob Obstet Gynecol Fertil  1994;37:693-704
Recurrent  Loss  Epidemiology ,[object Object],[object Object],[object Object],Lee  Semin Reprod Med  2000;18(4):433-40
SPAB  Epidemiology  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Wilcox  NEJM  1988;319:189-194
SPAB or RPL? ,[object Object],[object Object],[object Object],Cramer  Semin Reprod Med  2000;18(4):331-9
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
PCOS & Pregnancy Loss ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Metformin Reduces Pregnancy Loss in PCOS ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology  Anatomic Factors ,[object Object],[object Object],[object Object],[object Object],Propst & Hill  Semin Reprod Med  2000;18(4):341-50
Etiology  Anatomic Factors ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology  Anatomic Factors ,[object Object],[object Object],[object Object]
Acquired Uterine Defects
Etiology  Infection ,[object Object],[object Object],[object Object],[object Object],Lee  Semin Reprod Med  2000;18(4):433-40
Etiology  Genetic Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],% Chromosomal Abnormal by Gestational  Age % abnormal Gestational age 60 12 45 16 12 20 6 24 ~1 40
Etiology  Genetic Factors ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology  Genetic Factors
Etiology  Genetic Factors ,[object Object],[object Object],[object Object],[object Object],Ward  Semin Reprod Med  2000;18(4):425-32
 
Etiology  Genetic Factors ,[object Object],[object Object],[object Object],[object Object]
Etiology  Genetic Factors ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology  Genetic Factors ,[object Object],[object Object],[object Object],[object Object],[object Object]
Lobo, R. A. N Engl J Med 2005;353:64-73 Decline in the Number of Oocytes  from Birth to Menopause
Heffner, L. J. N Engl J Med 2004;351:1927-1929 Fertility and Miscarriage Rates as a Function of Maternal Age
Etiology   Thrombophilia ,[object Object],[object Object],Kutteh  Semin Reprod Med  2006;24(1):54-65
Etiology   Thrombophilia   Venous ,[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia   Venous ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia   Arterial ,[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Thrombophilia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Luteal Phase Defect ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology  Endocrine Factors ,[object Object],[object Object],[object Object],[object Object]
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Fausett & Branch Semin Reprod Med 2000;18(4):379-392
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object],Levine NEJM 2002;346:752-63
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object],[object Object]
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],Fausett Semin Reprod Med 2000;18(4):379-92
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object]
Etiology   Autoimmune Factors ,[object Object],[object Object]
Etiology   Autoimmune Factors ,[object Object],[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],Porter Semin Reprod Med 2000;18(4):393-400
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object]
Etiology   Alloimmune Factors ,[object Object],[object Object],[object Object],Hill  Semin Reprod Med  2000;18(4):401-405
Etiology   Male Factor ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology   Male Factor ,[object Object],[object Object],[object Object]
Etiology -  Environmental Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Gardella & Hill  Semin Reprod Med  2000;18(4):407-424 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology -  Environmental Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Etiology -  Idiopathic ,[object Object],[object Object],[object Object],Lee  Semin Reprod Med  2000;18(4):433-40
Evaluation ,[object Object],[object Object],[object Object],[object Object],[object Object]
Evaluation ,[object Object],[object Object],[object Object]
Evaluation ,[object Object],[object Object],[object Object]
Evaluation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
 
Evaluation ,[object Object],[object Object],[object Object],[object Object],[object Object]
Evaluation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Hill  ASRM 2002 Course 6  p.58-59
Treatment - Thrombophilia ,[object Object],[object Object]
Treatment - APS ,[object Object],[object Object],[object Object],[object Object]
Treatment - Thrombophilia ,[object Object],[object Object],[object Object]
Empiric Treatment  ,[object Object],[object Object]
Treatment - Immunotherapy ,[object Object],[object Object],[object Object],[object Object],[object Object]
Treatment - Immunotherapy ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Treatment - Immunotherapy ,[object Object],[object Object],[object Object],[object Object]
Supportive Treatment ,[object Object],[object Object],[object Object],[object Object]
Supportive Treatment ,[object Object],[object Object],[object Object],[object Object]
Management: Genetic Losses ,[object Object],[object Object],[object Object],[object Object],[object Object]
Van Voorhis B. N Engl J Med 2007;356:379-386 The Process of IVF
Rebar, R. W. et al. N Engl J Med 2004;350:1603-1604 Embryos and Blastocysts during Assisted Reproduction (x20)
Van Voorhis B. N Engl J Med 2007;356:379-386 Biopsy and Preimplantation Genetic Diagnosis of a 3-Day-Old (Eight-Cell) Embryo
Embryo Evaluation  “omics” ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Braude P. N Engl J Med 2006;355:541-543 In Vitro Fertilization and Preimplantation Genetic Haplotyping
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
Management: Genetic Losses ,[object Object],[object Object],[object Object],[object Object],[object Object]
Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Blastocyst Apposition and Adhesion
Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Blastocyst Implantation
Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Maintenance of Early Pregnancy
Summary ,[object Object],[object Object],[object Object]

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Recurrent Pregnancy Loss Evaluation and Treatment Approaches

  • 1. Recurrent Pregnancy Loss Mark Perloe, M.D. Georgia Reproductive Specialists Atlanta, Georgia
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  • 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
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  • 17. Etiology Genetic Factors
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  • 23. Lobo, R. A. N Engl J Med 2005;353:64-73 Decline in the Number of Oocytes from Birth to Menopause
  • 24. Heffner, L. J. N Engl J Med 2004;351:1927-1929 Fertility and Miscarriage Rates as a Function of Maternal Age
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  • 80. Van Voorhis B. N Engl J Med 2007;356:379-386 The Process of IVF
  • 81. Rebar, R. W. et al. N Engl J Med 2004;350:1603-1604 Embryos and Blastocysts during Assisted Reproduction (x20)
  • 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
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  • 84. Braude P. N Engl J Med 2006;355:541-543 In Vitro Fertilization and Preimplantation Genetic Haplotyping
  • 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
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  • 87. Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Blastocyst Apposition and Adhesion
  • 88. Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Blastocyst Implantation
  • 89. Norwitz, E. R. et al. N Engl J Med 2001;345:1400-1408 Maintenance of Early Pregnancy
  • 90.

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  23. 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.
  24. 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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  80. 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.
  81. 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.
  82. 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.
  83. 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.
  84. 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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  86. 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.
  87. 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.
  88. 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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