The document outlines various aspects of fertility and assisted reproductive technology (ART), including evaluation, treatment options, and fertility preservation methods. It highlights fertility factors affecting both men and women, discusses infertility statistics, and details the IVF process, including embryo transfer and success rates based on age and diagnosis. Additionally, it addresses psychological support, financial options, and the importance of lifestyle choices in reproductive health.

1. Fertility Options Mark Perloe, M.D. Georgia Reproductive Specialists www.ivf.com

2. Objectives Discuss general fertility factors Describe basic evaluation and treatment Describe A ssisted R eproductive T echnology (ART) at GRS Understand fertility preservation options

3. Fertility Preservation Indications Chemotherapy, radiation therapy, surgery On-hold for career Haven’t found partner Criteria: Age, Antral follicle count, AMH Success: 2-5% chance for each stored oocyte Cost: Cryopreservation cycles: ~$9-$21,000 (1-3x) Thaw, culture & transfer: $5,000

4. Infertility…. Inability to conceive after an interval of unprotected intercourse One year for women under 35 Six months for women over 35 Medical history and physical findings may dictate earlier evaluation and treatment

5. Scope At any given time, 10% of reproductive age couples seeking conception are unable to do so 6.1 million women and their partners 15% of all reproductive age women have an infertility-related office visit each year Half of couples experiencing fertility problems never seek treatment

6. Fertility Factors Ovulation factors 25% Male factor 40% Tubal/anatomic factors 35% Endometriosis 35% or more Multiple factors 25% Unexplained 30%

7. Months % women pregnant Cumulative frequency of pregnancy in couples trying to conceive Let’s look first at how easy, or difficult, it is to get pregnant… Fecundity

8. Graafian follicle Oocyte Membrana granulosa Theca interna Basement membrane Antrum

9. -50 -4 +10 -9 +1 -180 Time (days) 0 Very little atresia Ovulation Corpus luteum Large antral Recruited Growing 50 - 80% atresia Primordial Small Antral Pre-ovulatory Possible time of action of nutrition on folliculogenesis Selected

11. Blastomeres undergo compaction and form morula. Gap junctions and tight junctions will form placenta. The cells gain distinct polarity (i.e. have inside and outside faces) and flatten against each other. Embryo growth

12. Embryo Cleavage The cleavage divisions produce cells called blastomeres.

13. Fertilization occurs in the ampulla of the oviduct, implantation in the uterus. Motile systems are important: cilia and smooth muscle. The Fallopian tube produces secretions which control and provide a vehicle for transport. Control over embryo transport may also operate at the ampullary isthmic junction and at the utero-tubal junction. Embryo transport

14. Hatching from zona The zona pellucida must be lost before the embryo can contact the uterine epithelium. Observations in vitro suggests that the blastocyst squeezes out of fractures in the zona (“hatches”). Identical twins may be produced if the embryo breaks into two during this process. Empty zona Zona free blastocysts

15. Apposition Attachment Invasion Uterine responses In humans, the maternal epithelium and stroma in invaded by the embryo…

16. The syncytiotrophoblast proliferates and invades the extracellular matrix of the stroma. Cytotrophoblast cells migrate between the syncytia, followed by fetal stroma - leading to placental villi. Implantation

17. Ovulation Factors Insulin resistance PCOS, hyperandrogenism Hypothalamic dysfunction Exercise induced, eating disorders, stress Pituitary disorders hyperprolactinemia Ovarian Failure Chemotherapy, Age, Surgery

18. Polycystic Ovary Syndrome Low glycemic diet Metformin, TZD, GLP-1 Exercise Ovarian drilling Clomiphene/letrozole Injectable gonadotropins OHSS risk High multiple birth rate IVF or IVM

19. PCOS Ovarian Drilling 65-85% success not effective in smokers 1/3 require ovulation meds requires surgery adhesion formation

20. Endometriosis Presence of uterine lining in locations outside the uterus 35-55% of infertile women demonstrate endometriosis at laparoscopy Not all women with endometriosis have infertility Surgical treatment and Lupron do not enhance success rates

21. Age related infertility Reduced pregnancy rates Increased miscarriage rates Increased risk fetal anomalies

22. Pregnancy, Live Birth, and Singleton Live Birth by Age,* 2001 *For consistency, all rates are based on cycles started.

23. Miscarriage Rates by Age, 2001

24. Male Factor Infertility Causes varicocele infection smoking genetic cancer, radiation, chemorx hot tub bicycle riding medications Testing Semen analysis SCSA/SDFA: DNA fragmentation

25. Sperm Chromatin Structure Assay SCSA®/SDFA test is a good predictor, relative to other sperm measures, for the clinical diagnosis of male infertility

26. DNA Fragmentation Study Results 998 cycles from 637 patients Unexplained infertility, with sufficient sperm count did IUI Female factor infertility did IVF <500,000 sperm after gradient did ICSI Bungum, Human Reprod , 2007

27. P34H Testing

28. P34H Testing Sullivan, Fertil & Steril, 2006

29. SDD Study A Retrospective study of 58 patients receiving IUI or IVF (w/o ICSI) None with abnormal SDD had live birth Those with normal SDD had a 28% success rate Study B Prospective ICSI only study..50 patients 20 with abnormal SDD 30 with normal SDD ICSI success rates were not statistically different

30. Advanced Sperm Testing Panel

31. Uterine Evaluation

32. Uterine Fibroids

33. 5. Analyze Results Real-time continuous monitoring with 3D dose accumulation and thermometry determines whether treatment can proceed as planned or has to be changed. This interactive process continues until the entire region of treatment has been ablated.

34. Congenital Uterine Anomalies Bicornuate Vs Septate Uterus

35. Hydrosalpinx

36. Abnormal Hysterosalpingogram

37. Pelvic Adhesions

38. Hydrosalpinx

39. What do we know about pregnancy losses?? 6 20 40 Weeks gestation 100 50 % Pregnancies can easily be recognized clinically by 6 wks. Ovulation rates are high! So probably are fertilization rates! Early human embryos may show a high incidence of developmental abnormalities. 10-15% of of all clinically recognised pregnancies are lost in the 1st trimester; 2-3% are lost later. 50% of these losses have cytogenetic abnormalities. 1/3 of all pregnancies are lost soon after implantation - before they are clinically recognised.

40. Unexplained Infertility Letrozole or Clomid/IUI Letrozole/HMG/IUI IVF

41. Injectable Gonadotropins

42. Assisted Reproductive Technology (ART) In vivo = inside the body In vitro = in glass = outside the body IVF = in vitro fertilization ART involves both the sperm and the egg in the laboratory Fertilization and early embryo development usually achieved in vivo accomplished in vitro

43. In vitro fertilization Screening Optimize reproductive health Psychological counseling Financial counseling Nursing education Ovarian hyperstimulation Egg retrieval Embryo culture Embryo transfer Cryopreservation The wait!

44. Lifestyle Smoking Up to 13% of infertility problems may be attributable to smoking Conception delay Egg depletion and diminished quality Higher miscarriage rates, ectopic pregnancies Passive smoking equivalent to active smoking Possibly lower IVF delivery rates Male smoking may pose greater risk

45. Emotional Support Psychological counseling requirement prior to cycle initiation; continued referral as necessary Patient support groups, AFA, INCIID, RESOLVE “Mind, Body…Baby” Program Acupuncture Massage Exercise Support

46. Financial Support Assisted Reproductive Technology Financial Options “ Making IVF Affordable Plan” Includes all Frozen Embryo Transfers No “Hidden Fees” for extra visits or ICSI FREE second IVF treatment cycle Shared Risk Program Refund IVF Global Fee IVF Global Frozen Embryo Transfer IVF PLUS Advanced Reproductive Care (ARC) financing 60% of patients have some degree of insurance coverage

47. IVF Overview Stimulation phase ~ 8-12 days Over-ride usual ovulation status Intentionally hyperstimulate ovaries with injectable hormones Monitor closely with vaginal ultrasound and blood hormone levels Anticipate 4-6 clinic visits

48. IVF Overview Retrieval ~ 20 minutes Outpatient minor surgery under IV sedation Vaginal ultrasound guided oocyte retrieval All visible follicles entered and aspirated Recovery ~ 1 hour in clinic, remainder of day at home Goal: multiple eggs to work with in the laboratory

49. IVF Overview Laboratory ~ 3-5 days Provide semen specimen Combine sperm and eggs at appropriate intervals Inject sperm into eggs as required Incubate and allow to grow for 3-5 days Embryologists update patients regarding progress

50. IVF Overview Transfer Plan transfer for Day 3 or 5 after retrieval Abdominal ultrasound visualization requires a FULL bladder; Valium available Transfer catheter containing embryos threaded though cervix Embryos gently injected into uterus Normal activity after transfer

51. IVF Overview Number of embryos transferred based on patient age and embryo quality General for Day 3: < 35 years: 2-3 embryos 35-37: 3 embryos 38-40: 3-4 embryos >40: 4-5 embryos Blastocysts (Day 5): 2 embryos up to age 40

52. Embryos Day 3 Day 5

53. IVF Overview 14 days after retrieval… Check pregnancy test Progesterone supplementation from just after retrieval until outcome known Intramuscular progesterone Continues through the 10 th week of pregnancy

54. Special Issues Intracytoplasmic sperm injection (ICSI) Individual sperm can be injected into each egg Important for profound male factor Pre-implantation genetic diagnosis (PGD) Prevention of genetic disease Recurrent pregnancy loss Egg donation anonymous vs. known donor Fertility preservation

55. Special Issues ICSI PGD

56. Success Rates (2001 SART Data) Age Clinical Pregnancy Live Birth < 35 47.1% 36.5% 35-37 28.6% 23.8% 38-40 21.4% 14.3% 41-42 3/5 2/5

57. 2007 GRS IVF Statistics Age <35 35-37 38-40 >40 Donor # cycles 105 63 39 12 28 birth/cycle 33.3% 27.0% 28.2% 2/12 60.7% Avg # ET %Twins %FET del 2.3 29.2 30.8 2.4 29.2 33.2 2.9 7.6 42.8 3.3 - - 2.0 - 36.8

58. Success Rates: What do they mean? Pregnancies per cycle Live births per retrieval Live births per cycle Live births per transfer Singleton live births per transfer Singleton live births per cycle

59. Live Birth Rates by Diagnosis, 2001

60. Live Birth Rates by Woman’s Age and Previous Live Births, 2001

61. Live Birth Rates by Age and History of Miscarriage, with No Prior Births,* 2001 *Women reporting only previous ectopic pregnancies or pregnancies that ended in induced abortion were not included in the above statistics.

62. Live Birth Rates by Woman’s Age and History of Previous ART Cycles, 2001

63. Live Births per Transfer and % Multiple Births in Women <35 by Number of Embryos Transferred, 2001 (100.0)* (59.3)* (39.6)* (53.4)* (38.8)* (7.8)* (49.1)* (41.3)* (9.6)* (43.3)* (46.8)* (9.9)* *Percentages of live births that were singletons, twins, and triplets or more are in parentheses. Note: In rare cases a single embryo may divide and thus produce twins. For this reason a small percentage of triplets resulted when two embryos were transferred. 30.0 51.7 46.9 42.9 43.1 (1.2)*

64. Frozen Embryos vs. Fresh Embryos, 2001 Frozen embryos Fresh embryos

65. Live Births per Transfer Using Fresh Embryos From Own and Donor Eggs, by ART Patient’s Age, 2001

66. Success Rates vs. Multiple Births Type of ART

67. Embryo Evaluation “omics” GENomics FISH CGH SNPs TRANSCIPTomics Gene transcription PROTEomics Proteins Secretomics METABOLomics Metabolites Amino Acids

68. Multiple Births rates are NOT 1996, 2000 and 2001

76. GRS Meridian Mark Drs. Perloe, Kaplan and Singleton Alpharetta Dr. Conway DeKalb Medical Center Dr. Kaplan Please join us for a complimentary 20 minute visit…. Please join us for a complimentary 20 minute visit….