Focused Issue of This Month In Vitro Fertilization Program ShinYong Moon, MD Department of Obstetrics and Gynecology, Seoul National University College of Medicine Email : shmoon@snu.ac.kr J Korean Med Assoc 2007; 50(5): 431-439 Abstract Rapid progress has been made in the field of infertility since the first IVF (in vitro fertilization) baby was born in 1978. Controlled ovarian stimulation with FSH is currently the standard procedure for ovarian stimulation before follicular aspiration. Gonadotropinreleasing hormone agonists and antagonists have been used to prevent endogenous LH surge during controlled ovarian hyperstimulation.the goal of controlled ovarian stimulation with gonadotropins is to obtain a large number of mature oocytes and thereby improve the likelihood of obtaining an adequate number of embryos for subsequent transfer. IVF was initially presented as a treatment for tubal factor infertility but was quickly utilized in other areas in the field of infertility, such as male factor infertility and even ovarian failure. ICSI (intracytoplasmic sperm injection) is a more recent approach for male factor treatment, which allows the sperm to be directly injected into the egg using micromanipulation. Preimplantation genetic diagnosis can be performed on embryos prior to the embryo transfer. The complications associated with the IVF program include ovarian hyperstimulation syndrome and multiple pregnancies. The multiple pregnancies are directly related to the practice of transferring multiple embryos at embryo transfer. Each IVF clinic publishes its pregnancy rates. However, comparisons between clinics are difficult because the success rates vary depending on the distribution of underlying causes and age of the patients. The current takehomebaby rate is only 34.7%. In 2005, the Korean government enacted a law to regulate many aspects of IVF practice. Keywords : In vitro fertilization; Assisted reproductive technology; Infertility 431
Moon SY Oocyte retrieval In vitro fertilization Controlled ovarian hyperstimulation Follicle Growth Embryo math ration Pregnancy Implantation Figure 1. Controlled ovarian hyperstimulation and In vitro fertilizationembryo transfer. 432
In Vitro Fertilization Program Table 1. Precycle testing Day 3 FSH Sperm morphology Semen WBC stain or culture Antisperm antibodies (ASA) Chlamydia culture or antibiotic treatment Infection screen: HIV or Hepatitis B, RPR Sperm penetration assay (SPA) Trial placement of the transfer catheter Uterotubal abnormalities Sexual dysfunction; frozen semen Severe endometriosis 433
Moon SY Table 2. Subjective assessment of embryo quality Blastomere size and regularity Blebbing / fragmentation Presence of vacuoles, inclusion bodies, refractile bodies Granularity of cytoplasm Thickness of zona Cell number * ovum pickup Figure 2. Gonadotropinreleasing hormone agonist long protocol. * ovum pickup Figure 3. Gonadotropinreleasing hormone antagonist protocol. 434
In Vitro Fertilization Program Table 3. Factors influencing embryo quality Oocyte quality Choice of ovulation induction protocolrole of GnRH analogues Laboratory quality control programs cumulus expansion corona expansion/radiance zona thickness cumulus clumping in vitro maturation accuracy of grading oocyte maturity timing of hcg injection relative to oocyte retrieval preincubation periods prior to insemination need for altered sperm concentrations embryo quality in GnRH cycle media quality and type choice of bioassay for evaluating laboratory parameter serum source; testing of serum source maternal versus donor serum serum free/defined culture conditions 435
Moon SY A A B SNUH IVF lab, (X 400). A) 4 cell embryo B) 8 cell embryo Figure 5. 4 cell & 8 cell embryos. B SNUH IVF lab, (X 400). A) mature oocyte B) immature oocyte C) degenerated oocyte Figure 4. Classification of oocytes. C 436
In Vitro Fertilization Program Table 4. Indications for oocyte donation Table 6. Diseases amenable to preimplantation genetic diagnosis Premature ovarian failure Gonadal dysgenesis Iatrogenic: surgery, radiation, chemotherapy Poor responders to controlled ovarian hyperstimulation Carriers of undesirable genetic traits: XLinked or autosomal dominant Repeated failure of fertilization in vitro Unexplained repeated pregnancy wastage Anatomically inaccessible ovaries Xlinked disease Single gene defects Lesch Nyhan syndrome Duchenne muscular dystrophy Xlinked mental retardation Adrenoleukodystrophy Hemophilia Sicklecell anemia Thalassemia Cystic fibrosis Tay Sach's disease Table 5. Indications for intracytoplasmic sperm injection (ICSI) (10) Total motile sperm count (TMC) < 1 million < 4 % normal morphology and TMC < 5 million No or poor fertilization in the first IVF cycle when TMC < 10 million No poor fertilization in two IVF cycles when TMC > 10 million Epididymal or testicular spermatozoa SNUH IVF lab, (X 400). Figure 6. Intracytoplasmic sperm injection. 437
Moon SY 11. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978; 2: 366. 12. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta analysis and comparison with basal folliclestimulating hormone level. Fertil Steril 2005; 83: 291-301. 13. Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER. Performance of basal folliclestimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a metaanalysis. Fertil Steril 2003; 79: 1091-1100. 14. Oehninger S, Gosden RG. Should ICSI be the treatment of choice for all cases of invitro conception? No, not in light of the scientific data. Hum Reprod 2002; 17: 2237-2242. 15. Sharara FI, Queenan JT Jr, Springer RS, Marut EL, Scoccia B, Scommegna A. Elevated serum Chlamydia trachomatis IgG antibodies. What do they mean for IVF pregnancy rates and loss? J Reprod Med 1997; 42: 281-286. 16. Edwards RG, Steptoe PC, Purdy JM. Establishing fullterm human pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol 1980; 87: 737-756. 17. Ubaldi F, Rienzi L, Ferrero S, Baroni E, Iacobelli M, Sapienza F Miansi MG, Cobellis L, Romano S, Scarselli F, Greco E. Natural in vitro fertilization cycles. Ann N Y Acad Sci 2004; 1034: 245-251. 18. Wright VC, Chang J, Jeng G, Macaluso M. Assisted reproductive technology surveillanceunited States, 2003. MMWR Surveill Summ 2006; 55: 1-22. 19. Van Steirteghem AC, Liu J, Joris H, Nagy Z, Janssenswillen C, Tournaye H, Derde MP, Van Assche E, Derroev P. Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Hum Reprod 1993; 8:1055-1060. 10. Hamberger L, Lundin K, Sjogren A, Soderlund B. Indications for intracytoplasmic sperm injection. Hum Reprod 1998; 13(S 1): 128-133. 11. Kashyap S, Moher D, Fung MF, Rosenwaks Z. Assisted reproductive technology and the incidence of ovarian cancer: a metaanalysis. Obstet Gynecol 2004;103:785-794. 12. Fortin A, Morice P, Thoury A, Camatte S, Dhainaut C, Madelenat P. Impact of infertility drugs after treatment of borderline ovarian tumors: results of a retrospective multicenter study. Fertil Steril 2007; 87: 591-596. 438
In Vitro Fertilization Program 13. Caperton L, Murphey P, Yamazaki Y, McMahan CA, Walter CA, Yanagimachi R, McCarrev JR. Assisted reproductive technologies do not alter mutation frequency or spectrum. Proc Natl Acad Sci U S A 2007;104: 5085-5090. Peer Reviewer Commentary 439