Dr. Vandana Bansal MS, D.Phil.(Gold Medalist), DGO, FCGP

1. THIRD PARTY REPRODUCTION & CURRENT CONCEPTS IN ART Dr. Vandana Bansal MS, D.Phil.(Gold Medalist), DGO, FCGP Senior Gynaecologist & Obstetrician Infertility & IVF Specialist ArpitTest Tube Baby Centre JeevanJyotiHospital, Allahabad

2. From the holy city of Sangam; Allahabad

3. Introduction The process of reproduction has long fascinated man kind particularly from scientific perspectives. The sole objective of any living organism is to procreate i.e. to reproduce itself. With an average monthly fecundity rate of 20%, human beings are not fertile mammals. 10-15% of couples has difficulties in conceiving and seeks special fertility care at least once during their reproductive life time.

4. Origin of Reproduction (Genesis 1:27-28) So, God created man in His own image, in the image of God created He him; male and female created. And God blessed them and God said unto them. Be fruitful and multiply and replenish the earth and Subdue it.

5. Infertility Infertility is defined as a failure to conceive within one year of regular unprotected coitus • Primary Infertility –patient’s who have never conceived • Secondary Infertility – indicates previous pregnancy but failure to conceive subsequently’. 80% of couple conceive within 1st year 10% conceive by the end of 2nd year 10% remain infertile by end of 2nd year Incidence - 10% to 15%

6. InfertilityPrevalence and Overview of Treatments • The overall incidence of infertility has remained relatively unchanged for the past 30 years (Speroff & Fritz, 2005). • Approximately half of all women who receive fertility care achieve conception leading to a live birth (Speroff & Fritz, 2005).

7. Treatment Options… Overcoming Infertility Nearly 90% of all infertility cases, both male and female factor, can be successfully treated. Treatment options are: • Ovulation Induction • Medical & Surgical treatment of Male • Laparoscopic & Hysteroscopic Surgery for Female • Intrauterine Insemination (IUI) • Assisted Reproductive Technology (ART) • Third party Reproduction

8. Human Reproduction – Changed Landmark Event in Reproductive Revolution Science Proves Wonders 25th July, 1978 Louise Joy Brown World’s First Successful Test Tube Baby

9. Third Party Reproduction Third party reproduction refers to the use of oocytes, sperm, embryos, or uterus that has been provided by a third person (donor) to enable an infertile individual or couple (intended parent) to become parents. Ethical, moral, religious and legal concerns play a significant role in these treatments They have allowed the miracle of childbirth to those who might otherwise be unable to achieve this goal.

10. With increasing age, the woman’s ovaries run out of eggs(limited ovarian reserve) The only option these women have for having a baby is IVF egg donation …third party

11. There is also an increasing incidence of Premature Ovarian Failure & Diminished Ovarian Reserve • For these women to concieve the only way out is to use donor eggs(third party) • Aged women • Oophrectomy cases • Cancer ovary and operated or irradiated • Premature ovarian failure(premature menopause)

12. There is an increasing incidence of non obstructive azospermia The only chance these couple have to have a baby is through sperm donation……third party

13. Some women have untreatable uterine abnormality RKH, endometrial TB, hystrectomy, etc

14. The only chance of these couples to have babies is through ……..…… …………Third party reproduction

15. Indications for Third-party reproduction Women without functional ovaries • Advanced maternal age • Surgical or natural menopause • Premature ovarian failure • Previous chemotherapy or radiotherapy • Women born without functional ovaries Women with functional ovaries • Recurrent pregnancy loss • Repetitive IVF failures/poor response • Women without functioning uterus • Uterus that is unsuitable for pregnancy such as extensive fibroids, adenomyosis, or Asherman’s • Women with a serious medical condition that increases significant morbidity, or even mortality if pregnancy occurs • Inheritable disorders (carriers of genetic diseases & chromosomal abnormalities) Male & Female same sex couple

16. Types of Third Party Reproduction • Oocyte donation • Sperm Donation • Embryo Donation • Surrogacy • Traditional surrogacy • Gestational surrogacy

17. What is Oocyte Donation? • Egg donation is the part of third party reproduction. • Eggs are retrieved from a young woman ( < 33 yrs ) called the donor. • These eggs are fertilized with the sperms of the recipient’s husband. • Resultant embryo is transferred to the uterus of the recipient. • Oocyte donation has been used for more than 20 years to help infertile couples become pregnant through IVF • The first pregnancy achieved with egg donation was reported in 1984.

18. Oocyte Donation: Indications Women without ovarian function: Advanced maternal age Surgical or natural menopause Premature ovarian failure Women born without functional ovaries Previous chemotherapy or radiotherapy Women with ovarian function: Recurrent pregnancy loss Repetitive IVF failures/poor response Inheritable disorders Male same sex couple

19. Treating Women of Advance Reproductive Age Age > 40 - ovarian functions is reduced Oocytes are of poorer quality Ovulation is less likely Corpus luteum may be deficient in hormone Blastocyst hatching is reduced

20. Steps of Egg Donation Selection of Donor Selection of Recipient Appropriate Stimulation of donor Successful fertilization Proper synchronization of donor and recipient Endometrial preparation of recipient Atraumatic Embryo transfer Hormonal support of recipient Finally, adequate management of pregnancy

21. Psychological consultation for oocyte donor recipients • The decision to proceed with donated oocytes is complex, and patients and their partners (if applicable) may benefit from psychological counseling • clinician should strongly recommend psychological counseling by a qualified mental health professional • The assessment should include a clinical interview and, where appropriate, psychological testing. • In cases of directed donation, the potential impact of the relationship between the donor and recipient should be explored

22. Evaluation of the oocyte recipient A. Medical and reproductive history B. A complete general physical examination including a pelvic examination. C. Assessment of the uterine cavity (HSG, saline infusion ultrasonography) D. Standard preconceptional testing and counseling a. Blood type, Rh factor, and antibody screen. b. Rubella and varicella titers. c. HIV, syphilis, Hepatitis, Neisseria gonorrhoeae and Chlamydia trachomatis

23. Evaluation of the partner of the oocyte recipient 1. Semen analysis for male partners. 2. Blood type and Rh factor. 3. Serologic test for syphilis. 4. Hepatitis B surface antigen. 5. Hepatitis B core antibody (IgG and IgM). 6. Hepatitis C antibody and NAT. 7. HIV-1 (AB and NAT), HIV-2 AB testing 8. Appropriate genetic screening and testing based on history

24. Classification of Donors Oocyte donors can be classified based on the anonymity of their identity. • Anonymous Donors: • Recruited and screened by the ART program or by a private agency. • Directed donors: • Generally recruited by the recipients, and screened by agencies or centers • The donor is generally a close relative or friend • IVF programs: • Women undergoing IVF may agree to donate their excess eggs to infertile patients

25. SOURCE OF OOCYTE DONORS • The demand for donor oocytes far outstrips the supply of donors. 1 Volunteers 2 Known donors 3 Spare oocytes 4 Sterilization patients 5 Professional oocyte donors

26. Selection of Donors Donors should be over 21 and under 34 years old Younger donors tend to provide better eggs Previous pregnancies by the donor is an asset Detailed personal medical and family history Blood tests for: infectious diseases, hepatitis B and HIV (AIDS) Screened for any X chromosome-linked genetic disorders Anonymity

27. Matching the Intended Parent to an Oocyte Donor • Donors are matched as closely as possible with the recipient couple for characteristics, such as hair color, eye color, ancestry; occupation, educational level; previous donation history • Medical matching (Blood group) • Compensated for their time & effort • Compensation remains the same no matter how many oocytes are retrieved

28. Screening of egg donors: phase 1 Donor age between 21 and 34 Both ovaries present Not overweight Nonsmoker Off hormonal contraception for >2 months Not adopted If donor meets above criteria, then proceed to phase 2

29. Screening of egg donors: phase 2 Review questionnaire: Eliminate those with serious functional or cosmetic handicaps or unknown family background Eliminate those with high-risk behaviour for STDs If OK: evaluate basal FSH, LH, and estradiol If OK: review psychological evaluation If OK: donor should come to clinic for phase 3

30. Screening of egg donors: phase 3 Physical examination Cervical cultures Gonorrhea Mycoplasma (ureaplasma) Herpes Chlamydia Blood tests Syphilis serology HIV-1 and HIV-2 (antigen and antibody tests) Hepatitis B and C

31. Potential Risks to Egg Donors • Inconvenience/ time commitment • Discomfort associated with injections/blood draws • Psychological risks - short and long term • Side effect of drugs: • - GnRH - hot flushes/ fatigue/ emotional liability • - Gonadotropins - bloating/ cramping

32. PotentialRisks to Egg Donors From retrieval: • Pain • Infection • Bleeding • Unexpected reaction to anaesthesia • Ovarian hyperstimulation syndrome • Sterility/Infertility from egg retrieval • Unknown risk of ovarian cancer

33. SELECTION OF RECIPIENTS Should have an in-date cervical smear Immunity to Rubella Normal hemoglobin, blood group Blood sugar level if above 40 years Recipient and her partner should be Negative for HIV I&II, Hepatitis B&C

34. Screening of egg recipients

35. Screening of egg recipients Cont..

36. Screening of egg recipients Cont..

37. COUNSELLING OF DONORS AND RECIPIENTS All patients and their partners require a detailed explanation of the procedures involved in egg donation and counseling on the moral, ethical and legal implications. • Implications counseling • Support counseling • Therapeutic counseling

38. Methods And Protocols for Oocyte Donation Egg donation consists of undergoing an IVF Cycle up to the point of egg retrieval in Donor. In Vitro fertilization with embryo formation. Fresh / Frozen - Embryo Transfer. Cyclic / Acyclic - Recipient with or without ovarian function.

39. Egg Donation Treatment SequenceActual treatment is individualized

40. Protocols for Oocyte Donation Fresh embryo transfer • Careful synchronization of the donor and recipient cycle. • While donor undergoes super ovulation and egg retrieval. • Recipient receives the hormonal therapy to prepare the endometrium for implantation.

41. Protocols for Oocyte Donation • Markers of adequate endometrial development. 1. Serum Estradiol level 2. Endometrial Thickness (USG) 3. Late Luteal phase endometrial biopsy in a test cycle. • Egg sharing.

42. ADAVANTAGE OF FROZEN EMBRYO TRANSFER. To overcome Endometrial Asynchrony To maintain Anonymity For embryo storage while donor has her blood re-tested for HIV.

43. PROTOCOL FOR OOCYTE DONATION(in cyclic women) • Synchronize the donor and recipient cycle by • Norethisterone or Giving GnRH Agonist • When both donor and recipient are down regulated • Recipient starts Estrogen and donor starts ovarian stimulation 5-6 days later. • Progesterone started to recipient on the day of ovum pickup of donor. • Resulting embryos are transferred 3-5 days later or cryopreserved

44. Schematic Diagram of an Oocyte Donor Stimulation Protocol Alternative protocols using GnRH antagonist can also be used

45. Schematic Diagram of a Recipient Protocol. • If the pregnancy test is positive, recipients are asked to continue the estrogen and progesterone replacement until 10 weeks of gestation. • If the pregnancy test is negative, patient can stop the hormonal replacement. E – estrogen; P –progesterone.

46. Endometrial Receptivity • Endometrial receptivity is the window of time when the uterine environment is conductive to embryo acceptance and subsequent implantation • Endometrial receptivity can be accessed by • Trans vaginal USG • Colour Doppler • Recently using 3D/4D USG • Parameters for assessing endometrial receptivity: • endometrial thickness (>7 - <14 mm) • endometrial pattern (triple-line pattern) • endometrial and subendometrial blood flow (within Zone 3 )

47. Window of Receptivity Post ovulatory Days • The condition of uterus becomes optimal for implantation for a brief period during leuteal phase known as Window of receptivity • Short - last for 4 days (Day 20-24 of the menstrual cycle) • +6 to 10 (Bergh and Navot 1992) • +3.5 (Rogers 1989) • +5 to 7 (Psychoyochos 1993) • During this period endometrium undergoes important changes that makes it receptive to the implanting embryo • Key factor in implantation is the synchrony between embryo development & endometrial receptivity

48. STEROID REPLACEMENT AFTER EMBRYO TRANSFER(Estradiol Valurate) Estrogen dose is increased. Progesterone is started from the day of ovum pick up in donor. Continue till pregnancy test is if positive. Increase progynova (Estrogen) to 8mg/day orally. Continue Estrogen and Progesterone until luteal placental shift occurs i.e. upto 10-12 weeks of pregnancy.

49. Luteal Phase Support • Vaginal progestin Pressaries • 100 BD- if CC/FSH/HMG cycle • 200 TDS- if GnRHa+HMG/FSH • Oral – Dehydrogestone10 mg BD • HCG 2000-2500 IU IM day 3 • Progesterone – 50-100 mg IM Rationale and Indications • COH results in abnormal endometrial Development • High level of estrogen seen in COH may cause premature luteolysis • Pituitary down regulation with GnRHa is detrimental to luteal phase • Ovarian aspiration disrupts granulosa cells • Important to synchronise embryo and endometrium for successful implantation

50. Concerns & Complications • Ethical, legal, religious & social issues • Relationship between biological & social parents, & safeguarding of the interests of the off spring, may be resolved by specific legislation pertaining to each country • Adequate study of the health risks of oocyte extraction, including long-term risks • Medical costs for adverse effects caused by the procedure • True informed consent from women who provide oocytes • Exploitation of poor women • No meaningful oversight