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IVF – ICSI in PCOS DIFFICULTIES AND SOLUTIONS Dr. Sharda Jain Dr. Jyoti Bhaskar Dr. Jyoti Agarwal Dr. Abhishek Parihar


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IVF – ICSI in PCOS DIFFICULTIES AND SOLUTIONS Dr. Sharda Jain Dr. Jyoti Bhaskar Dr. Jyoti Agarwal Dr. Abhishek Parihar

  1. 1. IVF – ICSI in PCOS DIFFICULTIES AND SOLUTIONS Dr. Sharda Jain Dr. Jyoti Bhaskar Dr. Jyoti Agarwal Dr. Abhishek Parihar
  3. 3. CHALLENGES IN IVF cycles in PCOS • Selection of patients of PCOS for IVF • Pre IVF work-up • Pre IVF Treatment • Which Protocol to be used & Rationale • Prevention of OHSS in PCOS patients • Challenges in titrating Gonadotropin dose rationale • Unpredictable & exaggerated ovarian response & OHSS prevention. • Early treatment of early and late OHSS • Increased risk of cycle cancellation • Increased risk of spontaneous pregnancy loss
  4. 4. OVERVIEW of PPT • Selection of patients of PCOD for IVF • Pre IVF work-up • Pre IVF Treatment if any • Which Protocol to be used & Rationale • Challenges in titrating Gonadotropin dose rationale • Prevention of OHSS in our PCOS patients
  5. 5. CLASSIFICATION WHO • I - Hypothalamic pituitary failure (Hypogonadotrophic hypogonadism) Kallman’s, Sheehan’s, anorexia • II - Hypothalamic pituitary dysfunction (PCOS) • III – Ovulatory Failure – Hypergonadotrophic hypogonadism, Turner’s, autoimmune, mumps, RT, CT
  6. 6. DIAGNOSIS OF PCOS ( Rotterdam’s Criteria) Diagnosis of PCOS is made in the prsence of at least two of the following three criteria, when congenital adrenal hyperplasia (CAH), androgen- screening tumors, or Cushing syndrome have been excluded. • Oligo – Ovulation or Anovulation • Clinical / biochemical evidence of hyperandrogenism • Polycystic ovarian on ultrasonography (>12 small antral follicle in an ovary)
  7. 7. Selection of PCOS Patients for IVF Patients who fail to conceive following the use of •First & second Line Ovulation Induction Medications and / or • Laparoscopic Ovarian diatheramy or • THREE IUI in conjunction with ovulation induction
  8. 8. It is Good to RULE OUT Diagnosis of following before start of IVF Treatment Ensure good general health of women to ensure safe pregnancy in case of success BMI Pre-Diabetes Hypertension Fatty Liver Diabetes type II Hyperlipidemia Insulin Resistance Hypo-Thyroidism Metabolic Syndrome Vitamin-D Deficiency
  10. 10. Pre. IVF Considerations in PCOS Patients • Weight Loss In Overweight Women * Structured weight loss * Place of Orlistat * Bariatric Surgery • Metformin • OCP Prior to IVF • Hysteroscopy & EB to R/O TB
  11. 11. Obesity 60 – 65 % of our patients are over weight or obese Over weight BMI > 24 Obese BMI > 27 Morbid Obesity is >32.5 Literature shows that patients of BMI > 29, they are likely to take longer to conceive. So it is good to lose weight by structured weight loss programme and not be allowed to do on their own It is our policy not to take patients over BMI 30
  12. 12. BMI Cutoff for INDIAN -2.5 in Each Category BMI Cutoff Weight Status Comments <18.5 UNDERWEIGHT Being underweight also puts you at risk for developing many health problems. 18.5 - 23.9 HEALTHY WEIGHT RANGE Your weight is within normal range. You can continue to keep a healthy weight through physical activity and healthy eating. Keep up with the good work! 24 - 26.9 OVERWEIGHT Being overweight can put you at risk for developing many chronic diseases >27 OBESE Obesity increases risks for developing many chronic diseases such as heart disease and diabetes, and decreases overall quality of life.
  13. 13. FAT DISTRIBUTION –CENTRAL OBESITY android, APPLE SHAPE Central Obesity is High Risk For Co-Morbidities / Complications PEAR SHAPE Even if the BMI is the normal central obesity judged by size of the waist is detrimental to conception
  14. 14. Good to Take Patients Below 80kg
  15. 15. Lifestyle Modifications Before the initiation of IVF, importance of lifestyle modification should be stressed, particularly • Weight loss (Structured weight loss programme is always better) • Increase Exercise • Smoking Cessation & • Reduced Alcohol consumption
  16. 16. PHARMACOTHEREPY for Weight Loss All drugs are banned except Orlistat . This decreases the absorption of fat by 30% but also decreases absorption of fat – soluble vitamins, such as vitamine D We recommend multivite containing Vitamin – D either before or after orlistat treatment. It is not advised in patients with cholestasis and malabsorption syndrome
  17. 17. Bariatric Surgery A serious approach to serious problem We try to motivate patients once the BMI is 32 + LAP Adjustable Gastric Banding Given - up procedure in India SLEEVE Gastrectomy & Gastric Bypass surgery are the only alternative & done routinely Weight Loss of 40-50 kg is Expected
  18. 18. Pre - Pregnancy counseling after Bariatric surgery When ever possible, pregnancy should be delayed TILL WEIGHT LOSS STABILIZES for 12-24 months, use active contraception
  19. 19. Nutrient Supplements After Bariatric Sx (In Non-Pregnant) Supplement Dose per day Multivit 1-2 Calcium Citrate 1200-2000 mg Vit-D 400-800 IU Folic Acid 400 ug Elemental Iron 40-65 mg Vit-B12 350 ug orally or 1000 ug IM/month
  20. 20. Role of Metformin in IVF ADVANTAGES ESHRE and ASRM international workshop concluded that metformin should no longer be considered as a first – line medication in PCOS,anovulatory infertility and should be restricted to those women with demonstrable glucose intolerance. We also use It in patients with BMI > 30 The use of Metformin to decrease Incidence of OHSS in high responders is known to be beneficial, so it should be started a month or two prior to IVF
  21. 21. DOSE OF METFORMIN • DOSE : 1500 mg in divided doses • GI Side-effects are known • Risk of Lactic acidosis is minimum in non-diabetic women • However serum creatinine, SGOT/SGPT must be done
  22. 22. Laparoscopic Ovarian Drilling as an Adjunct to I.V.F. • May decrease the frequency and severity of OHSS in women with a previous episode of OHSS • May facilitate ovarian stimulation in the brittle PCOS patient (Ferraretti, Fertil Steril 2001)
  23. 23. OCP We continue to use it as it gives rise to : • Similar size of cohort follicles • Decreases LH levels
  24. 24. Our Aim & Which Protocol Should Be AIM - Optimal Ovarian Stimulation for Used in PCOS Patients IVF AIM : • Avoid understimulation • Avoid overstimulation • Minimize cycle cancellation • Minimize if not avoid altogether OHSS OOVVEERR SSTTIIMMUULLAATTIIOONN OOPPTTIIMMAALL SSTTIIMMUULLAATTIIOONN UUNNDDEERR SSTTIIMMUULLAATTIIOONN 150 187.5 112.5
  25. 25. WHICH PROTOCOL LITERATURE NOW SHOWS Pregnancy Rate Same in Agonist Long Protocol & Antagonist Protocol
  26. 26. CDC Report also shows 2008 Pregnancy Rate same in FRESH / FROZEN – thawed cycles
  27. 27. DEVROEY 2011 Mortality due to critical OHSS in IVF is Unacceptable
  28. 28. INCIDENCE of OHSS MILD – 33% Now Omitted in IVF Cycles MODERATE – 3-6% SEVERE – 2% Critical – 0.1 – 0.2% WE SHOULD ALL AIM FOR OHSS FREE IVF PREGNANCY Dr Razia S 28
  29. 29. We have to be careful…. PRIMARY RISK FACTORS for OHSS WHO are AT HIGH RISK BEFORE OI – in IVF Young patients Lean women Polycystic Ovarian PCOS Previous OHSS Easily Recognized SENSITIVE OVARIES AFC over 16 (Both Ovaries) (>- 10 follicle of 4-10mm in each ovary) • Raised AMH 25.0 pmol/l for a high response ( >6 ng/ml
  30. 30. Optimal IVF Cycle Management in the PCOS Patient • Careful titration of the gonadotropin dose • Measures to prevent OHSS – GnRHa for triggering final oocyte maturation – Cabergoline before ovulation trigger – Single Blasto cysts transfer vs Cryopreservation of all embryos – Coasting ???
  31. 31. Clinics providing ovarian stimulation with Gonadotrophins for IUI/IVF - Protocol should be in place for preventing, diagnosing and managing Ovarian Hyperstimulation Syndrome Nice Guideline 2004
  32. 32. Proposed Protocol of Zero% OHSS STEPS 3 Steps • The use of the GnRH antagonist protocol for OI instead of long protocol • Ovulation Triggering with GnRH agonist Instead of HCG trigger • Cryopreservation of all oocytes and embryos ↓ ET in frozen – thawed cycle I II III
  33. 33. STEP III CRYO PRESERVATION of oocytes & embryo A valuable modality… But Skill - is the key Oocyte / embryo vitrification – ↑ P.R. (40% - 80%) ↓ Severe OHSS to 0% Results better than COASTING Ethical Issue of freezing embryo
  34. 34. GnRH Antagonist Flexible Protocol Day 2 Follicle size 14 mm Or 6th Day HCG OPU GnRH antagonist Follicle size 18-20 mm & endometrium 08 mm+ Day 1 REC FSH / HMG Blood Test – LH, E2 Progesterone TVS Injection Rec FSH / HMG 34 and half hrs later
  35. 35. Protocols Used at Lifecare IVF & Surrogacy Centre • Gonadotrophin of choice …. FSH at least for first four days • Dose: Varies between 150-300units Depends on BMI, AFC, AMH • Change over to HMG after 4-6 days of FSH
  36. 36. ANTAGONIST PROTOCOL We have given up Agonist protocol in PCOD patients • All PCOD patients are taken for antagonist protocol to minimise risk of OHSS • We freeze all embryos & do ET in next cycle or do blastocyst transfer Fragmentation of IVF
  37. 37. Predictors of Ovarian Reserve Before Starting IVF Protocol CHARACTERISTICS FOR A GOOD MARKER AGE AMH FSH AFC PREDICTION OF POOR RESPONSE + +++ ++ ++ + PREDICTION OF HYPER – RESPONSE + +++ _ ++ COST +++ _ _ _ *FSH and antral follicle count (AFC) are not informative in patients on OCP or GnRH agonist treatment. Moreover the count of antral follicle may be difficult in women with ovarian cysts or with previous pelvic surgeries
  38. 38. How we modify FSH dose according to AMH nmol/L Negligible < 1 Low 1 - 2 Normal 2 - 6 High (over 6) Very poor responder High cycle cancellation Treatment Donor Egg IVF Poor/ average responder High dose FSH – 300 IU Good Responder FSH dose 225 Hyper – responder/ OHSS Low dose FSH 150 IU Significance of AMH levels prior to IVF
  40. 40. ANTAGONIST PROTOCOL • Flexible Protocol Antagonist added when lead follicle is 14mm. • Monitoring is done by Transvaginal Sonography Alone • Trigger is given when at least 4 -5 follicles are 18-20mm.
  41. 41. TRIGGER • In our experience, minimum of 10 days of stimulation is essential to get mature oocytes. • Trigger used is 1. Agonist trigger 2. Recombinant HCG trigger 3. HCG: 5000 -10000 units • OPU done 34 ½ hours after trigger
  42. 42. Adjuvant Therapy to Prevent OHSS • Metformin • Cabergolin 0.5gm OD (to be started before giving the HCG trigger)
  43. 43. METFORMIN AND OHSS • Two meta-analyses found that metformin co-administration in PCOS women undergoing IVF decreased the incidence of OHSS • The beneficial effect was observed in all RCTs regardless of duration and dosage of metformin • Number of oocytes collected and peak E2 levels were unaffected by metformin Costello et al. 2006 Hum. Rep. 21(6);1387 – 1399 Moll et al. 2007 Hum. Reprod. Update 13(6); 527 - 537
  44. 44. GGnnRRHHaa TTrriiggggeerriinngg ooff OOooccyyttee MMaattuurraattiioonn--hhiinnttss aanndd ttiippss • Lower implantation rates reported in some studies may be attributed to the luteolytic effect of the GnRHa • Titration of the luteal phase support is important Both these issues are irrelevant as we do not do ET in stimulation Cycle
  46. 46. PROTOCOLS FOR FET • HRT CYCLE • GnRH Agonist Downregulated Cycle
  47. 47. FET PROTOCOL ET Follicle size 14 mm Or 6th Day HCG OPU GnRH antagonist Follicle size 18-20 mm & endometrium 08 mm+ OPU Rec FSH / HMG Blood Test – LH, E2 Progesterone TVS Injection Rec FSH / HMG 34 and half hrs later
  48. 48. FET Protocol Day 2 Day12 -14 B HCG ET ET 8- 12 mm Oestiadiol Valerable 2mg TDS Ultrasound , ET , Dopplers Injection Progesterone 100 mg i/m daily According to embryo dating S. Prg >0.5 ng/ml Cycle cacel
  49. 49. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) • D2 P (prog > 0.9 ng/ml cycle cancellation) 6mg E2 Valerate • Ultrasound Monitoring of endometrium. • D12-14 .. When ET > 8mm, Triple line, Doppler assessment… P measurement (for spontaneous ovulation) (prog>0.9 ng/ml cycle cancellation) • And Injectable Progesterone 100 mg daily till ET( LPS ) • ET according to Embryo dating • β-hCG after 15 days of ET • If pregnancy is present, E2 and P dose x2 is maintained until placental autonomy.
  50. 50. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) D21(Luteal) GnRH-a 10-14 days Day 2 ... Confirm Down regulation (P‹ 0.5ng, E2 ‹50pg, LH ‹ 5 mIU) did not occur, treatment is maintained for one more week and values are repeated After down regulation, the duration of proliferative phase which will last until the commencement of progesteron is approximately 12-20 days.
  51. 51. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) HRT is initiated after down regulation. D1-D8 E2 Valerate 2 mg D9-D12 4-6 mg D12-14 .. When ET > 8mm, Triple line, Doppler assessment… P measurement (for spontaneous ovulation) Injectable Progesterone 100 mg daily till ET ET according to Embryo dating Luteal Phase support with progesterones to continue β-hCG after 15 days of ET If pregnancy is present, E2 and P dose x2 is maintained until placental autonomy.
  53. 53. PROGESTERONE • Micronised Progesterone started on day of OPU • Mode of administration; -- Intramuscular for 14 days -- Vaginal Pessary 400 mg BD or TDS • Beta HCG estimation is done of day 15 of ET to confirm pregnancy • NO HCG TO BE GIVEN
  54. 54. OOuuttccoommee ooff IIVVFF iinn PPCCOOSS
  55. 55. • The outcome in terms of pregnancy and implantation rates is similar for patients with PCOS when compared with patients undergoing IVF for other indications. • There are some questions regarding oocyte and embryo quality in women with PCOS. This manifests itself in lower fertilization rate and decreased embryo quality in some studies. However, increased numbers of oocytes available for insemination or ICSI compensate for decreased fertilization rates and embryo quality. • More recent studies suggest higher cumulative conception rates in women with PCOS when compared with controls.
  56. 56. Pirinen et al’s study was designed to evaluate cumulative live birth rates after an in vitro fertilisation (IVF) programme in polycystic ovary syndrome (PCOS) women. Despite a lower pregnancy rate among women with PCOS versus controls, the cumulative baby take-home rate did not differ between the groups . The first cycle was the most successful cycle for living birth rate in PCOS group. One-third of PCOS women, who did not continue after unsuccessful treatment, had more miscarriage but not more OHSS compared to those who continued. They concluded - Although the baby take-home rate was similar among women with PCOS, and controls, the outcomes of consecutive cycles were not equal. Cumulative data give more realistic information than pooled cycles.
  57. 57. From Heijnen Hum Reprod Update 2006
  58. 58. OUR RESULTS 1. OHSS in PCOS has made us give - up long protocol. 2. We use antagonist cycles in all PCOS 3. Lately we freeze all embryos & transfer in next cycle. 4. Blastocyst if formed is transferred in the same cycle 5. Our pregnancy rate are much better in frozen cycle than fresh cycle in PCOS cases. 6. Success has improved from 25 – 30% to 50%
  59. 59. IN VITRO MATURATION (IVM) • IVM of the oocytes has evolved as an alternative in PCO patients, since it entails no stimulation. • Germinal vesicle stage oocytes are retrieved from antral follicles 2–10 mm diameter and IVM is performed until the M-II stage. • Advantages of IVM include simplification of treatment, avoidance of the side-effects associated with the use of gonadotrophins and thus reduction in treatment costs due to minimal amount of medication that is used. • IVM gives reasonable pregnancy rates in women with PCO, and should be considered as a treatment option in this group of women if they require treatment with IVF.
  60. 60. IVM We have no experience
  61. 61. IVM vs IVF in PCOS • Randomized trials do not exist • Comparative studies, non-comparative case series and randomized trials comparing different protocols of IVM show: – Favorable maturation, fertilization, pregnancy and live birth rates with IVM compared to IVF – The rate of congenital anomalies appear to be similar – Urgent randomized trials are needed
  62. 62. CONCLUSIONS • PCOS patient is the most difficult to treat with IVF • Cycle cancellation rates and risk of OHSS are higher • Fine tailoring of ovarian stimulation is necessary to avoid major complication like OHSS. • It is good to use antagonist protocol, give agonist trigger & freeze all embryos. • Treating IVF experts should be aware of the difficulties (OHSS & multiple pregnancies) and their remedies and solutions.
  63. 63. Conclusion PCOS infertile women have a better change of Conception today then they did a decade ago. To optimise results, however it is important that patients taken in IVF programme selected properly & counselled
  64. 64. ADDRESS 11 Gagan Vihar, Near Karkari Morh Flyover, Delhi - 51 CONTACT US 9650588339, 011-22414049, WEBSITE : E-MAIL ID & Thank You