Research & infertility


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How research can affect management of infertility? this talk will illustrate this impact in a simple way

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Research & infertility

  1. 1. Impact of Research On Infertility Treatment Hesham Al-Inany, M.D, PhD
  2. 2. How to make decision? • Between two drugs • Between surgery and medical therapy • safety of intervention • Etc
  3. 3. Answer Clinical Expertise Research Evidence Patient Preferences
  4. 4. The Hierarchy Of Research Research ComparativeDescriptive ExperimentalObservational RCT Non-RCT Cohort Case-control Cross-sectional Case report Case series Prevalence Investigators Do Not Assign The Intervention Investigators Assign The Intervention No Control Group Control Group
  6. 6. Case Report Describe a rare or unexpected condition warnings system (new disease or unexpected effect of a drug).
  7. 7. A 28-year-old woman admitted to the emergency department in coma after a closed head injury was found to have a positive serum beta-HCG level of 27 mIU/mL. She remained comatosed for more than 240 days. At 36 to 37 weeks' gestation, she had contractions and elevations in her blood pressure. A healthy female infant was born by an operative vaginal delivery with Apgar scores of 9 and 9. Hnat MD, Sibai BM, Kovilam O. An initial Glasgow score of 4 and Apgar scores of 9 & 9: a case report of a pregnant comatose woman. Am J Obstet Gynecol. 2003;189(3):877-9
  8. 8. Case Series Description of a number of subjects receiving a new therapy or having a particular disease or condition.
  9. 9. 568 endometrial ablations were performed. The mean operative time was 32.5 minutes & hospital stay was 8 hours. Postoperatively 4 patients developed pulmonary edema, & 1 developed endometritis…………… Baggish MS, Sze EH. Endometrial ablation: a series of 568 patients treated over an 11-year period. Am J Obstet Gynecol. 1996 Mar;174(3):908-13.
  12. 12. Prospective Retrospective Observational Studies Exposure Study Direction Outcome Exposure Outcome Cohort Study Case Control Study Outcome Exposure Cross Sectional Study
  13. 13. [B] OBSERVATIONAL STUDIES: I. Cohort Study
  14. 14. Objective: To investigate the potential long term consequences of the use of oral contraceptives. Design: 122,000 married registered nurses in 1976 were enrolled in the study to be followed prospectively with questionnaires mailed every 2 years. Population was divided into OCs users & nonusers Outcome: The use of OCs have been related to the development of a wide range of chronic illnesses among women (DVT, Breast cancer, …..) The Nurses health study
  15. 15. Cohort Study A group of subjects with the condition of interest (exposed) and others without (controls), are followed-up in time until the occurrence of the outcome. The frequency of the outcome in the two groups is then compared.
  16. 16. Exposed Exposure Outcome Cohort Study Risk of Outcome Risk of Outcome Un Exposed Prospective Prospective Prospective Relative Risk
  17. 17. 17 Clinical scenario • Pat.: woman, 32 years, oligomenorrhea • Complaint: primary subfertility x 2 yrs • Interventions: Clomiphene citrate 50 mg dd • Question: (ab)normal baby?
  18. 18. 18 PICO Patient woman 32 years, primary subfertility, oligomenorrhea Intervention clomiphene citrate pregnancy Comparison non-clomiphene pregnancy Outcome congenital malformations newborn
  19. 19. 19 Cohort study children congenital malformations % malf. CC conception 935 21 2.2 % Spontaneous 30.033 520 1.7 % Congenital malformations of newborn infants after clomiphene-induced ovulation. Kurachi K, Aono T, Minagawa J, Miyake A. Fertil Steril 1983 Aug;40(2):187-9
  20. 20. [B] OBSERVATIONAL STUDIES: II. Case-Control Study
  21. 21. RetrospectiveExposure Outcome Case Control Study Cases Controls Retrospective Odds of Exposure Odds of Exposure Retrospective Odds Ratio
  22. 22. 22 Fertility drugs and ovarian cancerWhittemore et al. 1992 • Study: Case-control • Case: ovary Ca • Control: no ovary Ca • Exposure: “fertility drugs” • Conclusion: risk + Venn et al. 1999 • Study: Cohort • Case: IVF indication, IVF treatment • Control: IVF indication, no IVF treatment • Outcome: ovary Ca • Conclusion: risk =
  23. 23. 23 Whittemore fertility drugs ovarian cancer patients Venn subfertility patients ovarian cancer
  24. 24. [B] OBSERVATIONAL STUDIES: III. Snap Shot In Time Cross-Sectional Study
  25. 25. Outcome Exposure Cross Sectional Study % Outcome Cases % Outcome Controls
  26. 26. Objective: To determine whether parameters of ovarian blood flow distinguish between women with who ovulate and those who do not. Design: a cross-sectional comparison of Ovarian blood flow by color Doppler in 12 ovulatory patients and 20 anovulatory ones. Conclusion: There are differences in ovarian blood flow in anovulatory versus ovulatory women. The alterations in blood flow in anovulatory women may contribute to or result from anovulation. Carmina E, Longo A, Lobo RA. Does ovarian blood flow distinguish between ovulatory and anovulatory patients with PCOS? Am J Obstet Gynecol. 2003 Nov;189(5):1283-6.
  27. 27. Cross Sectional Study A study in which the exposure and outcome are determined simultaneously. Cause and effect relationship can not be clearly established.
  28. 28. [C] EXPERIMENTAL STUDIES (Prospective)
  29. 29. Experimental Intervention Outcome R. C. T. % Outcome % Outcome Prospective Prospective ProspectiveControl Investigators are the ones who decide who takes the intervention and who takes the control one.
  30. 30. Clinical Research Descriptive Study Is there a control group? Comparative Study NO YES Case report Did the investigators determine the intervention? Case series Prevalence study
  31. 31. Clinical Research Did the investigators determine the intervention? Randomized C. T. NO YES Non R.C.T. Observational Study Was the allocation at random NO YES Study Direction
  32. 32. Prospective Retrospective Clinical Research Exposure Study Direction Outcome Exposure Outcome Cohort Study Case Control Study Outcome Exposure Cross Sectional Study
  33. 33. The RCT The Gold Standard Of Clinical Research
  34. 34. 34 subfertile men with varicocele r1 r2 surgery no surgery pregnancy no pregn. pregnancy no pregn. Randomized clinical trial: varicocele Direction of research
  35. 35. When adequately conducted, it gives almost true results reflecting those in the true population. The RCT Why on the very top?
  36. 36. RCT Anatomy Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group OutcomeCompared
  37. 37. A golden rule in scientific research: - The intervention and the control groups should be: “similar in all aspects except for the intervention being studied” Importance Of Randomization
  38. 38. Group I CC + Metformin Group II CC 50% Pregnancy rate 35% Pregnancy rate Effect of CC + Metformin on infertile women with PCO
  39. 39. Group I Regimen I Group II Regimen II Lower BMD Higher BMD Effect of 2 HRT regimens on osteoporosis
  40. 40. Importance Of Randomization 2 0 1 5 1 0 5 0 Number of trials on TENS for pain relief Positive Negative Caroll et al., 1996 17 2 15 2 Non-randomized Randomized Non-randomization exaggerates the treatment effect
  41. 41. Methods Of Randomization • Tossing a coin • Rolling a dice • Random number tables • Computer generated random numbers
  42. 42. How To Design A Randomized Controlled Trial?
  43. 43. How To Design A RCT? Formulate the P. I. C. O. question P In infertile patients with PCO; I would metformin + clomiphene C compared to clomiphene alone O give a higher pregnancy rate?
  44. 44. Infertile Anovulatiory Population PCO Age >40 Diabetics Drilling Inclusion Criteria: Infertile anovulatory women with PCO. Exclusion Criteria:  age > 40  Had Drilling before  Diabetics  etc….
  45. 45. Infertile Anovulatiory Population PCO Age >40 Diabetics Drilling S Sample How To Design A RCT? Population
  46. 46. Primary (Main) Outcome: Pregnancy rate. Secondary Outcomes: Ovulation rate Side effects Abortion rate ….………….. How To Design A RCT? Outcome
  47. 47. How RCTs would be conducted A Model
  48. 48. Current practice of O.i in IUI Clomiphene Citrate hMG or FSH ______________________________________________
  49. 49. Emerging protocol: Reversed hMG/CC Clomiphene Citrate hMG or FSH ______________________________________________
  50. 50. • Some cases are CC resistant • about 25% of IUI cycles suffer from premature LH surge cancellation. WHY
  51. 51. If true : Double Benefits • The use of hMG at start of cycle for few days will avoid CC resistant cases • use of CC till the day of hCG will prevent LH surge
  52. 52. Rational • its antiestrogenic effect may suppress premature LH rise while maintaining a positive influence on ovarian follicle development if continued till the day of hCG
  53. 53. Outcome Parameters Primary outcome parameters Clinical pregnancy rate per women randomised (i.e. fetal heart pulsations demonstrated by TVS at 6 –7 weeks’ gestation) Premature LH Secondary outcome parameters E2 levels, Number of mature follicles Endometrial thickness On day of HCG
  54. 54. Sample size calculation • if premature LH surge rate among the hMG only group is 20%. • Assuming CC is effective by reducing it by 15% • Then hMG + CC group will be 5%, • So we will need to study 75 couples in each arm in order to reach a power of 80%.
  55. 55. Drop out cases • In order to compensate for discontinuations, we recruited 115 women in each arm • If more than 10% drop out cases, this would affect the validity of the trial
  56. 56. Novel protocol 75 IU/HMG CD3 CD?7 150 mg CC hCG IUI DF ≥ 18 mm 34-36h DF ≥ 12 mm
  57. 57. Control group 75 IU/HMG CD3 hCG IUI DF ≥ 18 mm CD7 34-36h DF ≥ 12 mm CD?7
  58. 58. Results Variable Group I (n=115) Group II (n=115) P value Age (years) 27.3 ± 4.7 28.4 ± 2.7 NS Duration of infertility (years) 3.1 ± 1.9 2.4 ± 1.6 NS Cause of infertility Mild male factor Unexplained infertility 61 (53%) 54 (47%) 58 (50.4%) 57 (49.6%) NS NS BMI 28.5 ± 1.6 28.1 ± 3.1 NS
  59. 59. Results (cont.) Variable Group I (n=110) Group II (n=107) P value Number of cancelled cycles Inadequate response Hyper response 5/110 4/5 1/5 8/107 6/8 2/8 NS NS NS Basal LH (mIU/mL) 6.4 ± 2.2 5.8 ± 2.4 NS Basal FSH (mIU/mL) 6.7 ± 2.5 7.2 ± 4.8 NS Days of stimulation 7.2 ± 1.8 8.1 ± 1.3 NS E2 at time of HCG (pg/mL) 360.3 ± 162.9 280 ± 110.0 P <.05*
  60. 60. Results (cont.) Variable HMG/CC (n=110) HMG (n=107) P value LH on day of hCG (miu/ml) for cases with no premature LH surge 7.3 ± 1.8 7.8 ± 2.2 NS Number of Follicles ≥ 16 mm 2.4 ± 0.97 1.3 ± 1.1 P < 0.05* Number of patients with premature LH surge 6 (5.45%) 17 (15.89%) P<0.001* End. Thickness (mm) 5.9 ± 0.7 4.9 ± 1.9 NS Clinical Pregnancy 11 (10%) 9 (8.41%) NS
  61. 61. For whom • This protocol is especially suitable for young women, for those with unexplained infertility or mild male factor i.e good responders
  62. 62. Postcoital Test • Do not use routine post-coital testing of cervical mucus as it has no predictive value for pregnancy rate
  63. 63. Medical and Surgical Management of Male Fertility Problems • Men with hypogonadotrophic hypogonadism should be offered gonadotrophins • Men with idiopathic semen abnormalities should not be offered anti-oestrogens, androgens, bromocriptine or kinin-enhancing drugs
  64. 64. Gonadotrophins for idiopathic male infertility: A Cochrane SR 2007 • Compared to placebo or no treatment, gonadotrophins showed a significantly higher pregnancy rate per couple randomized within three months of completing therapy ( OR 4.17, 95% CI 1.30 to 7.09).
  65. 65. ?? Varicocele • Do not offer surgery for varicocoele as there is no improvement in pregnancy rate (Evers & Collins Lancet 2006)
  66. 66. Factors affecting the outcome of in vitro fertilisation (IVF) I • Women with hydrosalpinges should have laparoscopic salpingectomy before IVF • Natural cycle IVF is not recommended except where Gn are contraindicated • Assisted hatching should not be routine excet for women above 38 years
  67. 67. ET • Embryo Transfer is as effective on days 2-3 or 5-6 • Do not replace if endometrium is <5 mm • Embryo transfer (ET) should be ultrasound guided
  68. 68. Post ET • Bed rest post-transfer does not help • Luteal support improves pregnancy rate • Do not routinely use hCG through the luteal phase
  69. 69. Why to perform RCT For Tomorrow Better Health
  70. 70. THANK YOU