This document discusses how evidence-based medicine is changing attitudes in gynecologic practice. It provides an example of a randomized controlled trial comparing two ovarian induction protocols for intrauterine insemination. The trial found that using clomiphene citrate along with human menopausal gonadotropin reduced the rate of premature luteinizing hormone surges compared to human menopausal gonadotropin alone, with no significant differences in clinical pregnancy rates. The document outlines how evidence from randomized trials, prognostic models, economic analyses and other studies can inform clinical decision-making and change practices in gynecology.

1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫الر‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬

2. EBM IS CHANGING
ATTITUDES IN
GYNECOLOGIC PRACTICE
kasr al ainy school of Medicine
Cairo University

3. WHY
 Clinical medicine is currently in transition
from experience-oriented practice to an
evidence-based one which requires the best
available evidence that answers our clinical
questions

4. FOR
 Better efficacy
 Better safety

5. HOW RCTS WOULD
CHANGE ATTITUDE

6. THE BEST MODEL
 Breech Trial

7. WHAT ABOUT GYNECOLOGY
 HRT: WHI study

8. OUTLINE OF THIS TALK
 Why changing attitude
 How RCTs would change attitude
 How Economic evaluation would change attitude
 How Prognosis evaluation would change attitude
 How Diagnostic tests would change attitude
 Others

9. MODEL IN DETAILS

10. CURRENT PRACTICE OF O.I IN IUI
Clomiphene Citrate
hMG or FSH
______________________________________________

11. EMERGING PROTOCOL: REVERSED HMG/CC
Clomiphene Citrate
hMG or FSH
______________________________________________

12. Some cases are CC resistant
 about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY

13. 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

14. 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

15. 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

16. 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%.

17. 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

18. 18
NEW CONCEPT HAS TO BE TESTED
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group

19. NOVEL PROTOCOL
75 IU/HMG
CD3 CD?7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
DF ≥ 12 mm

20. CONTROL GROUP
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
DF ≥ 12 mm
CD?7

21. 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

22. 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*

23. 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

24. FOR WHOM
 This protocol is especially suitable for young
women, for those with unexplained infertility or mild
male factor i.e good responders

25. EVIDENCE BASED PROGNOSIS
EVALUATION WOULD CHANGE
ATTITUDES

26. IN INFERTILITY: HOW TO ESTIMATE
 Chance to conceive naturally (home conception)
(treatment independent pregnancy)
 Chance to get pregnant after IVF

27. http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel

28. CLINICAL CONSEQUENCES
• Couples with prognosis <30% = IVF
• Couples with prognosis > 40% =
expectant management
• Couples with prognosis 30-40% = IUI

29. Lintsen, A.M.E. et al. Hum. Reprod. 2007

30. ACCORDINGLY
 classified for each woman into one of three groups,
i.e.,
 (i) predictor of good prognosis
 (ii) intermediate prognosis
 (iii) predictor of poor prognosis.

31. EVIDENCE BASED DIAGNOSIS WOULD
CHANGE YOUR ATTITUDE

32. BEST MODEL
 AMH
0 3 6 9 12
0
1
2
3
4
follicles
AMH

33. THE MOST RECENTLY EMERGING ATTITUDE
Cytogenetic Medicine

35. Embryo biopsy
Diagnosis
by
Transfer
2 unaffected
embryos
Fertilisation in vitro
(IVF or ICSI)
PCRFISH
Accurate
genetic
diagnosisAppropriate
Genetic
Counselling
DENATURING
ANNEALING
EXTENSION
PRIMER
TAQ
TAQ

36. DISEASE PREVENTION: IVF + PGD
Transfer only unaffected embryos to the woman
affected affectedaffected

37. DEMOGRAPHICS: THALASSEMIA
 Found most frequently
in the Mediterranean

38. haemophilia.
(a) Bleeding around elbow. (b) A retinal bleed. (c) Repeated bleeds into
joints produce severe arthritis.

39. USING FISH FOR PGD OF
X-LINKED DISORDERS
 Three colour FISH
 X ( green)
 Y (red)
 Chromosome 18 to
control for normal
diploidy
Male
Female

40. EVIDENCE BASED ECONOMIC
ANALYSIS WOULD CHANGE
ATTITUDE: GN

41. ECONOMIC ANALYSIS
 IVF/ICSI cycle, there are probabilities
- Pregnancy
- No pregnancy
- Abortion
- Repeat trial (usually up to 3 cycles)
- Stop trial

42. EXAMPLE : HMG, 1ST CYCLE
Start Cycle
10,000
Ovum Pickup
No OHSS
Ovum Pickup
OHSS
9810
190
Fertilization
& Transfer
No Oocytes
373+7=380
9437+183=9620
Clinical
Pregnancy
-ve βHCG
2982
6638
Ongoing
Pregnancy
Miscarriage
405
2577
3246
3392
Continue
Stop
Goal!
Therefore, for a cohort of 10,000 individuals the expected,
mathematically exact, outcome at the end of the 1st cycle is
380+405+3392 = 4177 patients who will restart the cycle, and
2577 who achieved ongoing pregnancy, and 3246 who gave
up on IVF from the first trial

43. MARKOV EV ANALYSIS: RFSH
rFSH: By the end of the 3rd cycle, the individual’s probability of ending at re-starting
the cycle is 6.6%, in ongoing pregnancy is 35.9%, and in discontinuing IVF is 57.5
%
% Start Cycle
% Pregnancy
% Stop IVF
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 stop
Cycle
Probability

44. MARKOV EV ANALYSIS: HMG
% Start Cycle
% Pregnancy
% Stop IVF
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 stop
Cycle
Probability
hMG: By the end of the 3rd cycle, the individual’s probability of ending at re-starting
the cycle is 6%, in ongoing pregnancy is 40.8%, and in discontinuing IVF is 53.2 %

45. HOW TO MAKE DECISION ABOUT DRUG

46. OTHERS

47. IN IVF
 Multiple pregnancy is no longer considered as a
bless
 Mild IVF
 Blastocyst transfer

48. DESTONIX FOR PREVENTION OF OHSS
 VEGF induces VP (vascular permeability)1,2
 Effects of Cb2 attributable to VEGF receptor dephosphorylation3
 Cb2 prevents VP in a dose dependent manner without affecting
angiogenesis and implantation in humans (n = 35 treated in face of
OHSS)4
 Cb2 reduced the amount of ascites, hemoconcentration and
incidence of moderate-severe OHSS5
 Cb2 0.5 mg x 8 days (total of 4 mgs) starting day of trigger
1) McClure, et al, Lancet, 1994; 344: 235-236.
2) Bates, et al, Vascul Pharmacol, 2002; 39: 225-237.
3) Gomez, et al, Endocrinology, 2006; 147: 5400-5411.
4) Alvarez, et al, Hum Reprod, 2007; 22: 3210-3214.
5) Alvarez, et al, J Clin Endocrinol Metab, 2007; 92: 2931-2937.

49. PCOS
 Metformin is not an effective addition to
clomifene citrate as the primary method of inducing
ovulation in women with PCOS
 It can be added in cases with CC resistant women
BMJ & NEJM studies

50. OVARIAN DRILLING
 Should be taken with cautious and better
discouraged because it may diminish ovarian
reserve.

51. HCG ADMINISTRATION VS. LUTEINIZING H
MONITORING FOR IUI TIMING (KOSMAS ET AL 2007).
2623 patients
1461 received hCG 1162 spontaneous LH surges
Significantly lower PR Significantly higher PR
(OR, 0.74; 95% CI 0.57-0.96)

52. ET
 Women undergoing in vitro fertilisation treatment
should be offered ultrasound-guided embryo
transfer because this improves pregnancy rates.

53. MODEL IN KASR EL-AINI
 Supernatent fluid of stem cells to improve embryo
quality (Salit et al, 2010)

54. WHY EVIDENCE BASED TREATMENT
For Tomorrow Better
Health

55. THANK YOU
Dr. Hesham Al-Inany MD, PhD
e-mail : hesham@khosoba.com