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