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ن ا حم الره حيم بسم الله لره
EBM IS CHANGING
ATTITUDES IN
GYNECOLOGIC PRACTICE
kasr al ainy school of MedicineCairo University
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
FOR
Better efficacy
Better safety
HOW RCTS WOULD
CHANGE ATTITUDE
THE BEST MODEL
Breech Trial
WHAT ABOUT GYNECOLOGY
HRT: WHI study
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
MODEL IN DETAILS
CURRENT PRACTICE OF O.I IN IUI
Clomiphene Citrate
hMG or FSH
______________________________________________
EMERGING PROTOCOL: REVERSED HMG/CC
Clomiphene Citrate
hMG or FSH
______________________________________________
Some cases are CC resistant
about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY
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
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
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
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%.
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
NEW CONCEPT HAS TO BE TESTEDParticipants
R a
n d
o m
l
y
A s
s i
g n
e
d
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
NOVEL PROTOCOL
75 IU/HMG
CD3 CD?7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
DF ≥ 12 mm
CONTROL GROUP
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
DF ≥ 12 mm
CD?7
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
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*
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
FOR WHOM
This protocol is especially suitable for young
women, for those with unexplained infertility or mild
male factor i.e good responders
EVIDENCE BASED PROGNOSIS
EVALUATION WOULD CHANGE
ATTITUDES
IN INFERTILITY: HOW TO ESTIMATE
Chance to conceive naturally (home conception)
(treatment independent pregnancy)
Chance to get pregnant after IVF
http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel
CLINICAL CONSEQUENCES
• Couples with prognosis <30% = IVF
• Couples with prognosis > 40% =
expectant management
• Couples with prognosis 30-40% = IUI
Lintsen, A.M.E. et al. Hum. Reprod. 2007
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.
EVIDENCE BASED DIAGNOSIS WOULD
CHANGE YOUR ATTITUDE
BEST MODEL
AMH
0 3 6 9 120
1
2
3
4
follicles
AMH
THE MOST RECENTLY EMERGING ATTITUDE
Cytogenetic Medicine
Embryo biopsy
Diagnosis
by
Transfer2 unaffected
embryos
Fertilisation in vitro
(IVF or ICSI)
PCRFISH
Accurate
genetic
diagnosisAppropriate
Genetic
Counselling
DENATURING
ANNEALING
EXTENSION
PRIMER
TAQ
TAQ
DISEASE PREVENTION: IVF + PGD
Transfer only unaffected embryos to the woman
affected affectedaffected
DEMOGRAPHICS: THALASSEMIA
Found most frequently
in the Mediterranean
haemophilia.
(a) Bleeding around elbow. (b) A retinal bleed. (c) Repeated bleeds into
joints produce severe arthritis.
USING FISH FOR PGD OF
X-LINKED DISORDERS
Three colour FISH
X ( green)
Y (red)
Chromosome 18 to control for normal diploidy
Male
Female
EVIDENCE BASED ECONOMIC
ANALYSIS WOULD CHANGE
ATTITUDE: GN
ECONOMIC ANALYSIS
IVF/ICSI cycle, there are probabilities
- Pregnancy
- No pregnancy
- Abortion
- Repeat trial (usually up to 3 cycles)
- Stop trial
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
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
Pro
ba
bili
ty
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
Pro
ba
bili
ty
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 %
HOW TO MAKE DECISION ABOUT DRUG
OTHERS
IN IVF
Multiple pregnancy is no longer considered as a
bless
Mild IVF
Blastocyst transfer
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.
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
OVARIAN DRILLING
Should be taken with cautious and better
discouraged because it may diminish ovarian
reserve.
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)
ET
Women undergoing in vitro fertilisation treatment
should be offered ultrasound-guided embryo
transfer because this improves pregnancy rates.
MODEL IN KASR EL-AINI
Supernatent fluid of stem cells to improve embryo
quality (Salit et al, 2010)
WHY EVIDENCE BASED TREATMENT
For Tomorrow Better
Health
