Evidence based infertility management
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Transcript of Evidence based infertility management
حمن الر الله بسمحيم الر
EVIDENCE BASED INFERTILITY TREATMENT
kasr al ainy school of MedicineCairo University
OUTLINE OF THIS TALK EBM : Introduction Model of creating evidence : RCT Model of creating evidence : Systematic
review Economic evaluation Prognosis Others
EBMClinical 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
EBM - WHAT IS IT?
Clinical Expertise
Research Evidence
Patient Preferences
EVIDENCE THAT MATTERS Meaning focusing the efforts to find evidence
that is more practical and useful to the patient
patient-oriented evidence
For infertility : Conception
IS ALL EVIDENCE CREATED EQUAL!!
RCT ANATOMYParticipants
R a
n d
o m
l y
A
s s
i g
n e
dIntervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
9
PICO
Patient woman, 34 years, 2ys 1ry unexplained inf.
Intervention IUI
Comparison wait
Outcome Pregnancy
months to ongoing pregnancy363024181260
Cum
ulat
ive o
ngoi
ng p
regn
ancy
rate
1,0
0,8
0,6
0,4
0,2
0,0
IUI-censoredexp-censoredIUIexp
exp=1, IUI=2
-- delayed treatment-- early treatment
RR: 1,0 (CI: 0,86-1,2)
N= 90 (71%)N= 90 (71%)
OUTLINE OF THIS TALK EBM : Introduction Model of creating evidence : RCT Model of creating evidence : Systematic
review Economic evaluation Prognosis Others
MODEL OF RCT : REVERSED HMG/CC PROTOCOL
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
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
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
NEW CONCEPT HAS TO BE TESTED
To study the effectiveness of Clomiphene citrate (CC) in preventing a premature LH surge in women undergoing IUI
RCT STUDY Setting: Kasr Al-AiniUniversity
hospital.Duration: January 2008 to July 2009 Registered :
(ACTRN12607000568415)
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
Each couple were included only once in this trial
in order to prevent a possible unit-of-analysis
error in interpreting the results
23
RCT ANATOMYParticipants
R a
n d
o m
l y
A
s s
i g
n e
dIntervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
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
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%)
NSNS
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
it may also be suitable for PCOS women to avoid the risk of severe OHSS
CONCLUSION
This is a novel protocol for O.I in IUI The protocol is simple, safe and appears to be
very cost effective.
JUST A QUESTION
Would u change ur O.I from CC/hMG to hMG/CC ??
OUTLINE OF THIS TALK EBM : Introduction Model of creating evidence : RCT Model of creating evidence : Systematic
review Economic evaluation prognosis Others
MODEL OF SR : GN
TYPES OF GONADOTROPIN MARKETED Human derived gonadotropins –
hMG,HP-hMG, HP-FSH
Recombinant human gonadotropins - follitropin alfa and follitropin beta,
THE IDEAL COH PROTOCOL .. ..
Improve pregnancy rate Reduce complications (OHSS) Consider the financial status
of patients.
Meta-analysis :Al-Inany et al, 2005
hMG was associated with a pooled 4 % increase in live birth rate when compared with rFSH (CI 1-7%)
RECENTLY RELEASED
GN: FINAL WORD
Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G Al-Inany
TYPES OF STUDIES RCTs only.
PRIMARY OUTCOMES: PATIENT ORIENTED Effectiveness:
live birth per woman or, if not reported, pregnancy ongoing beyond 20 weeks
Adverse:Rate of severe OHSS
SECONDARY OUTCOMES Effectiveness:
frozen-thawed embryo transfers Clinical pregnancy rate
Patient acceptability/satisfaction
Adverse:Multiple pregnancy rate Miscarriage rate per woman
42 RCTS
The total number of participants was 9606
RESULTS
There was no evidence of a difference in live birth or pregnancy ongoing beyond 20 weeks (28 trials, N=7339; OR 0.97, 95% CI 0.87 - 1.08) for rFSH versus urinary gonadotrophins.
Meaning 25% live birth rate (22-26% in different centers)
SEVERE OHSS There was no evidence of a difference in the
primary safety outcome OHSS (32 trials, N=7740; OR 1.18, 95% CI 0.86 -
1.61). Typical rate of 2% OHSS
47
HOW TO INTERPRET THE FIGURES! A benefit from recombinant FSH would be
displayed graphically to the left of the centre-line.
A benefit from hMG would be displayed graphically to the right of the centre-line
LIVE BIRTH RATE
OHSS
FRESH/FROZEN CYCLES
MULTIPLE PREGNANCY
MISCARRIAGE
CONCLUSION
Gonadotrophins are
Gonadotrophins are
Gonadotrophins
OUTLINE OF THIS TALK EBM : Introduction Model of creating evidence : RCT Model of creating evidence : Systematic
review Economic evaluation Prognosis Others
MODEL OF ECONOMIC ANALYSIS : GN
HOW TO MAKE DECISION ABOUT DRUG
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 PickupNo OHSS
Ovum PickupOHSS
9810
190
Fertilization& Transfer
No Oocytes
373+7=380
9437+183=9620
ClinicalPregnancy
-ve βHCG
2982
6638
OngoingPregnancy
Miscarriage
405
2577
3246
3392Continue
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
babi
lity
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
babi
lity
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
HCG VS. LH MONITORING If normoovulatory (e.g male factor), LH
monitoring is preferred If ovulatory dysfunction: hCG is preferred
Meta-analysis by Kosmos et al, 2007
OUTLINE OF THIS TALK EBM : Introduction Model of creating evidence : RCT Model of creating evidence : Systematic
review Economic evaluation Prognosis Others
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
IVF
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.
OTHERS
CABERGOLINE (CB2) THERAPY IN FACE 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.
DESTONIX FOR PREVENTION OF OHSS
Favours cabergoline Favours control
MALE INFERTILITY A Cochrane review of eight randomized
studies comparing varicocelectomy versus no varicocelectomy showed no benefit of varicocele treatment over expectant treatment or 1.10 (95% C.I 0.73-1.68) (Evers and Collins 2004).
KARYOTYPE Only in men with a severe male factor or
non-obstructive azoospermia, the man’s karyotype should be investigated
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
OVARIAN DRILLING The clear benefit and role of surgical therapy
in ovulation induction in women with PCOS is uncertain.
OVULATION : THE DILEMMA
IUI alone IUI + O.I
Timed intercourse O.I alone
IUI/CC VS IUI/GN
299 COUPLES(UNEXPLAINED INFERTILITY OR MALE SUBFERTILITY
Received daily 50 IU rec FSH from day 3
When follicles are 13-14 mm
Randomized
0.25 mg antagonist no antagonist
Clinical PR 12.2% Clinical PR 12.6%
NS
GnRH antagonists in IUI(Crosignani et al 2007)
148 151
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)
TYPE OF CATHETER FOR IUI
Catheter choice is not important and does not affect pregnancy outcome
Abousetta et al, 2006
REST AFTER IUI 15 minutes' immobilisation after insemination is
an effective modification. Immobilisation for 15 minutes should be offered to
all women treated with intrauterine insemination.
Custer et al, 2009
THE FUTURE OF IUI
IUI + O.I 10% success rate Cost 100$IVF + sET 25% success rate Cost 1000$NC IVF 20% success rate Cost 350$
PLEASE VOTE
IUI + O.I
IVF + sET
NC IVF
TUBAL SURGERY For women with mild tubal disease, tubal
surgery may be more effective than no treatment in centres where appropriate expertise is available.
HYDROSALPINX
Women with ultrasound visible hydrosalpinges should be offered salpingectomy before IVF because this improves the chance of a live birth
ENDOMETRIOSIS Medical treatment of minimal and mild
endometriosis does not enhance fertility in subfertile women and should not be offered
ENDOMETRIOMA Women with ovarian endometriomas should
be offered laparoscopic cystectomy because this improves the chance of pregnancy.
LIVE BIRTH RATE AFTER IVF FOR UNEXPLAINED INFERTILITY: COCHRANE REVIEW (PANDIAN ET AL 2005)
IVF vs. Expectant TT 2 trials OR 3.24; 95% CI 1.07-9.8
IVF vs. IUI 1 trial OR 1.96; 95% CI 0.88-4.4
IVF vs. COH/IUI 2 trials OR 1.15; 95% CI 0.55-2.4
IVF vs. GIFT 3 trials OR 2.57; 95% CI 0.93-7.08
ICSI VS IVF ICSI improves fertilisation rates compared to
IVF, but once fertilisation is achieved the pregnancy rate is no better than with in vitro fertilisation
GROWTH HORMONE
ET Women undergoing in vitro fertilisation
treatment should be offered ultrasound-guided embryo transfer because this improves pregnancy rates.
ET Bed rest of more than 20 minutes’ duration
following embryo transfer does not improve the outcome of in vitro fertilisation treatment
ASSISTED HATCHING Assisted hatching is not recommended
because it has not been shown to improve pregnancy rates
LUTEAL PHASE SUPPORT Women who are undergoing in vitro
fertilisation treatment using GnRHa for pituitary down-regulation should be informed that luteal support using progesterone improves pregnancy rates
RISK a possible association between ovulation
induction therapy and ovarian cancer remains uncertain.
Practitioners should confine the use of ovulation induction agents to the lowest effective dose and duration of use
CHILDREN Current research is broadly reassuring about
the health and welfare of children born as a result of assisted reproduction
THANK YOUDr. Hesham Al-Inany MD, PhDe-mail : [email protected]