Our practice should be based on evidence but how to track all evidence: this talk may help in this

1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬

2. EVIDENCE BASED
INFERTILITY TREATMENT
kasr al ainy school of Medicine
Cairo University

3. OUTLINE OF THIS TALK
 EBM : Introduction
 Model of creating evidence : RCT
 Model of creating evidence : Systematic review
 Economic evaluation
 Prognosis
 Others

4. EBM
 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

5. EBM - WHAT IS IT?
Clinical
Expertise
Research
Evidence
Patient
Preferences

6. 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

7. IS ALL EVIDENCE CREATED EQUAL!!

8. RCT ANATOMY
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group

9. 9
PICO
Patient
woman, 34 years, 2ys 1ry
unexplained inf.
Intervention IUI
Comparison wait
Outcome Pregnancy

11. months to ongoing pregnancy
363024181260
Cumulativeongoingpregnancyrate
1,0
0,8
0,6
0,4
0,2
0,0
IUI-censored
exp-censored
IUI
exp
exp=1, IUI=2
-- delayed treatment
-- early treatment
RR: 1,0 (CI: 0,86-1,2)
N= 90 (71%)
N= 90 (71%)

12. OUTLINE OF THIS TALK
 EBM : Introduction
 Model of creating evidence : RCT
 Model of creating evidence : Systematic review
 Economic evaluation
 Prognosis
 Others

13. MODEL OF RCT :
REVERSED HMG/CC
PROTOCOL

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

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

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

17. 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

18. 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

19. NEW CONCEPT HAS TO BE TESTED
To study the effectiveness of Clomiphene
citrate (CC) in preventing a premature LH
surge in women undergoing IUI

20. RCT STUDY
Setting: Kasr Al-AiniUniversity hospital.
Duration: January 2008 to July 2009
Registered : (ACTRN12607000568415)

21. 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%.

22. 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. 23
RCT ANATOMY
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group

24. 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

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

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

27. 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

28. 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*

29. 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

30. 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

31. CONCLUSION
 This is a novel protocol for O.I in IUI
 The protocol is simple, safe and appears to be very cost
effective.

32. JUST A QUESTION
 Would u change ur O.I from CC/hMG to hMG/CC
??

33. OUTLINE OF THIS TALK
 EBM : Introduction
 Model of creating evidence : RCT
 Model of creating evidence : Systematic review
 Economic evaluation
 prognosis
 Others

34. MODEL OF SR : GN

35. TYPES OF GONADOTROPIN
MARKETED
 Human derived gonadotropins – hMG,HP-
hMG, HP-FSH
 Recombinant human gonadotropins
- follitropin alfa and follitropin beta,

36. THE IDEAL COH PROTOCOL .. ..
 Improve pregnancy rate
 Reduce complications (OHSS)
 Consider the financial status
of patients.

37. Meta-analysis :
Al-Inany et al, 2005

38. hMG was associated with a pooled 4 % increase
in live birth rate when compared with rFSH (CI 1-7%)

39. RECENTLY RELEASED

40. GN: FINAL WORD
Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane
Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G
Al-Inany

41. TYPES OF STUDIES
 RCTs only.

42. PRIMARY OUTCOMES: PATIENT ORIENTED
 Effectiveness:
live birth per woman or, if not reported, pregnancy
ongoing beyond 20 weeks
 Adverse:
Rate of severe OHSS

43. SECONDARY OUTCOMES
 Effectiveness:
frozen-thawed embryo transfers
 Clinical pregnancy rate
Patient acceptability/satisfaction
Adverse:
Multiple pregnancy rate
Miscarriage rate per woman

44. 42 RCTS
 The total number of participants was 9606

45. 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)

46. 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. 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

48. LIVE BIRTH RATE

49. OHSS

50. FRESH/FROZEN CYCLES

51. MULTIPLE PREGNANCY

52. MISCARRIAGE

53. CONCLUSION
Gonadotrophins
are
Gonadotrophins
are
Gonadotrophins

54. OUTLINE OF THIS TALK
 EBM : Introduction
 Model of creating evidence : RCT
 Model of creating evidence : Systematic review
 Economic evaluation
 Prognosis
 Others

55. MODEL OF ECONOMIC
ANALYSIS : GN

56. HOW TO MAKE DECISION ABOUT DRUG

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

58. 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

59. 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

60. 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 %

61. HOW TO MAKE DECISION ABOUT DRUG

62. 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

63. OUTLINE OF THIS TALK
 EBM : Introduction
 Model of creating evidence : RCT
 Model of creating evidence : Systematic review
 Economic evaluation
 Prognosis
 Others

64. PROGNOSIS

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

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

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

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

69. 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.

70. OTHERS

71. 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.

72. DESTONIX FOR PREVENTION OF OHSS
Favours cabergoline Favours control

73. 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).

74. KARYOTYPE
 Only in men with a severe male factor or non-
obstructive azoospermia, the man’s karyotype
should be investigated

75. 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

76. OVARIAN DRILLING
 The clear benefit and role of surgical therapy in
ovulation induction in women with PCOS is
uncertain.

77. OVULATION : THE DILEMMA
IUI alone IUI + O.I
Timed intercourse O.I alone

78. IUI/CC VS IUI/GN

79. 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

80. 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)

81. TYPE OF CATHETER FOR IUI
 Catheter choice is not important and does not affect
pregnancy outcome
Abousetta et al, 2006

82. 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

83. 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$

84. PLEASE VOTE
IUI + O.I
IVF + sET
NC IVF

85. TUBAL SURGERY
 For women with mild tubal disease, tubal surgery
may be more effective than no treatment in centres
where appropriate expertise is available.

86. HYDROSALPINX
 Women with ultrasound visible hydrosalpinges
should be offered salpingectomy before IVF
because this improves the chance of a live birth

87. ENDOMETRIOSIS
 Medical treatment of minimal and mild
endometriosis does not enhance fertility in
subfertile women and should not be offered

88. ENDOMETRIOMA
 Women with ovarian endometriomas should be
offered laparoscopic cystectomy because this
improves the chance of pregnancy.

89. 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

90. 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

91. GROWTH HORMONE

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

93. ET
 Bed rest of more than 20 minutes’ duration
following embryo transfer does not improve the
outcome of in vitro fertilisation treatment

94. ASSISTED HATCHING
 Assisted hatching is not recommended because it
has not been shown to improve pregnancy rates

95. 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

96. 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

97. CHILDREN
 Current research is broadly reassuring about the
health and welfare of children born as a result of
assisted reproduction

98. THANK YOU
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com