How research can affect management of infertility? this talk will illustrate this impact in a simple way

1. Impact of Research
On Infertility Treatment
Hesham Al-Inany, M.D, PhD

2. How to make decision?
• Between two drugs
• Between surgery and medical therapy
• safety of intervention
• Etc

3. Answer
Clinical
Expertise
Research
Evidence
Patient Preferences

4. The Hierarchy Of Research
Research
ComparativeDescriptive
ExperimentalObservational
RCT
Non-RCT
Cohort
Case-control
Cross-sectional
Case report Case series
Prevalence Investigators Do Not
Assign The Intervention
Investigators Assign
The Intervention
No Control Group Control Group

5. [A]
DESCRIPTIVE STUDIES

6. Case Report
Describe a rare or unexpected condition
warnings system (new disease or unexpected effect of
a drug).

7. A 28-year-old woman admitted to the
emergency department in coma after a
closed head injury was found to have a
positive serum beta-HCG level of 27 mIU/mL.
She remained comatosed for more than 240
days. At 36 to 37 weeks' gestation, she had
contractions and elevations in her blood
pressure. A healthy female infant was born
by an operative vaginal delivery with Apgar
scores of 9 and 9.
Hnat MD, Sibai BM, Kovilam O. An initial Glasgow score of 4
and Apgar scores of 9 & 9: a case report of a pregnant
comatose woman. Am J Obstet Gynecol. 2003;189(3):877-9

8. Case Series
Description of a number of subjects receiving a
new therapy or having a particular disease or
condition.

9. 568 endometrial ablations were performed.
The mean operative time was 32.5 minutes &
hospital stay was 8 hours.
Postoperatively 4 patients developed
pulmonary edema, & 1 developed
endometritis……………
Baggish MS, Sze EH. Endometrial ablation: a series of 568
patients treated over an 11-year period. Am J Obstet Gynecol.
1996 Mar;174(3):908-13.

10. COMPARATIVE
STUDIES

11. [B]
OBSERVATIONAL
STUDIES

12. Prospective
Retrospective
Observational Studies
Exposure
Study Direction
Outcome
Exposure Outcome
Cohort Study
Case Control Study
Outcome
Exposure
Cross Sectional
Study

13. [B]
OBSERVATIONAL
STUDIES:
I. Cohort Study

14. Objective: To investigate the potential long term
consequences of the use of oral
contraceptives.
Design: 122,000 married registered nurses in
1976 were enrolled in the study to be followed
prospectively with questionnaires mailed
every 2 years.
Population was divided into OCs users &
nonusers
Outcome: The use of OCs have been related to
the development of a wide range of chronic
illnesses among women (DVT, Breast cancer,
…..)
The Nurses health study

15. Cohort Study
A group of subjects with the condition of
interest (exposed) and others without
(controls), are followed-up in time until the
occurrence of the outcome.
The frequency of the outcome in the two
groups is then compared.

16. Exposed
Exposure Outcome
Cohort Study
Risk of
Outcome
Risk of
Outcome
Un
Exposed
Prospective
Prospective
Prospective
Relative Risk

17. 17
Clinical scenario
• Pat.: woman, 32 years, oligomenorrhea
• Complaint: primary subfertility x 2 yrs
• Interventions: Clomiphene citrate 50 mg dd
• Question: (ab)normal baby?

18. 18
PICO
Patient
woman 32 years, primary
subfertility, oligomenorrhea
Intervention clomiphene citrate pregnancy
Comparison non-clomiphene pregnancy
Outcome congenital malformations newborn

19. 19
Cohort study
children
congenital
malformations
% malf.
CC conception 935 21 2.2 %
Spontaneous 30.033 520 1.7 %
Congenital malformations of newborn infants after clomiphene-induced ovulation.
Kurachi K, Aono T, Minagawa J, Miyake A. Fertil Steril 1983 Aug;40(2):187-9

20. [B]
OBSERVATIONAL
STUDIES:
II. Case-Control Study

21. RetrospectiveExposure Outcome
Case Control Study
Cases
Controls
Retrospective
Odds of
Exposure
Odds of
Exposure
Retrospective
Odds Ratio

22. 22
Fertility drugs and ovarian cancerWhittemore et al. 1992
• Study: Case-control
• Case: ovary Ca
• Control: no ovary Ca
• Exposure:
“fertility drugs”
• Conclusion: risk +
Venn et al. 1999
• Study: Cohort
• Case: IVF indication, IVF
treatment
• Control:
IVF indication,
no IVF treatment
• Outcome: ovary Ca
• Conclusion: risk =

23. 23
Whittemore
fertility drugs ovarian cancer patients
Venn
subfertility patients ovarian cancer

24. [B]
OBSERVATIONAL
STUDIES:
III. Snap Shot In Time
Cross-Sectional Study

25. Outcome
Exposure
Cross Sectional
Study
% Outcome
Cases
% Outcome
Controls

26. Objective: To determine whether parameters of
ovarian blood flow distinguish between women
with who ovulate and those who do not.
Design: a cross-sectional comparison of Ovarian
blood flow by color Doppler in 12 ovulatory
patients and 20 anovulatory ones.
Conclusion: There are differences in ovarian
blood flow in anovulatory versus ovulatory
women. The alterations in blood flow in
anovulatory women may contribute to or result
from anovulation.
Carmina E, Longo A, Lobo RA. Does ovarian blood flow
distinguish between ovulatory and anovulatory patients with
PCOS? Am J Obstet Gynecol. 2003 Nov;189(5):1283-6.

27. Cross Sectional Study
A study in which the exposure and
outcome are determined simultaneously.
Cause and effect relationship can not be
clearly established.

28. [C]
EXPERIMENTAL
STUDIES
(Prospective)

29. Experimental
Intervention Outcome
R. C. T.
% Outcome
% Outcome
Prospective
Prospective
ProspectiveControl
Investigators are the ones who decide who
takes the intervention and who takes the
control one.

30. Clinical Research
Descriptive Study
Is there a control group?
Comparative Study
NO YES
Case report Did the
investigators
determine the
intervention?
Case series
Prevalence study

31. Clinical Research
Did the investigators determine the intervention?
Randomized C. T.
NO YES
Non R.C.T.
Observational
Study
Was the allocation
at random
NO YES
Study Direction

32. Prospective
Retrospective
Clinical Research
Exposure
Study Direction
Outcome
Exposure Outcome
Cohort Study
Case Control Study
Outcome
Exposure
Cross Sectional
Study

33. The RCT
The Gold Standard Of
Clinical Research

34. 34
subfertile
men with
varicocele
r1 r2
surgery
no
surgery
pregnancy
no pregn.
pregnancy
no pregn.
Randomized clinical trial: varicocele
Direction of research

35. When adequately conducted, it gives
almost true results reflecting those in the
true population.
The RCT
Why on the very top?

36. RCT Anatomy
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
OutcomeCompared

37. A golden rule in scientific research:
- The intervention and the control
groups should be:
“similar in all aspects except for the
intervention being studied”
Importance Of Randomization

38. Group I
CC + Metformin
Group II
CC
50% Pregnancy rate 35% Pregnancy rate
Effect of CC + Metformin on infertile women
with PCO

39. Group I
Regimen I
Group II
Regimen II
Lower BMD Higher BMD
Effect of 2 HRT regimens on osteoporosis

40. Importance Of Randomization
2
0
1
5
1
0
5
0
Number of trials on TENS for pain relief
Positive Negative
Caroll et al.,
1996
17
2
15
2
Non-randomized Randomized
Non-randomization exaggerates the treatment
effect

41. Methods Of Randomization
• Tossing a coin
• Rolling a dice
• Random number
tables
• Computer generated
random numbers

42. How To Design A
Randomized
Controlled Trial?

43. How To Design A RCT?
Formulate the P. I. C. O. question
P In infertile patients with PCO;
I would metformin + clomiphene
C compared to clomiphene alone
O give a higher pregnancy rate?

44. Infertile
Anovulatiory
Population
PCO
Age >40
Diabetics Drilling
Inclusion Criteria:
Infertile anovulatory
women with PCO.
Exclusion Criteria:
 age > 40
 Had Drilling before
 Diabetics
 etc….

45. Infertile
Anovulatiory
Population
PCO
Age >40
Diabetics Drilling
S Sample
How To Design A RCT?
Population

46. Primary (Main) Outcome:
Pregnancy rate.
Secondary Outcomes:
Ovulation rate
Side effects
Abortion rate
….…………..
How To Design A RCT?
Outcome

47. How RCTs would be
conducted
A Model

48. Current practice of O.i in IUI
Clomiphene Citrate
hMG or FSH
______________________________________________

49. Emerging protocol: Reversed hMG/CC
Clomiphene Citrate
hMG or FSH
______________________________________________

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

51. 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

52. 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

53. 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

54. 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%.

55. 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

56. Novel protocol
75 IU/HMG
CD3 CD?7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
DF ≥ 12 mm

57. Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
DF ≥ 12 mm
CD?7

58. 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

59. 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*

60. 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

61. For whom
• This protocol is especially suitable for
young women, for those with
unexplained infertility or mild male factor
i.e good responders

62. Postcoital Test
• Do not use routine post-coital testing of
cervical mucus as it has no predictive value for
pregnancy rate

63. Medical and Surgical Management of Male
Fertility Problems
• Men with hypogonadotrophic hypogonadism
should be offered gonadotrophins
• Men with idiopathic semen abnormalities
should not be offered anti-oestrogens,
androgens, bromocriptine or kinin-enhancing
drugs

64. Gonadotrophins for idiopathic male
infertility: A Cochrane SR 2007
• Compared to placebo or no treatment,
gonadotrophins showed a significantly higher
pregnancy rate per couple randomized within
three months of completing therapy ( OR 4.17,
95% CI 1.30 to 7.09).

65. ?? Varicocele
• Do not offer surgery for varicocoele as there is
no improvement in pregnancy rate (Evers &
Collins Lancet 2006)

66. Factors affecting the outcome of in vitro
fertilisation (IVF) I
• Women with hydrosalpinges should have
laparoscopic salpingectomy before IVF
• Natural cycle IVF is not recommended except
where Gn are contraindicated
• Assisted hatching should not be routine excet for
women above 38 years

67. ET
• Embryo Transfer is as effective on days 2-3 or
5-6
• Do not replace if endometrium is <5 mm
• Embryo transfer (ET) should be ultrasound
guided

68. Post ET
• Bed rest post-transfer does not help
• Luteal support improves pregnancy rate
• Do not routinely use hCG through the luteal
phase

69. Why to perform RCT
For Tomorrow Better
Health

70. THANK
YOU