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Impact of Research
On Infertility Treatment
Hesham Al-Inany, M.D, PhD
How to make decision?
• Between two drugs
• Between surgery and medical therapy
• safety of intervention
The Hierarchy Of Research
Case report Case series
Prevalence Investigators Do Not
Assign The Intervention
No Control Group Control Group
Describe a rare or unexpected condition
warnings system (new disease or unexpected effect of
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
Description of a number of subjects receiving a
new therapy or having a particular disease or
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
Baggish MS, Sze EH. Endometrial ablation: a series of 568
patients treated over an 11-year period. Am J Obstet Gynecol.
Objective: To investigate the potential long term
consequences of the use of oral
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 &
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
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.
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
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.
Cross Sectional Study
A study in which the exposure and
outcome are determined simultaneously.
Cause and effect relationship can not be
R. C. T.
Investigators are the ones who decide who
takes the intervention and who takes the
Is there a control group?
Case report Did the
Did the investigators determine the intervention?
Randomized C. T.
Was the allocation
Case Control Study
The Gold Standard Of
Randomized clinical trial: varicocele
Direction of research
When adequately conducted, it gives
almost true results reflecting those in the
Why on the very top?
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
CC + Metformin
50% Pregnancy rate 35% Pregnancy rate
Effect of CC + Metformin on infertile women
Lower BMD Higher BMD
Effect of 2 HRT regimens on osteoporosis
Importance Of Randomization
Number of trials on TENS for pain relief
Caroll et al.,
Non-randomization exaggerates the treatment
Methods Of Randomization
• Tossing a coin
• Rolling a dice
• Random number
• Computer generated
• Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
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
• its antiestrogenic effect may suppress
premature LH rise while maintaining a positive
influence on ovarian follicle development if
continued till the day of hCG
Primary outcome parameters
Clinical pregnancy rate per women randomised (i.e.
fetal heart pulsations demonstrated by TVS at 6 –7
Secondary outcome parameters
Number of mature follicles
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
150 mg CC
DF ≥ 18 mm
DF ≥ 12 mm
CD3 hCG IUI
DF ≥ 18 mm
DF ≥ 12 mm
Variable Group I
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
BMI 28.5 ± 1.6 28.1 ± 3.1 NS
Variable Group I
Number of cancelled cycles
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*
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
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
• This protocol is especially suitable for
young women, for those with
unexplained infertility or mild male factor
i.e good responders
• Do not use routine post-coital testing of
cervical mucus as it has no predictive value for
Medical and Surgical Management of Male
• Men with hypogonadotrophic hypogonadism
should be offered gonadotrophins
• Men with idiopathic semen abnormalities
should not be offered anti-oestrogens,
androgens, bromocriptine or kinin-enhancing
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).
• Do not offer surgery for varicocoele as there is
no improvement in pregnancy rate (Evers &
Collins Lancet 2006)
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
• Embryo Transfer is as effective on days 2-3 or
• Do not replace if endometrium is <5 mm
• Embryo transfer (ET) should be ultrasound
• Bed rest post-transfer does not help
• Luteal support improves pregnancy rate
• Do not routinely use hCG through the luteal