Impact of ResearchOn Infertility Treatment

Hesham Al-Inany, M.D, PhD

How to make decision?

• Between two drugs • Between surgery and medical therapy• safety of intervention• Etc

Answer

Clinical Expertise

Research Evidence

Patient Preferences

The Hierarchy Of ResearchResearch

ComparativeDescriptive

ExperimentalObservational

RCT

Non-RCT

Cohort

Case-control

Cross-sectional

Case report Case series

Prevalence Investigators Do NotAssign The Intervention

Investigators AssignThe Intervention

No Control Group Control Group

[A]DESCRIPTIVE STUDIES

Case Report

Describe a rare or unexpected condition warnings system (new disease or unexpected effect of

a drug).

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

Case Series

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

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.

COMPARATIVE

STUDIES

[B]OBSERVATIONAL

STUDIES

Prospective

Retrospective

Observational Studies

Exposure

Study Direction

Outcome

Exposure Outcome

Cohort Study

Case Control Study

Outcome

ExposureCross Sectional

Study

[B] OBSERVATIONAL

STUDIES:I. Cohort Study

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 & nonusersOutcome: 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

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.

Exposed

Exposure Outcome

Cohort Study

Risk of Outcome

Risk of Outcome

UnExposed

Prospective

Prospective

Prospective

Relative Risk

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

PICO

Patient woman 32 years, primary subfertility, oligomenorrhea

Intervention clomiphene citrate pregnancy

Comparison non-clomiphene pregnancy

Outcome congenital malformations newborn

19

Cohort study

children

congenital malformatio

ns% 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

[B]OBSERVATIONAL

STUDIES:II. Case-Control Study

RetrospectiveExposure Outcome

Case Control Study

Cases

Controls

RetrospectiveOdds of Exposure

Odds of Exposure

Retrospective

Odds Ratio

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

Whittemore

fertility drugs ovarian cancer patients

Venn

subfertility patients ovarian cancer

[B] OBSERVATIONAL

STUDIES:III. Snap Shot In TimeCross-Sectional Study

Outcome

Exposure

Cross Sectional Study

% Outcome

Cases

% Outcome

Controls

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.

Cross Sectional Study

A study in which the exposure and outcome are determined simultaneously.

Cause and effect relationship can not be clearly established.

[C] EXPERIMENTAL

STUDIES(Prospective)

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.

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

Clinical ResearchDid the investigators determine the intervention?

Randomized C. T.

NO YES

Non R.C.T.

Observational Study

Was the allocation at random

NO YESStudy Direction

Prospective

Retrospective

Clinical Research

Exposure

Study Direction

Outcome

Exposure Outcome

Cohort Study

Case Control Study

Outcome

ExposureCross Sectional

Study

The RCTThe Gold Standard Of

Clinical Research

34

subfertile men withvaricocele

r1 r2

surgery

nosurgery

pregnancy

no pregn.

pregnancy

no pregn.

Randomized clinical trial: varicocele

Direction of research

When adequately conducted, it gives almost true results reflecting those in the true population.

The RCTWhy on the very top?

RCT Anatomy

Participants

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

O u

t c

o m

e

C

o m

p a

r e

d

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

Group I

CC + Metformin

Group II

CC

50% Pregnancy rate 35% Pregnancy rate

Effect of CC + Metformin on infertile women with PCO

Group I

Regimen I

Group II

Regimen II

Lower BMD Higher BMD

Effect of 2 HRT regimens on osteoporosis

Importance Of Randomization20

15

10

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

Methods Of Randomization

• Tossing a coin• Rolling a dice• Random number

tables• Computer generated

random numbers

How To Design A Randomized

Controlled Trial?

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?

InfertileAnovulatioryPopulation

PCO

Age >40

Diabetics Drilling

Inclusion Criteria:

Infertile anovulatory women with PCO.

Exclusion Criteria:

age > 40

Had Drilling before

Diabetics

etc….

InfertileAnovulatioryPopulation

PCO

Age >40

Diabetics Drilling

S Sample

How To Design A RCT?Population

Primary (Main) Outcome: Pregnancy rate.

Secondary Outcomes:Ovulation rateSide effectsAbortion rate….…………..

How To Design A RCT?Outcome

How RCTs would be conducted

A Model

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 parametersClinical pregnancy rate per women randomised (i.e. fetal

heart pulsations demonstrated by TVS at 6 –7 weeks’ gestation)

Premature LH

Secondary outcome parametersE2 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

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

Postcoital Test

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

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

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).

?? Varicocele

• 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

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

Post ET

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

phase

Why to perform RCT

For Tomorrow Better Health

For Tomorrow Better Health

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YOU