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

PROGNOSIS

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 : kaainih@yahoo.com