Cochrane

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Cochrane Systematic reviews:

for best practice in assisted

reproduction

Hesham Al-inany, PhDCairo University

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Our challenge as clinicians/fertility specialists…

Meeting our patients needs

Offering the best treatments to improve their

chances of conceiving

Being up to date

Delays in dissemination

Competing knowledge sources

Medical journals – single studies, reviews

Conferences

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30-40% patients do not get treatments of

proven effectiveness

20-25% patients get care that is not needed or

potentially harmful

McGlyn et al 2003 NEJM

Grimshaw et al 2012 Implementation Science

The delivery of health care is variable

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What about fertility treatments?

Are we offering our patients the most effective treatments?

How do we know that we are not doing more harm than good?

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Reasoning

based on

patho-physiology Guidelines

Reasoning based on

observational studies Systematic

reviews

Improved health

care

There’s been a culture change

Randomised

controlled trials

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systematic reviews ……

Key features of a systematic review?

clearly stated objectives

pre-defined eligibility criteria

explicit, reproducible methodology

systematic search

assessment of validity of included studies

systematic synthesis and presentation of findings

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Preparing, maintaining and disseminating systematic reviews of the effects of health care

The Cochrane Collaboration

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Producing high-quality systematic reviews

Dissemination of review findings

Training in systematic reviews

What is the Cochrane Collaboration about?

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Advantages of Cochrane reviews

Updating of reviews regularly

Methodologically robust

Less likely to be biased

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How do (Cochrane) systematic reviews

reduce bias?

Prestated methods published

Limit publication bias

Systematic methodology

Limit commercial and industry

sponsorship of reviews

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“..we observed far superior

reporting standards of Cochrane

reviews compared to non-

Cochrane therapeutic ones.”

“For therapeutic reviews, all the

Cochrane ones reported assessing

the quality of included studies

whereas only half of the non-

Cochrane did.”

“The seven industry supported

reviews that had conclusions

recommended the

experimental drug without

reservations, compared with

none of the Cochrane reviews,

although the estimated

treatment effect was similar on

average

Better quality reviews

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Studies with funding bias are more likely to have

favourable results (Lundh et al 2012)

Add reviews on this topic

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The Cochrane Menstrual Disorders and

Subfertility Group

Produces systematic reviews for the Cochrane

Library

Editorial office at the University of Auckland

26 editors – methodologists, statisticians,

content experts

Work with about 800 authors

13

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The life cycle of a Cochrane reviewTitle

(registered)

Prepare Protocol

Register Protocol

Systematic Review

Review online

Time Frame

6 Months

12 Months

Lifelong

editorial + external review

searchesinclusions

qualitydata extraction

meta-analysis

editorial + external review

outside comments and criticisms

new data

2 or more reviewers

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An assisted reproduction cycle is a

series of individual steps….

Complex with

interactions between

steps

Benefits and harms

can take place with

each step

Trade-offs may be

necessary

Two patients to

consider – mother and

baby

Pre ARTDown

regulationOvulation induction

Ovulation trigger

Oocyte retrieval

+/- Sperm retrieval

Laboratory procedures

Embryotransfer

Luteal phase support

Thaw transfers

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Subfertility Cochrane reviews by

topic (August 2013) (n=110)

0

10

20

30

40

50

60

70

Assisted

conception

Male

subfertility

Female

subfertility

Unexplained

subfertility

Ectopic

pregnancy

Reviews

Protocols

Titles

16

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Classification

Effective interventions Review found evidence of effectiveness or improved safety for an intervention

Promising interventions Review found some evidence of effectiveness or improved safety for an intervention, but more evidence is needed

Ineffective interventions Review found evidence of a lack of effectiveness or reduced safety for an intervention: 10 reviews

Possibly ineffective interventions Review found evidence suggesting a lack of effectiveness of reduced safety for an intervention, but more evidence is needed: 3 reviews

No conclusions possible due to lack of evidence

Review found insufficient evidence to comment on the effectiveness or safety of an intervention.

www.cochranejournalclub.com

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Examples of effective interventions

Endometrial injury performed in the month prior to ovulation induction for ART increases both the live birth rate and clinical pregnancy rate

Laparoscopic tubal occlusion is an alternative to laparoscopic salpingectomy in improving IVF pregnancy rates in women with hydrosalpinges

The administration of GnRHa for a period of 3-6 months prior to IVF or ICSI in women with endometriosis increased the odds of clinical pregnancy by fourfold

Increased live birth rate associated with embryo culture using low oxygen concentrations

Increase in clinical pregnancy rate using ultrasound guided embryo transfer compared with clinical touch

www.cochranejournalclub.com

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Examples of ineffective interventions

Preimplantation genetic screening as currently performed significantly decreases live birth rates in women of advanced maternal age and those with repeated IVF failure. Trials in which PGS was offered to women with a good prognosis suggested similar outcomes

www.cochranejournalclub.com

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Examples of lack of evidence

Intralipids for elevated NK cells

Timelapse cinematography

Type of culture media

Fast track IVF

Mucous aspiration before ET

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How Cochrane SR can make an impact…..

PGS for advanced maternal age in IVF

cycles

GnRh agonist for triggering ovulation

Gn for COH

GnRH agonist vs GnRH antagonist

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There was enthusiasm for PGS

Advanced maternal age

Gianaroli 1999, Munne 1999, Kahraman 2000,

Obasaji 2001, Munne 2003; Montag 2004; Platteau

2005

Repeated IVF failure

Gianaroli 1999, Kahraman 2000, Pehlivan

2003,Munne 2003, Wilding 2004

Recurrent miscarriage

Pellicer 1999, Rubio 2003, Rubio 2005, Munne

2005

Severe male factor

Silber 2003, Platteau 2004

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Cochrane review 1st published in 2005

Only one RCT

Updated in 2010

9 RCTs – 1589 women

All used FISH

3 different populations

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Preimplantation genetic screening for

advanced maternal age – reduced live

birth rates

OR 0.59

(0.44, 0.81)

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ESHRE PGS Consortium

By 2008 over 16000 cycles of PGS were

undertaken…

Assuming a 20% live birth rate, it is estimated

that between 640 to 1728 fewer babies born

as a result

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ASRM Practice Committee 2008

Available evidence does not support

the use of PGS as currently performed to

improve live-birth rates in patients with

advanced maternal age or in patients

with previous implantation failure.

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The only effective way to resolve the

debate is to perform more well-designed

and well-executed clinical trials

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an ESHRE trial has recently been started

on patients with AMA using

polar body biopsy and array-comparative

genomic hybridization, which should bring

more information on this patient group in the

near future.

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Triggering – GnRH agonist or hCG?

Youssef et al, updated CR 2013

17 RCTs

9 report OHSS

5 report live birth rate

Risk of bias

Only 2/17 used blinding

4/17 studies stopped prematurely for

differing reasons

All studies were either funded by

pharmaceutical companies or did not

report their funding

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Ovarian hyperstimulation rate is reduced with

agonist trigger in high risk women only

OR 0.06

(0.01, 0.34)

Youssef et al, updated 2013

*4 studies no events in either arm

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Live birth rate reduced with GnRHa

triggering

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The trade off

Fewer live births – difference of 10%

between HCG and GnRHa triggers

Fewer cases of OHSS – difference of 2-3%

for high risk women

Who decides?

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Professor Hans Evers

Editorial, Human Reproduction

September 2013

“As an Editor of this journal, I would whole-heartedly

welcome a manuscript on the first sufficiently powered

RCT of GnRHa triggering in one arm, and traditional hCG

triggering in the other; with subsequent secondary

randomization to a ‘freeze-all’ strategy or a ‘fresh

transfer’ strategy in either of the two arms. “

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Gn,

Several systematic reviews compared

recombinantFSH with urinary

gonadotrophins (hMG, FSH-P, FSH-HP) Daya 1998; Larizgoitia 2000; Agrawal 2000; Daya2002;Van Wely 2003;NCC-WCH 2004;Al-Inany 2003;

Al-Inany 2008;Coomarisamy 2008).

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Effectiveness

Meta-analysis :

Al-Inany et al, 2005

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Conflicting results

Two reviews compared rFSH to urinary

FSH and found higher pregnancy rates

per cycle started for rFSH (Daya 2002,

updated from Daya 1998).

Three reviews compared rFSH with hMG

and reported evidence of a difference

in live birth and clinical pregnancy rate

per cycle between rFSH and hMG (Van

Wely 2002;Al-Inany 2008; Coomarisamy 2008).

Gn: Cochrane Word

Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane

Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G

Al-Inany

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Cochrane SR

Randomised controlled trials only.

Quasi-randomised controlled trials, in

which allocation was, for example, by

alternation or reference to case record

number or to dates of birth, were

excluded.

Crossover trials were excluded since the

design is not appropriate in this context

(Vail 2003)

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42 RCTs The total number of participants was

9606 There was no evidence of a difference

in live birth or pregnancy ongoing

beyond 20 weeks (OR 0.97, 95% CI 0.87 -

1.08) for rFSH versus urinary Gn.

Meaning 25% live birth rate (22-26% in

different centers)

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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

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Live Birth Rate

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OHSS

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Gonadotrophins

are

Gonadotrophins

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GnRH agonist vs antagonist,

2001

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Al-inany et al., 2006

O.R = 0.82, 95% CI = 0.68 to 0.97

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Al-Inany et al., 2011

45 RCTs

7532 participants

Conclusion

differed

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WHY:

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How to Explain

OHSS is an uncommon complication

Uncommon complications need large

number of participants to show if there is a

real difference between two drugs

In our current situation: agonist vs.

antagonist

OHSS in agonist group: 3.74% (84/3165)

OHSS in antagonist group: 1.91% (149/

2252)

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How to explain (continue)

More Studies were conducted on

women with PCOS after 2006 which

illustrated this difference

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CPR

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The trade off

Less CPR – difference of 3%

Less OHSS – mostly in PCOS women

Who decides?

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In Conclusion

There are many highly valid Cochrane

reviews in subfertiilty

Useful for clinicians seeking a summary

of studies

Highlight gaps in research

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@CochraneMDSG www.cochrane.org