Overview of Reviews

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Assisted reproductive technology: an overview of Cochrane Reviews

  1. Cindy Farquhar1,
  2. Josephine R Rishworth1,
  3. Julie Brown2,*,
  4. Willianne LDM Nelen3,
  5. Jane Marjoribanks1

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 22 AUG 2013

Assessed as up-to-date: 25 JUL 2013

DOI: 10.1002/14651858.CD010537.pub2


How to Cite

Farquhar C, Rishworth JR, Brown J, Nelen WLDM, Marjoribanks J. Assisted reproductive technology: an overview of Cochrane Reviews. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010537. DOI: 10.1002/14651858.CD010537.pub2.

Author Information

  1. 1

    University of Auckland, Obstetrics and Gynaecology, Auckland, New Zealand

  2. 2

    University of Auckland, The Liggins Instiute and Department of Obstetrics and Gynaecology, Auckland, New Zealand

  3. 3

    Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

*Julie Brown, The Liggins Instiute and Department of Obstetrics and Gynaecology, University of Auckland, FMHS, Auckland, New Zealand. j.brown@auckland.ac.nz.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 22 AUG 2013

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Table 1. Trial characteristics

Review IDDate assessed as up to dateNumber of included trialsPopulationInterventionComparison intervention/controlOutcomes Review limitations

1. Indication for ART

ZP672

Pandian 2012

In vitro fertilisation for unexplained subfertility
1/07/20116 RCTs733 couples with unexplained subfertilityIn vitro fertilisationExpectant management

Intra-uterine insemination Intra-uterine insemination +

ovarian stimulation

Clomiphene citrate
Live birth rate

Clinical pregnancy rate Multiple pregnancy rate OHSS
Some evidence was based

on a single trial. There were limitations in

imprecision and heterogeneity for some outcomes

AMY731

Yossry 2006

In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation
15/05/2009No RCTsN/AIn vitro fertilisationTubal re-anastamosisLive birth rate

Clinical pregnancy rate Multiple pregnancy rate OHSS
Empty review with no

trials. No longer being updated

CS1400

Siristatidis 2009

In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction
17/02/2011No RCTsN/AIn vitro maturationIn vitro fertilisation

Intra-cytoplasmic sperm injection
Live birth

Cycle cancellation Oocyte fertilisation rate OHSS

Miscarriage rate Preterm birth

Congenital abnormalities
Empty review with no

trials. No longer being updated

2. Pre-ART and adjuvant strategies

2.1 For unselected populations

KA992

Anderson 2010

Preconception lifestyle advice for people with subfertility
18/11/20091 RCT94 women who perceived that they may be infertileSmoking cessation

advice
Standard clinical adviceSmoking behaviour

change

Live birth
The trial did not report on fertility outcomes. Evidence was based on a

single trial

WM1504

Nastri 2011

Endometrial injury in women undergoing assisted reproductive technology
14/11/20115 RCTs591 women undergoing ARTEndometrial injuryNo endometrial injury

Mock procedure
Live birth rate

Clinical pregnancy rate

Multiple pregnancy rate

Miscarriage rate

Ongoing pregnancy rate Pain/bleeding

Implantation rate
Some evidence was based

on a single trial

Adverse events such as miscarriage rate and multiple pregnancy rate were poorly reported

Some methodological details were unclear

MGS1510

Showell 2010

Antioxidants for male subfertility
22/08/201034 RCTs2876 male partners of couples undergoing ART.AntioxidantPlacebo/no treatment

Antioxidant
Live birth

Pregnancy

Adverse events

DNA fragmentation Sperm parameters

Miscarriage
Methodologically there was a lack of clarity around randomisation and allocation concealment and blinding

JC1630

Showell 2013

Antioxidants for female subfertility
15/4/1328 RCTs3548 women attending an ART clinicAntioxidantPlacebo/no treatment

Antioxidant
Live birth

Pregnancy

Multiple pregnancy

Miscarriage
Not all trials described the sequence generation or allocation concealment methods, and most trials randomly assigned only small numbers of women.

IRS911

Cheong 2013

Acupuncture and assisted reproductive technology
22.7.1320 RCTs4544 women undergoing ARTAcupuncture

Repeated acupuncture
No acupuncture

Sham acupuncture

Acupuncture plus ART
Live birth

Ongoing pregnancy

Clinical pregnancy

Multiple pregnancy

OHSS

Miscarriage

Adverse effects
Study quality generally low, with over 75% failing to describe an adequate method of allocation concealment

KH291

Duffy 2010

Growth hormone for in vitro fertilisation
01/07/200910 RCTs440 couples undergoing IVFGrowth hormonePlaceboLive birth rate

Pregnancy rate

Number of women with at least one oocyte retrieved

Embryos transferred Ampoules of gonadotrophin

Adverse events
Lack of methodological clarity in reporting of randomisation and allocation concealment

VJP 951

Siristatidis 2011

Aspirin for in vitro fertilisation
15/06/201113 RCTs2653 women undergoing IVFAspirinPlacebo

No treatment
Live birth

Clinical pregnancy Multiple pregnancy Complications of IVF

Complications of pregnancy

Miscarriage

Ongoing pregnancy
Incomplete outcome data

not well described. Live birth only reported in 3 trials

2.2. For selected populations

NJ472

Johnson 2010

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation
28/10/20095 RCTs646 women due to undergo IVFSurgical treatment

for tubal disease
No interventions

Head to head
Live birth rate

Ongoing pregnancy Clinical pregnancy Ectopic pregnancy Miscarriage rate
None of the trials showed

evidence of blinding. Live birth was not reported in the included trials

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology
26/11/20104 RCTs312 women undergoing management of endometrioma prior to ARTSurgical or medical treatment prior to ARTPlacebo/no treatment

Other surgical or medical treatment prior to ART
Live birth rate

Clinical pregnancy rate

Adverse events

Quality of life

Pain

Recurrence

Oestradial levels

Number of mature oocytes
No live birth rates reported.

Two of the trials were open label

LDT120

Tso 2009

Metformin treatment before and during IVF or ICSI in women with polycystic ovary

syndrome
28/02/20086 RCTs474 women with

polycystic ovary syndrome
MetforminPlacebo

No treatment
Live birth

Clinical pregnancy Miscarriage

OHSS

Adverse events Number ofoocytes

retrieved

Total dose FSH (IU) Number of days

gonadotrophin treatment

Cycle cancellation rate Serum E2 level (nmol/l
Half the trials were not blinded and lacked details on allocation concealment and randomisation

3. Down-regulation with agonists or antagonists

LA541

Albuquerque 2013

Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary down regulation in assisted reproduction cycles
3/7/1216 RCTs963 women undergoing IVFGnRHa depotGnRHa dailyClinical pregnancy

Pregnancy per oocyte retrieval procedure

Pregnancy rate per embryo transferred

Number of ampoules of gonadotrophin employed

Number of days of gonadotrophin treatment

Number of oocytes retrieved

Abortion rate

Ongoing/delivered

pregnancy rates per cycle started

Multiple pregnancy rates

OHSS
Study quality was unclear due to poor reporting. Only four studies reported live births as an outcome and only five described adequate methods for concealment of allocation.

HA412

Al-Inany 2011

Gonadotrophin-releasing hormone antagonists for assisted reproductive

technology
01/03/201045 RCTs7511 women undergoing ARTGnRH antagonistLong course GnRH agonistLive birth

Ongoing pregnancy

Clinical pregnancy

Miscarriage OHSS

Cycle cancellation
Only 9 trials reported live birth

Trial methodology limited by lack of blinding

HNS 881

Sallam 2006

Long-term pituitary down- regulation before in vitro fertilization (IVF) for women with endometriosis
20/05/20103 RCTs165 women with endometriosis undergoing ARTGnRH agonistNo GnRH agonistClinical pregnancy

Dose of FSH/HMG (ampoule)

Duration of FSH administration (days)

Number of oocytes
No blinding

Unclear allocation concealment in all trials and no reporting of live birth

SD265

Maheshwari 2011

Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproductive treatment
24/01/201129 RCTsIncluded women undergoing ART: total number of participants unclear from reviewLong protocol

Short protocol
Short protocol

Ultra short protocol

Stop short protocol
Live birth

Clinical pregnancy

Ongoing pregnancy

Number of oocytes

Dose of gonadotrophins

Cycle cancellation
Only 3 trials reported live

birth

Methodology limited by lack of blinding and inadequate reporting of outcome data assessed

Overall very limited by methodology.

4. Ovarian stimulation

4.1 Medication type

AM1335

Gibreel 2012

Clomiphene citrate in combination with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilization
23/3/201214 RCTs2536 (12 trials)

Subfertile women undergoing ART
Clomiphene citrate

+/- additional treatments
Alternative treatments for

controlled ovarian hyperstimulation
Live birth rate

Miscarriage rate

Ectopic pregnancy

Fetal abnormality

Ongoing pregnancy rate

Cancellation rate

OHSS
Live birth only reported in 5 of the trials

Most studies suffered from suboptimal methodology and there was insufficient information on some outcomes.

AWP1710

Pouwer 2012

Long-acting FSH versus daily FSH for women undergoing assisted reproduction
10/10/20114 RCTs2335 women with subfertilityLong acting FSHDaily FSHLive birth rate

Ongoing pregnancy rate

Clinical pregnancy rate

OHSS

Multiple pregnancy rate

Miscarriage rate

Adverse events

Satisfaction
Two of the trials lacked adequate blinding and one of the trials provided insufficient details on allocation concealment and randomisation

MHM931

Mochtar 2007

Recombinant luteinizing hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles
14/06/201133 RCTs5624 women with subfertilityRecombinant

lutenising hormone plus recombinant follicle stimulating hormone
Recombinant follicle

stimulating hormone
Live birth

Adverse events

Ongoing pregnancy

Miscarriage

Amount of rFSH used

Serum oestrodial used

Number of oocytes retrieved
Live birth was reported in 5 of the trials

There was a lack of methodological details provided by the review authors with regards to blinding and inadequate outcome data assessed. Trials were also limited by information on randomisation and allocation concealment

IOK973

van Wely 2011

Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles
20/10/201042 RCTs9606 women undergoing ARTRecombinant

follicle stimulating hormone
Urinary gonadotrophinsLive birth/ongoing

pregnancy

OHSS

Clinical pregnancy

Multiple pregnancy

Miscarriage
The majority of the trials

were open labelled.

WPM1780

Martins 2013

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques
5/2/135 RCTs351 women undergoing COH for ART.Low dose human chorionic gonadotrophin in the late follicular phaseFollicle stimulating hormone throughout controlled ovarian hyperstimulationLive birth

OHSS

Ongoing pregnancy

Clinical pregnancy

Miscarriage

Total dose of FSH used

Oocytes retrieved
Only two studies reported live birth: both were at high risk of attrition bias.

Low precision due to small overall sample size

DHH752

Smulders 2010

Oral contraceptive pill, progestogen or estrogen pre- treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques
16/11/200823 RCTs2603 women with subfertilityCombined OCP

Progesterone Oestrogen
Placebo or no treatment

Combined OCP

Progesterone

Oestrogen
Live birth rate

Ongoing pregnancies

Clinical/ ongoing pregnancies

Oocytes retrieved

Gonadotrophin

treatment

Pregnancy loss

Ovarian cyst formation

Multiple pregnancies

OHSS
Live birth reported in 6 trials

Methodological limitations: poor reporting of randomisation procedures, high risk of attirtion bias in some studies, poor precision due to low sample numbers for individual comparisons

4.2 Monitoring

IOK972

Kwan 2008

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI)
24/01/20082 RCTs411 women undergoing ovarian stimulation with gonadotrophins in ARTUltrasound plus

oestradiol
Ultrasound onlyClinical pregnancy

Number ofoocytes

OHSS
One of the trials was

limited by methodological design. No live birth reported

4.3 Interventions for poor responders

RSS791

Pandian 2010

Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF)
16/03/200910 RCTs625 women considered to be 'poor responders' to COH in IVF treatmentStop protocol

GnRHa protocol

GnRHa flare up protocol

GnRH antagonist

Low dose GnHa

flare up protocol

Multiple dose GnRH antagonist

Flare up protocol Long protocol
Long protocol

GnRHa flare up protocol Spontaneous natural cycle

IVF

Mini dose long agonist protocol

Modified long protocol
Live birth rate per woman

Clinical pregnancy rate per woman

Ongoing pregnancy rate per woman

Miscarriage rate

Ectopic pregnancy

Cancellation rate

Oocytes retrieved

Dose of gonadotrophins

Total FSH used
Live birth rate only reported in one trial

Methodological limitations in terms of limited blinding, lack of details on addressing incomplete data outcome

4.4 Natural cycle IVF

TA1860

Allersma 2013

Natural cycle IVF for subfertile couples
5.3.135 RCTs382 subfertile women and couples undertaking IVF treatmentNatural cycle IVF

Modified natural cycle IVF
Controlled ovarian hyperstimulation IVFLive birth

OHSS

Pregnancy

Ongoing pregnancy

No of oocytes retrieved

Time to live birth

Number of cycles required to conceive

Cumulative pregnancy/live birth rate

Multiple pregnancy

Lack of embryos for cryopreservation

Cycle cancellation

Gestational abnormalities

Cancellation of treatment

Cost effectiveness
Few studies, live birth only reported in one very small trial.

Inclusion crieteria differed

5. Ovulation triggering

MM1690

Youssef 2011a

Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles
6/10/201011 RCTs1055 women undergoing ARTGnRH agonistHCGLive birth rate

Ongoing pregnancy rate

Clinical pregnancy rate

Multiple pregnancy rate

Miscarriage rate

OHSS
There was a lack of blinding in the included trials

Adverse events such as multiple pregnancy rate were not well reported

HA413

Youssef 2011

Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles
20/1/201014 RCTs2306 women undergoing ARTRecombinant hCG

Recombinant hLH
Urinary hCGLive birth

OHSS

Clinical pregnancy rate

Miscarriage rate

Oocytes retrieved

Tolerance
Authors combined ongoing pregnancy and live births together

6 of 14 trials reported on live birth

Four of the trials lacked details on allocation concealment, randomisation and blinding

6. Oocyte retrieval



IOK971

Kwan 2013

Pain relief for women undergoing oocyte retrieval for assisted reproduction
31/1/1321 RCTs2974 women undergoing transvaginal oocyte retrieval during IVF treatment.Intravenous

alfentanyl plus PCB

Intravenous midazolam

Intravenous sedation plus PCB

Patient controlled sedation

Patient-controlled inhalational Isodesox

Conscious sedation Intramuscular

pethedine
Electro-acupuncture plus

PCB

General anaesthesia Placebo plus PCB

Physician controlled sedation

intravenous analgesia Placebo

Piroksikam
Pain

Patient satisfaction

Pregnancy rate

Ongoing and live birth rate
Evidence was generally of low quality, mainly due to poor reporting of methods, small sample sizes and inconsistency between the trials.

Only one study reported live birth rate

SW811

Wongtra-ngan 2010

Follicular flushing during oocyte retrieval in assisted reproductive techniques
31/03/20104 RCTs208 women undergoing ARTFollicular flushingAspiration aloneClinical /ongoing

pregnancy

Oocyte retrieval

Adverse events

Duration of procedure

Pain
No reporting of live birth

Half trials did not report details of allocation concealment

Blinding poorly reported

7. Sperm retrieval

AMVP611

Proctor 2008

Techniques for surgical retrieval of sperm prior to intra-cytoplasmic sperm injection (ICSI) for azoospermia
12/12/2012

Review is stable and will no longer be updated
1 RCT59 men with obstructive or non-obstructive azoospermiaEpididymal or

testicular techniques for sperm retrieval
Epidydymal or testicular

techniques for sperm retrieval
Pregnancy rate

Sperm parameters

Fertilisation rate
No live birth reported

Based on single RCT

Poor methodology

8. Laboratory phase

MWS391

Carney 2012

Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI))
8/8/1231 RCTs5728 women undergoing ARTAssisted hatchingNo assisted hatchingLive birth

Multiple pregnancy

Clinical pregnancy

Miscarriage

Ectopic pregnancy

Monozygotic twinning

Congenital or chromosomal abnormalities

Failure to transfer any embryos

Embryo damage

In vitro blastocycst development
Few studies described adeqate allocation concealment. Most failed to report on live birth rates.

MVR461

Van Rumste 2003

Intra-cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in patients with non-male subfertility
24/1/2011

Review no longer being updated
1 RCT415 couples with non-male factor subfertilityIntracytoplasmic

sperm injection
In vitro fertilisationClinical pregnancy

Adverse events

Miscarriage
Evidence based on a single trial with unclear details on blinding

SB1283

Bontekoe 2012

Low oxygen concentrations for embryo culture in assisted reproductive technologies
4/11/20117 RCTs2422 couples undergoing ARTEmbryo culture

with low oxygen concentrations
Embryo culture with

atmospheric oxygen concentrations
Live birth

Ongoing pregnancy Clinical pregnancy Multiple pregnancy Miscarriage

Congenital abnormalities

Implantation rate

Embryo development

Cryopreservation rate
Only three of the trials reported on live birth outcomes

There were unclear methodological details in six of the trials

SMA991

Twisk 2006

Preimplanation genetic screening for abnormal numbers of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
15/07/20109 RCTs1589 women undergoing IVF or ICSI with and without PGS for all suggested indicationsIVF/ICSI with preimplantation genetic screeningIVF/ICSI with no

preimplantation genetic screening
Live birth

Clinical pregnancy Multiple pregnancy Miscarriage

Ongoing pregnancy

Congenital abnormalities
Six of the nine trials were open label and other methodological details were unclear

ZH1093

Huang 2013

Brief co-incubation of sperm and oocytes for in vitro fertilization techniques
26/3/138 RCTs733 women undergoing ARTBrief co-incubation of gametes for women undergoing IVFStandard overnight insemination protocol for women undergoing IVF.Live birth

Ongoing pregnancy

Clinical pregnancy

Miscarriage

Fertilisation

Polyspermy

Implantation
The trials provided low quality evidence. Only 3/8 gave information on how the randomization was achieved and all had unclear methods of allocation concealment. No studies reported live birth.

WPM1800

Teixeira 2013

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction
8/5/139RCTs2014 couples undergoing ARTIMSIICSILive birth

Clinical pregnancy

Miscarriage

Congenital abnormalities
Only one trial reported live birth. Issues such as risk of bias (differences between number of oocytes transferred), imprecision and strong suspicion of publication bias.

9. Embryo transfer

9.1 Developmental stage

DB551

Glujovsky 2012

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology
21/02/201223 RCTs3241 women undergoing ARTCleavage stage transferBlastocyst stage transferLive birth rate

Clinical pregnancy rate Multiple pregnancy rate Miscarriage rate

Embryo freezing rate

Failure to have a transfer

Cumulative pregnancy rate
Many of the trials had inadequate or unclear methodological details

9.2 Number of embryos

CO266

Gunby 2004

Day three versus day two embryo transfer following in vitro fertilisation or intracytoplasmic sperm injection
15/12/200316 trials2691 (12 studies) couples undergoing ARTDay 3 embryo transferDay 2 embryo transferLive birth

Ongoing pregnancy

Clinical pregnancy rate

Complication rate

Multiple pregnancy rate

Miscarriage rate

Ectopic pregnancy

Foetal abnormalities

Womens' evaluation
Live birth reported in only 3 trials

Many of the included trials lacked methodological details

ZP661

Pandian 2013

Number of embryos for transfer following in vitro fertilisation or intra cytoplasmic sperm injection
17/07/201214 RCTs2165 couples undergoing ARTSingle embryo transfer

Double embryo transfer
Double embryo transfer

Three embryo transfer

Four embryo transfer
Live birth rate

Pregnancy rate

Multiple pregnancy rate

Miscarriage rate
Many of the included studies were small, with half enrolling fewer than 60 participants. There was considerable clinical heterogeneity between the studies but little evidence of statistical heterogeneity for most analyses. The methodological quality of the studies was mixed.

9.3 Transfer techniques

DB552

Bontekoe 2010

Adherence compounds in embryo transfer media for assisted reproductive technologies
28/3/1216 RCTs3898 women undergoing ARTEmbryo transfer

media enriched with adherence

compounds

(hyaluronic acid or fibrin sealant)
Embryo transfer media

devoid of , or with a low dose of such adherence

compounds
Ongoing pregnancy

Clinical pregnancy

Multiple pregnancy Implantation rate

Adverse events
There were some methodological limitations including lack of reporting live birth outcomes and some imprecision

SV602

Derks 2009

Techniques for preparation prior to embryo transfer
18/03/200910 RCTs1693 women (9

RCTs) with any type of subfertility

undergoing IVF at embryo transfer stage
Straightening of the

utero-cervical angle

Cervical and endometrial preparation

Dummy transfer

Embryo afterloading
No intervention or no

treatment
Live birth

Clinical pregnancy

Multiple pregnancy

Miscarriage

Ectopic pregnancy

Adverse events - pain/ infection
Only one trial reported on

live birth outcomes, methodological procedures were inadequately explained I most of the included trials

EN1382

Kroon 2012

Antibiotics prior to embryo transfer in ART
23/11/20111 RCT350 women attending infertility clinicAntibioticsNo treatmentBacterial contamination rate of catheter

Clinical pregnancy rate
Analysis of bacterial contamination was not performed on all participants

JB604

Brown 2010

Ultrasound versus ‘clinical touch’ for catheter guidance during embryo transfer in women
9/11/200920 RCTs6524 women with any form of infertilityUltrasound guided

transfer
Clinical touch transferLive birth

Ongoing pregnancy

Clinical pregnancy

Multiple pregnancy

Miscarriage rate

Ectopic pregnancy

Foetal abnormalities

Complication rate

Ease of transfer
Trials lacked methodological details and live birth was not well reported

AAS605

Abou-Setta 2009

Post-embryo transfer interventions for in vitro fertilisation and intra- cytoplasmic sperm injection patients
5/11/20084 RCTs1392 women

with subfertility of any cause
Bedrest

Bladder emptying Mechanical

pressure on cervix Fibrin sealant
Different duration of

bedrest

No intervention
Live birth rate

Ongoing pregnancy

Clinical pregnancy rate

Multiple pregnancy rate

Miscarriage rate

Ectopic pregnancy rate

Adverse events – pain

Subjective experience
No live birth reported, lack of blinding

10. Luteal phase support

MV263

van der Linden 2011

Luteal phase support for ART cycles
25/05/201169 RCTs16,327 women with any cause of subfertilityProgesterone

hCG
Placebo or no treatment

hCG

Progesterone + oestrogen Progesterone + GnRH

agonist
Live birth rate

Clinical pregnancy rate

Ongoing pregnancy rate

Miscarriage rate

OHSS

Multiple pregnancy rate
Some of the trials lacked methodological details. There was poor reporting of live birth outcomes

CMB126

Boomsma 2012

Peri-implantation glucocorticoid administration for assisted reproductive technology cycles
20/09/201114 RCTs1879 couples with any cause of subfertilityGlucocorticoidsNo glucocorticoids

Placebo
Live birth

Ongoing pregnancy Pregnancy

Multiple pregnancy Miscarriage

Ectopic pregnancy

OHSS

Implantation rate
Only 3 trials reported live birth

Methodology limited by lack of blinding and inadequate reporting of outcome data assessed

Akhtar 2013

Heparin for assisted reproduction
6/5/133 RCTs386 subfertile women undergoing ARTHeparinPlacebo

No treatment
Live birth

Adverse effects

Clinical pregnancy

Multiple pregnancy

Maternal complications

Fetal complications
Only three small studies, one of which did not adequately describe allocation concealment. High heterogeneity reflecting differing participant inclusion criteria.

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

TH1338

Tang 2012

Cabergoline for

preventing ovarian hyperstimulation syndrome
2/09/20112 RCTs230 women at

high risk of OHSS

undergoing ART
CabergolinePlacebo/no treatment

Other treatment
OHSS

Live birth rate

Miscarriage

Clinical pregnancy rate

Multiple miscarriage rate

Adverse events
Allocation concealment not clearly reported. Blinding in one of the trials was not clearly reported and there were

issues around incomplete data reporting. No studies reported live birth rate

ADA 563

D'Angelo 2011

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome
19/07/20104 RCTs340 women

with PCOS

down-regulated by GnRH-a, undergoing super-ovulation in IVF or ICSI cycles
Coasting when

estradiol levels were > 2500 pg/mL or > 9000 pmol/L

Coasting when estradiol levels were > 2500 pg/mL or > 9000 pmol/L
Early unilateral follicular

aspiration

No coasting or other interventions
OHSS

Clinical pregnancy

Number of oocytes retrieved

Multiple pregnancy

Miscarriage

Live birth
Comparisons based on limited trial data

Live birth only reported in one trial

Trials lacked blinding and half the trials lacked details on allocation concealment and incomplete outcome assessment

ADA561

D'Angelo 2007

Embryo freezing for preventing ovarian hyperstimulation syndrome
26/11/2010

Review is considered to

be stable and will not be updated again
2 RCTs151 women

down-regulated by GnRH-a, undergoing superovulation in IVF and or ICSI cycles.
CryopreservationFresh embryo transfer

Intravenous albumin
OHSS

Clinical pregnancy

Live birth

Admissions
Evidence based on two trials, one for each comparison

Live birth only reported in one trial

Issues around methodological quality of both trials

PMA481

Youssef 2011b

Intra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome
02/11/20109 RCTs2147 women

having controlled ovarian hyperstimulation and at risk of severe OHSS
Human albumin

Hydroxyethyl starch
PlaceboOHSS

Clinical pregnancy
No reporting of live birth

Methodological issues especially around incomplete outcome addressed

12. Frozen embryo replacement cycles

TG691

Ghobara 2008

Cycle regimens for frozen- thawed embryo transfer (FET)
11/10/20077 RCTs1120 women

Studies included women with a range of causes of subfertility

The review does not provide details of the mean ages of the women
Oestrogen and

progesterone

GnRHa + day oestrogen + day progesterone

Clomiphene + HMG
Natural cycle

GnRHa + day oestrogen and progesterone

FSH

Clomiphene

Clomiphene

HMG
Live birth per woman

Clinical pregnancy per woman

Ongoing pregnancy per woman

Multiple pregnancy rate Cycle cancellation rate Miscarriage rate

Endometrial thickness
Of the included studies,

randomisation was unclear in six trials. Allocation concealment was adequately reported in three trials and there was no blinding reported in any of the trials.

Many of the outcomes associated with the comparisons in the trials are limited to a single trial.

DG1351

Glujovsky 2010

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos

derived from donor oocytes
7/10/200922 RCTs3451 women

11 trials used fresh donor oocyte embryo replacement cycles

11 trials used frozen embryo replacement cycles

There was a lack of detail on causes of infertility
GnRHa

Corticosteroids

Low dose aspirin

GnRHa

Intramuscular progesterone

Day of starting progesterone

Artificial cycle HCG before

retrieval
No treatment

GnRHa

Vaginal progesterone

Day of starting progesterone

Non artificial cycle

Placebo
Live birth

Clinical pregnancy rate

Multiple pregnancy rate

Cancelled cycle rates Endometrial thickness Pregnancy loss
Only eight trials reported adequate details of allocation concealment.

Only one trial reported on blinding


HMG - human menopausal gonadotrophin

FSH – follicle stimulating hormone

FET - frozen-thawed embryo transfer

GnRHa – gonadotrophin-releasing hormone agonist

ICSI – intracytoplasmic sperm injection

IVF - in vitro fertilisation

 
Table 2. AMSTAR assessment

Review noFirst authorREVIEW TITLEAMSTAR CRITERIA




Prespecified question and inclusion criteriaDuplicate study selection and data extractionComprehensive lit searchGrey lit includedLists included and excluded studiesDescribes characteristics of incldued studiesStudy quality assessedStudies combined using appropriate methodsLikelihood of publication bias considered/testedPotential for conflict of interest addressed

AAS605Abou-Setta 2009Post-embryo transfer interventions for in vitro fertilization and intracytoplasmic sperm injection patients

ADA561D'Angelo 2007Embryo freezing for preventing ovarian hyperstimulation syndrome

ADA563D'Angelo 2011Coasting (withholding gonadotrophins) for preventing ovarian
hyperstimulation syndrome

AM1335Gibreel 2012Clomiphene citrate for controlled ovarian stimulation in women undergoing in vitro fertilization

AMVP611Proctor 2008Techniques for surgical retrieval of sperm prior to intra-cytoplasmic sperm injection (ICSI) for azoospermia

AMY731Yossry 2006In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisationn/an/an/an/a

AWP1710Pouwer 2012Long-acting FSH versus daily FSH for women undergoing assisted reproduction

CMB1261Boomsma 2012Peri-implantation glucocorticoid administration for assisted reproductive
technology cycles

CO266Gunby 2004Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injectionx

CS1400Siristatidis 2009In vitro maturation in sub fertile women with polycystic ovarian syndrome undergoing assisted reproductionn/an/an/an/a

DB551Glujovsky 2012Cleavage stage versus blastocyst stage embryo transfer in assisted
reproductive technology

DB552Bontekoe 2010Adherence compounds in embryo transfer media for assisted reproductive technologies

DG1351Glujovsky 2010Endometrial preparation for women undergoing embryo transfer with
frozen embryos or embryos derived from donor oocytes

DHH752Smulders 2010Oral contraceptive pill, progestogen or estrogen pre-treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques

EN1382Kroon 2012Antibiotics prior to embryo transfer in ART

HA412Al-Inany 2011Gonadotrophin-releasing hormone antagonists for assisted reproductive technologyx

HA413Youssef 2011Recombinant versus urinary human chorionic gonadotrophin for final
oocyte maturation triggering in IVF/ICSI cycles

HNS881Sallam 2006Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosisx

IOK971Kwan 2013Pain relief for women undergoing oocyte retrieval for assisted reproduction

IOK972Kwan 2008Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI)x

IOK973van Wely 2011Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproduction technology cycles

IRS911Cheong 2013Acupuncture and assisted reproductive technology

JB604Brown 2010Ultrasound versus 'clinical touch' for catheter guidance during embryo
transfer in women
x

JC1630Showell 2013Antioxidants for female subfertility

KA992Anderson 2010Pre-conception lifestyle advice for people with subfertility

KH291Duffy 2010Growth hormone for in vitro fertilizationx

LA541Albuquerque 2013Depot versus daily administration of gonadotrophin releasing hormone
agonist protocols for pituitary desensitization in assisted reproduction
cycles

LDT1201Tso 2009Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

MA1441Akhtar 2013Heparin for assisted reproduction

MGS1510Showell 2010Antioxidants for male subfertility

MHM931Mochtar 2007Recombinant luteinizing hormone (rLH) for controlled ovarian
hyperstimulation in assisted reproductive cycles
x

MM1690Youssef 2011aGonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

MV263van der Linden 2011Luteal phase support in ART cycles

MVR461Van Rumste 2003Intra-cytoplasmic sperm injection versus conventional techniques for
oocyte insemination during in vitro fertilisation in patients with non-male
subfertility

MWS391Carney 2012Assisted hatching on assisted conception (IVF and ICSI)

NJ472Johnson 2010Surgical treatment for tubal disease in women due to undergo in vitro fertilisationx

PMA481Youssef 2011bIntra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome

RSS791Pandian 2010Interventions for 'poor responders' to controlled ovarian hyper stimulation
(COH) in in-vitro fertilisation (IVF)

SB1283Bontekoe 2012Low oxygen concentrations for embryo culture in assisted reproductive technologies

SD265Maheshwari 2011Gonadotropin-releasing hormone agonist protocols for pituitary suppression in assisted reproductive technology cycles

SG1241Benschop 2010Interventions for women with endometrioma prior to assisted reproductive technology

SMA991Twisk 2006Preimplantation genetic screening for abnormal number of chromosomes
(aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection

SV602Derks 2009Techniques for preparation prior to embryo transfer

SW811Wongtra-ngan 2010Follicular flushing during oocyte retrieval in assisted reproductive
techniques

TA1860Allersma 2013 Natural cycle IVF for subfertile couples

TG691Ghobara 2008Cycle regimens for frozen-thawed embryo transfer

TH1338Tang 2012Cabergoline for preventing ovarian hyperstimulation syndrome

VJP951Siristatidis 2011Aspirin for in vitro fertilisation

WM1504Nastri 2011Endometrial injury in women undergoing assisted reproductive techniques

WPM1780Martins 2013FSH replaced by low-dose hCG in the late follicular phase versus FSH alone for assisted reproductive techniques

WPM1800Teixeira 2013Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction

ZH1093Huang 2013Brief co-incubation of sperm and oocytes for in vitro fertilization techniques

ZP661Pandian 2013Number of embryos for transfer following in-vitro fertilisation or intracytoplasmic sperm injection

ZP672Pandian 2012In vitro fertilisation for unexplained subfertilityx

 
Table 3. Latest search date assessment

Review noFirst authorREVIEW TITLE< 3 yrs since last search

(to August 2013)


AAS605Abou-Setta 2009Post-embryo transfer interventions for in vitro fertilization and intracytoplasmic sperm injection patientsx

ADA561D'Angelo 2007Embryo freezing for preventing ovarian hyperstimulation syndromex

ADA563D'Angelo 2011Coasting (withholding gonadotrophins) for preventing ovarian
hyperstimulation syndrome

AM1335Gibreel 2012Clomiphene citrate for controlled ovarian stimulation in women undergoing in vitro fertilization

AMVP611Proctor 2008Techniques for surgical retrieval of sperm prior to intra-cytoplasmic sperm injection (ICSI) for azoospermia

AMY731Yossry 2006In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation

AWP1710Pouwer 2012Long-acting FSH versus daily FSH for women undergoing assisted reproduction

CMB1261Boomsma 2012Peri-implantation glucocorticoid administration for assisted reproductive
technology cycles

CO266Gunby 2004Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injectionx

CS1400Siristatidis 2009In vitro maturation in sub fertile women with polycystic ovarian syndrome undergoing assisted reproduction

DB551Glujovsky 2012Cleavage stage versus blastocyst stage embryo transfer in assisted
reproductive technology

DB552Bontekoe 2010Adherence compounds in embryo transfer media for assisted reproductive technologiesx

DG1351Glujovsky 2010Endometrial preparation for women undergoing embryo transfer with
frozen embryos or embryos derived from donor oocytes
x

DHH752Smulders 2010Oral contraceptive pill, progestogen or estrogen pre-treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniquesx

EN1382Kroon 2012Antibiotics prior to embryo transfer in ART

HA412Al-Inany 2011Gonadotrophin-releasing hormone antagonists for assisted reproductive technologyx

HA413Youssef 2011Recombinant versus urinary human chorionic gonadotrophin for final
oocyte maturation triggering in IVF/ICSI cycles
x

HNS881Sallam 2006Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosisx

IOK971Kwan 2013Pain relief for women undergoing oocyte retrieval for assisted reproduction

IOK972Kwan 2008Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI)x

IOK973van Wely 2011Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproduction technology cyclesx

IRS911Cheong 2013Acupuncture and assisted reproductive technology

JB604Brown 2010Ultrasound versus 'clinical touch' for catheter guidance during embryo
transfer in women

JC1630Showell 2013Antioxidants for female subfertility

KA992Anderson 2010Pre-conception lifestyle advice for people with subfertilityx

KH291Duffy 2010Growth hormone for in vitro fertilizationx

LA541Albuquerque 2013Depot versus daily administration of gonadotrophin releasing hormone
agonist protocols for pituitary desensitization in assisted reproduction
cycles

LDT1201Tso 2009Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.x

MA1441Akhtar 2013Heparin for assisted reproduction

MGS1510Showell 2010Antioxidants for male subfertility

MHM931Mochtar 2007Recombinant luteinizing hormone (rLH) for controlled ovarian
hyperstimulation in assisted reproductive cycles
x

MM1690Youssef 2011aGonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

WPM1800Teixeira 2013Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction

MV263van der Linden 2011Luteal phase support in ART cycles

MVR461Van Rumste 2003Intra-cytoplasmic sperm injection versus conventional techniques for
oocyte insemination during in vitro fertilisation in patients with non-male
subfertility

MWS391Carney 2012Assisted hatching on assisted conception (IVF and ICSI)

NJ472Johnson 2010Surgical treatment for tubal disease in women due to undergo in vitro fertilisationx

PMA481Youssef 2011bIntra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome

RSS791Pandian 2010Interventions for 'poor responders' to controlled ovarian hyper stimulation
(COH) in in-vitro fertilisation (IVF)
x

SB1283Bontekoe 2012Low oxygen concentrations for embryo culture in assisted reproductive technologies

SD265Maheshwari 2011Gonadotropin-releasing hormone agonist protocols for pituitary suppression in assisted reproductive technology cycles

SG1241Benschop 2010Interventions for women with endometrioma prior to assisted reproductive technologyx

SMA991Twisk 2006Preimplantation genetic screening for abnormal number of chromosomes
(aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
x

SV602Derks 2009Techniques for preparation prior to embryo transferx

SW811Wongtra-ngan 2010Follicular flushing during oocyte retrieval in assisted reproductive
techniques
x

TA1860Allersma 2013 Natural cycle IVF for subfertile couples

TG691Ghobara 2008Cycle regimens for frozen-thawed embryo transferx

TH1338Tang 2012Cabergoline for preventing ovarian hyperstimulation syndrome

VJP951Siristatidis 2011Aspirin for in vitro fertilisation

WM1504Nastri 2011Endometrial injury in women undergoing assisted reproductive techniques

WPM1780Martins 2013FSH replaced by low-dose hCG in the late follicular phase versus FSH alone for assisted reproductive techniques

ZH1093Huang 2013Brief co-incubation of sperm and oocytes for in vitro fertilization techniques

ZP661Pandian 2013Number of embryos for transfer following in-vitro fertilisation or intracytoplasmic sperm injection

ZP672Pandian 2012In vitro fertilization for unexplained subfertility

 
Table 4. Live birth per woman

Outcome

Intervention and comparison intervention
Assumed risk with ComparatorCorresponding risk with interventionRelative effect

(95%CI)
Number of participants

(Studies)
Quality of the evidence

(GRADE)
Comments

1. Indication for ART

Pandian 2012

IVF versus expectant management for unexplained subfertility
37 per 1000458 per 1000 (90

to 879)
OR 22 (2.56

to 189.37)
51 (1 study)LowEvidence based on a single study

Pandian 2012

IVF versus intra- uterine insemination for unexplained subfertility
259 per 1000407 per 1000 (235

to 604)
OR 1.96

(0.88 to

4.36)
113

(1 study)
Very lowEvidence of imprecision and based on a single trial

Pandian 2012

IVF versus intra- uterine insemination + ovarian stimulation for unexplained subfertility (treatment naïve women )
291 per 1000317 per 1000

(215 to 462)
RR 1.09

(0.74 to 1.59)
234

(2 studies)
ModerateBoth trials lacked an adequate explanation of blinding and one trial did not provide sufficient details on allocation concealment

2. Pre-ART and adjuvant strategies

2.1 For unselected populations

Nastri 2011

Endometrial injury prior to ovulation induction (pipelle induced) versus no endometrial injury
168 per 1000332 per 1000 (206 to 489)OR 2.46

(1.28 to 4.72)
200

(2 studies)
ModerateEvidence of imprecision and some methodological details were unclear

Showell 2010

Antioxidant versus control
20 per 100090 per 1000

(38 to 200)
OR 4.85

(1.92 to 12.24)
214

(3 studies)
Very lowInadequate explanation of methodologies, lack of head to head comparisons and evidence of imprecision

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment
367 per 1000420 per 1000

(99 to 827)
OR 1.25

(0.19 to 8.26)
97

(2 studies)
Very lowSerious imprecision, some methodological details were unclear, types of subfertility and antioxidants used differed across trials.

Cheong 2013

Acupuncture versus no acupuncture on the day of embryo transfer
281 per 1000323 per 1000

(254 to 399)
OR 1.22

(0.87 to 1.7)
2505

(8 studies)
LowImprecision, inadequate explanation of methods, high statistical heterogeneity (I-squared =69%)

Cheong 2013

Acupuncture versus no ac up[uncture around the time of oocyte retrieval
357 per 1000326 per 1000

(247 to 418)
OR 0.87

(0.59 to 1.29)
464

(2 studies)
LowImprecision, inadequate explanation of methods, high statistical heterogeneity (I-squared =69%)

Duffy 2010

Growth hormone versus placebo
146 per 1000184 per 1000 (64

to 431)
OR 1.32 (0.4 to 4.43)80

(2 studies)
ModerateSome evidence of imprecision

Duffy 2010

Growth hormone versus placebo – poor responders
50 per 1000221 per 1000

(90 to 447)
OR 5.39

(1.89 to 15.35)
165

(4 studies)
ModerateSome of the studies did not provide adequate explanation of randomisation and/or allocation concealment

Siristatidis 2011

Aspirin versus placebo or no treatment
227 per 1000211 per 1000

(170 to 266)
RR 0.91

(0.72 to 1.15)
1053

(3

studies)
ModerateSome evidence of methodological limitations

2.2 For selected populations


Tso 2009

Metformin versus placebo or no treatment
287 per 1000236 per 1000

(98 to 467)
OR 0.77

(0.27 to 2.18)
272

(3 studies)
LowEvidence of lack of precision and heterogeneity

3. Down-regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection
4 per 10023 per 100

(181 to 292)
OR 0.95

(0.7 to 1.31)
873
(7 studies)
lowNo differences in the results were detected on sensitivity analysis for adequate allocation concealment: OR 0.95 (0.64 to 1.41). 514 participants in 4 studies.

Most of the studies were classified as at unclear risk of bias for all domains.
The total number of events was fewer than 300.
There were insufficient studies to assess publication bias

Al-Inany 2011

GnRH antagonist versus long course GnRH agonist
314 per 1000282 per 1000

(240 to 331)
OR 0.86

(0.69 to 1.08)
1515

(9

studies)
ModerateLack of detail for some trials on methodological details and a lack of blinding due to the nature of the interventions

Maheshwari 2011

Long versus short protocol for pituitary suppression in ART
134 per 1000218 per 1000

(124 to 351)
OR 1.8 (0.92 to 3.5)251

(3 studies)
Very lowSerious methodological limitations in the included studies and only 3 of 29 studies reported on live birth

Maheshwari 2011

Long versus ultra-short protocol for pituitary suppression in ART
122 per 1000198 per 1000

(91 to 376)
OR 1.78

(0.72 to 4.36)
150 (1 study)Very lowEvidence based on a single trial with wide confidence intervals and methodological limitations

4. Ovarian stimulation

4.1 Medication type

Gibreel 2012

Clomiphene citrate with gonadotropins (with or without mid-cycle GnRH antagonist) versus gonadotropins with GnRH agonists protocols in IVF and ICSI cycles
228 per 1000215 per 1000

(169 to 268)
OR 0.93

(0.69 to 1.24)
1079
(5 studies)
lowWide 95% confidence intervals

Method of allocation concealment was either not described or not mentioned at all in some included trials.

Pouwer 2012

Long acting FSH (low dose) versus daily FSH
288 per 1000198 per 1000

(142 to 269)
OR 0.61

(0.41 to 0.91)
645

(3 studies)
LowOpen label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (medium dose) versus daily FSH
336 per 1000343 per 1000

(298 to 391)
OR 1.03

(0.84 to 1.27)
1657 (3

studies)
LowOpen label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (high dose) versus daily FSH
375 per 1000161 per 1000

(29 to 533)
OR 0.32

(0.05 to 1.9)
33 (1 study)Very lowOpen label trials included with evidence of imprecision due to low events and evidence based on a single trial

Mochtar 2007

Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) versus rFSH alone for controlled ovarian hyperstimulation
233 per 1000247 per 1000

(194 to 307)
OR 1.14

(0.84 to 1.54)
963 (5 studies)LowSome methodological detail was unclear and one of the studies was open label. Heterogeneity was >50% (I-squared)

van Wely 2011

rFSH versus urinary gonadotrophins
245 per 1000239 per 1000

(220 to 260)
OR 0.97

(0.87 to 1.08)
7339 (28

studies)
HighThere was a lack of blinding

Martins 2013

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques
14 per 10022 per 100RR 1.56

(0.75 to 3.25)
130 (2 studies)V ery lowVery serious imprecision, high risk of bias

Smulders 2010

Combined oral contraceptive plus antagonist versus antagonist
292 per 1000150 per 1000
(43 to 417)
OR 0.43
(0.11 to 1.74)
45
(1 study)
⊕⊝⊝⊝
very low
Serious risk of imprecision, risk of bias

Smulders 2010

Combined oral contraceptive plus antagonist versus agonist
187 per 1000187 per 1000
(99 to 325)
OR 1
(0.48 to 2.1)
182
(1 study)
⊕⊝⊝⊝
very low
Serious risk of imprecision, risk of bias

4.3 Interventions for poor responders

Pandian 2010

Low dose GnRHa flare up versus spontaneous natural cycle IVF
85 per 100086 per 1000

(26 to 245)
OR 1.01

(0.29 to 3.5)
129 (1 study)LowEvidence based on a single trial with evidence of imprecision

4.4 Natural cycle IVF

Allersma 2013125 per 100028 per 1000

(1 to 393)
OR 0.20

(0.01 to 4.54)
30 (1 study)Very lowHigh risk of performance bias. Very serious imprecision

5. Ovulation triggering

Youssef 2011a

GnRH agonist versus HCG
345 per 1000237 per 1000

(185 to 302)
OR 0.59

(0.43 to 0.82)
744

(6 studies)
ModerateNo evidence of blinding in many of the trials

Youssef 2011

rhCG versus uhCG
400 per 1000409 per 1000

(345 to 477)
OR 1.04

(0.79 to 1.37)
1019

(6 studies)
Moderate2 of the trials were open label and one of the trials lacked details on randomisation, allocation concealment and blinding

Youssef 2011

rhLH versus uhCG
199 per 1000189 per 1000

(110 to 304)
OR 0.94

(0.5 to 1.76)
280

(2 studies)
LowOne of the trials lacked adequate methodological details and there was evidence of imprecision

6. Oocyte retrieval

Kwan 2013

Conscious sedation (IV alfentanyl) plus paracervical block versus electroacupuncture plus paracervical block
176 per 1000334 per 1000 (184

to 601)
OR 2.35 (1.09 to 5.05)149 (1 study)LowEvidence based on a single trial

8. Laboratory phase

Carney 2012

Assisted hatching versus no assisted hatching
305 per 1000311 per 1000 (271 to 356)OR 1.03

(0.84 to 1.26)
1921 (9

studies)
ModerateMany of the trials had some methodological limitations or missing information

Bontekoe 2012

Embryo culture with low oxygen concentrations versus atmospheric oxygen concentration
309 per

1000
383 per 1000 (332

to 440)
OR 1.39

(1.11 to 1.76)
1291 (3 studies)ModerateIn one of the trials there was no allocation concealment and in another trial the method of allocation concealment was unclear

Twisk 2006

Preimplantation genetic screening versus no screening in women with advanced age
259 per 1000171 per 1000 (133 to 221)OR 0.59

(0.44 to 0.81)
1062 (5 studies)ModerateOnly one of the studies described an adequate method of allocation concealment.

Twisk 2006

Preimplantation genetic screening versus no screening in women with good prognosis
416 per 1000263 per 1000 (130

to 461)
OR 0.5 (0.21 to 1.2)388 (3 studies)Very lowMethodological details were unclear or inadequate, heterogeneity was high >60%, evidence of imprecision

Teixeira 2013

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection
38 per 10044 per 100

(30 to 63)
RR 1.14

(0.79 to 1.64)
168

(1 study)
LowSerious imprecision

9. Embryo transfer

9.1 Developmental stage

Glujovsky 2012

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology
312 per 1000389 per 1000 (339

to 441)
OR 1.4 (1.13 to 1.74)1510 (12

studies)
ModerateSome methodological details were unclear or inadequate

Gunby 2004

Day 3 versus Day 2 embryo transfer
315 per 1000330 per 1000 (279

to 387)
OR 1.07

(0.84 to 1.37)
1200 (3

studies)
LowHeterogeneity >60% and evidence of imprecision

9.2 Number of embryos

Pandian 2013

Double embryo transfer versus single embryo transfer (one cycle only)
292 per 1000460 per 1000

(409 to 514)
OR 2.07

(1.68 to 2.57)
1564

(9 studies)
High36% of women noncompliant with treatment allocation in one study: however no heterogeneity detected (I2 = 0%).

Pandian 2013

Double embryo transfer versus repeated single embryo transfer
374 per 1000421 per 1000

(354 to 492)
OR 1.22

(0.92 to 1.62)
811

(3 studies)
LowNone of studies describe adequate allocation concealment, imprecision

Pandian 2013

Double embryo transfer versus three embryo transfers
273 per 1000130 per 1000 (33

to 410)
OR 0.4

(0.09 to 1.85)
45 (1 study)Very lowRandomisation and blinding were unclear, evidence is based on a single trial with evidence of imprecision

Pandian 2013

Double embryo transfer versus four embryo transfers
536 per 1000288 per 1000

(113 to 548)
OR 0.35

(0.11 to 1.05)
56 (1 study)Very lowRandomisation, allocation concealment and blinding were unclear, evidence is based on a single trial with evidence of imprecision

9.3 Transfer techniques and procedures

Bontekoe 2010

Transfer medium enriched with hyaluronic acid versus medium devoid of hyaluronic acid
366 per 1000438 per 1000 (332

to 550)
OR 1.35

(0.96 to

2.12)
324 (3 studies)ModerateEvidence of imprecision

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer
213 per 1000236 per 1000 (201

to 273)
OR 1.14

(0.93 to

1.39)
2264 (3

studies)
LowNo reporting of blinding and evidence of heterogeneity >60%

Derks 2009

Cervical dilatation versus no intervention
190 per 100097 per 1000 (60 to 155)OR 0.46

(0.27 to 0.78)
288 (1 study)ModerateEvidence based on a single trial

10. Luteal phase support

van der Linden 2011

hCG versus placebo/no treatment
120 per

1000
235 per 1000

(48 to 653)
OR 2.25

(0.37 to 13.8)
38 (1 study)LowEvidence is based on a single trial. Insufficient methodological details provided. Evidence of imprecision.

van der Linden 2011

Progesterone versus placebo/no treatment
38 per 1000104 per 1000

(39 to 253)
OR 2.95

(1.02 to 8.56)
156 (1 study)LowEvidence is based on a single trial. Insufficient methodological details provided. Evidence of imprecision.

Boomsma 2012

Peri-implantation glucocorticoids versus no glucocorticoids
115 per 1000136 per 1000

(80 to 224)
OR 1.21

(0.67 to 2.19)
424

(3 studies)
LowLacked details around methodology and there was evidence of imprecision

Akhtar 2013

Heparin versus control or no heparin
173 per 1000271 per 1000

(183 to 378)
OR 1.77

(1.07 to 2.90)
386

(3 studies)
Very lowSelection Bias found in one study. High Heterogeneity. Results sensitive to choice of statistical model

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

D'Angelo 2007

Cryopreservation versus fresh embryo transfer
373 per 1000380 per 1000

(1 to 128)
OR1.03

(0.5 to 2.12)
125 (1 study)LowEvidence based on a single open label study with insufficient methodological details provided. Evidence of imprecision

D'Angelo 2011

Coasting versus no coasting
265 per 1000148 per 1000

(48 to 369)
OR 0.48

(0.14 to 1.62)
68 (1 study)Very lowEvidence based on a single conference abstract, evidence of imprecision, there were insufficient methodological details provided

12. Frozen embryo replacement cycles

Ghobara 2008

Oestrogen + progesterone frozen thawed embryo transfer (FET) versus GnRHa, oestrogen and progesterone preparations FET
197 per

1000
85 per 1000 (40

to 170)
OR 0.38

(0.17 to

0.84)
234 (1 study)LowEvidence based on a single trial and open label

Glujovsky 2010

GnRH agonists versus control for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
85 per 1000197 per 1000

9100 to 351)
OR 2.62

(1.19 to

5.78)
234 (1 study)Very lowEvidence based on a single, open label trial. Evidence of imprecision.

Glujovsky 2010

Intramuscular progesterone versus vaginal progesterone for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
214 per

1000
326 per 1000 (188

to 501)
OR 1.77

(0.85 to

3.68)
153 (1 study)Very lowEvidence based on a single, open label trial. Insufficient methodological details provided. Evidence of imprecision.

 
Table 5. Clinical pregnancy per woman

Outcome

Intervention and comparison intervention
Assumed risk with ComparatorCorresponding risk with interventionRelative effect

(95%CI)
Number of participants

(Studies)
Quality of the evidence

(GRADE)
Comments

1. Indication for ART

Pandian 2012

IVF versus expectant management for unexplained subfertility
122 per 1000310 per 1000

(129 to 576)
OR 3.24

(1.07 to

9.8)
86 (2

studies)
Very LowMethodological design limitations including inadequate details of blinding in both trials. One trial also had inadequate details of allocation concealment and high attrition bias. Heterogeneity was high at 80%

Pandian 2012

IVF versus intra-uterine insemination + ovarian stimulation for unexplained subfertility (treatment naïve women
224 per 1000241 per 1000

(148 to 370)
OR 1.1

(0.6 to

2.03)
232 (2

studies)
ModerateThe trials lacked adequate methodological details

2. Pre-ART and adjuvant strategies

2.1 For unselected populations

Nastri 2011

Endometrial injury prior to ovulation induction (pipelle induced) versus no endometrial injury
211 per 1000411 per 1000

(314 to 515)
OR 2.61

91.71 to

3.97)
435 (4

studies)
ModerateSome evidence of imprecision and some methodological details were unclear

Showell 2010

Antioxidant versus control
31 per 1000118 per 1000

(78 to 174)
4.18 (2.65

to 6.59)
964 (15

studies)
Very lowInadequate details of methodology, lack of head to head comparisons

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment
231 per 1000281 per 1000

(217 to 357)
OR 1.30

(0.92 to 1.85)
2441

(13 studies)
Very lowSerious imprecision, some methodological details were unclear, types of subfertility and antioxidants used differed across trials.

Duffy 2010

Growth hormone compared with placebo
273 per 1000401 per 1000

(155 to 709)
OR 1.78

(0.49 to

6.5)
42 (1 study)ModerateEvidence based on a single trial and some evidence of imprecision

Duffy 2010

Growth hormone compared with placebo – poor responders
122 per 1000313 per 1000

(195 to 463)
OR 3.28

(1.74 to

6.2)
279 (8

studies)
HighAdequate description of methodology, no evidence of imprecision or heterogeneity

Siristatidis 2011

Aspirin versus placebo or no treatment
299 per 1000317 per 1000

(290 to 347)
RR 1.03

(0.91 to

1.17)
2142 (10

studies)
LowAll of the trials failed to provide adequate information on incomplete outcome data. There was also inadequate details on allocation concealment and blinding in some of the trials

Cheong 2013

Acupuncture versus no acupuncture on or around the day of embryo transfer
375 per 1000399 per 1000

(343 to 460)
OR 1.11

(0.87 to 1.42)
3632

(14 studies)
Very lowOnly 3/14 studies described adequate allocation concealment, serious heterogeneity (I-squared =66%), imprecision

Cheong 2013

Acupuncture versus no acupuncture around the time of oocyte retrieval
346 per 1000372 per 1000

(292 to 461)
OR 1.12

(0.78 to 1.62)
912

(6 studies)
LowInadequate descriptio of study methods, serious imprecision

2.2 For selected populations

Johnson 2010

Salpingectomy versus no surgical treatment
189 per 1000359 per 1000

(258 to 441)
OR 2.2

(1.26 to

3.82)
329

(3 studies)
ModerateNo evidence of blinding in any of the trials. Heterogeneity: I-squared 52%

Johnson 2010

Tubal occlusion versus no surgical treatment
123 per 1000396 per 1000

(234 to 585)
OR 4.66

(2.17 to

10.01)
209

(2 studies)
ModerateRandomisation methods not fully described

Johnson 2010

Aspiration of hydro salpingeal fluid versus no surgical treatment
188 per 1000313 per 1000

(125 to 592)
OR 1.97

(0.62 to

6.29)
64

(1 study)
Very lowEvidence based on a single trial with imprecision

Benschop 2010

Aspiration of endometrioma versus expectant management prior to ART
200 per 1000244 per 1000

(101 to 476)
OR 1.29

(0.45 to

3.64)
81

(1 study)
LowEvidence was based on a single trial, wide confidence intervals which cross line of no effectl

Benschop 2010

Cystectomy of endometrioma versus expectant management prior to ART
317 per 1000348 per 1000

(194 to 542)
OR 1.15

(0.52 to

2.55)
109

(1 study)
LowEvidence was based on a single trial, wide confidence intervals which cross line of no effectl

Benschop 2010

GnRH agonist versus GnRH antagonist prior to ART
242 per 1000206 per 1000

(77 to 448)
OR 0.81

(0.26 to

2.54)
67

(1 study)
LowEvidence was based on a single trial, wide confidence intervals which cross line of no effect

Benschop 2010

Ablation versus cystectomy prior to ART
366 per 1000293 per 1000

(126 to 545)
OR 0.72

(0.25 to 2.08)
65

(1 study)
Very lowUnclear risk of bias related to sequence generation. Single small study, wide confidence intervals cross line of no effect

Tso 2009

Metformin versus placebo or no treatment
329 per 1000258 per 1000

(160 to 385)
OR 0.71

(0.39 to

1.28)
426

(5 studies)
ModerateThree of the trials were open label and there was inadequate details provided for allocation concealment

3. Down-regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection
30 per 10029 per 100

(25 to 35)
OR 0.96

(0.75 to 1.23)
1259
(11 studies)
moderateNo differences in the results were detected on sensitivity analysis for adequate allocation concealment: OR 0.96 (0.68 to 1.37). 574 participants in 5 studies.

Most of the studies were classified as at unclear risk of bias for all domains.

Al-Inany 2011

GnRH antagonist versus long course GnRH agonist
315 per 1000279 per 1000

(257 to 302)
OR 0.84

(0.75 to

0.94)
6571

(41 studies)
ModerateLack of detail for some trials on methodological details and a lack of blinding due to the nature of the interventions

Sallam 2006

Ultralong GnRH agonist versus conventional stimulation protocols
395 per 1000516 per 1000

(340 to 687)
OR 1.63

(0.79 to 3.36)
149

(3 studies)
Very lowAll of the trials were subject to methodological limitations, the outcome is an intermediate outcome and there was evidence of lack of precision

Maheshwari 2011

Long versus short protocol for pituitary suppression in ART
177 per 1000244 per 1000

(200 to 293)
OR 1.5

(1.16 to 1.93)
1437

(20 studies)
LowThere were serious methodological limitations associated with many of the included trials

Maheshwari 2011

Long versus ultra-short protocol for pituitary suppression in ART
154 per 1000220 per 1000

(127 to 354)
OR 1.55

(0.8 to

3.01)
230

(2 studies)
LowThere were serious methodological limitations associated with both trials

4. Ovarian stimulation

4.1 Medication type

Gibreel 2012

Clomiphene citrate with gonadotropins (with or without mid-cycle GnRH antagonist) versus gonadotropins with GnRH agonists protocols in IVF and ICSI cycles
231 per 1000243 per 1000

(203 to 285)
OR 1.07

(0.85 to 1.33)
1864
(10 studies)
moderateMethod of allocation concealment was either not described or not mentioned at all in some included trials.

Mochtar 2007

Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) versus rFSH alone for controlled ovarian hyperstimulation
260 per 1000300 per 1000

(268 to 335)
OR 1.22

(1.04 to

1.43)
3209

(15 studies)
ModerateSome of the trials lacked sufficient methodological details

van Wely 2011

rFSH versus urinary gonadotrophins
282 per 1000280 per 1000

(263 to 299)
OR 0.99

(0.91 to

1.09)
9482

(41 studies)
ModerateNo evidence of blinding conducted in most of the studies

Martins 2013

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques
35 per 10041 per 100

(32 to 54)
RR 1.19 (0.92 to 1.55351

(5 studies)
LowImprecision, high risk of bias

Smulders 2010

Combined oral contraceptive plus agonist versus agonist
333 per 1000373 per 1000
(209 to 571)
OR 1.19
(0.53 to 2.66)
102
(1 study)
very lowSingle study. Wide confidence intervals which cross line of no effect.

Smulders 2010

Combined oral contraceptive plus antagonist versus antagonist
255 per 1000191 per 1000
(146 to 248)
OR 0.69
(0.5 to 0.96)
847
(4 studies)
lowImprecision, high risk of bias

Smulders 2010

Combined oral contraceptive plus antagonist versus agonist
245 per 1000210 per 1000
(147 to 290)
OR 0.82
(0.53 to 1.26)
472
(3 studies)
lowImprecision, one study does not describe satisfactory method of sequence generation, one does not describe satisfactory method of allocation concealment, one at high risk of attrition bias.

4.2. Monitoring

Kwan 2008

Ultrasound + estradiol versus ultrasound only
309 per 1000330 per 1000

(238 to 460)
RR 1.07

(0.77 to 1.49)
297 (1 study)ModerateEvidence based on a single trial

4.3 Interventions for poor responders

Pandian 2010

Cessation of GnRHa on stop protocol versus conventional GnRHa long protocol
176 per 1000138 per 1000

(43 to 370)
OR 0.75

(0.21 to

2.74)
70 (1 study)LowEvidence based on a single trial with no blinding

Pandian 2010

GnRH antagonist versus conventional GnRHa long protocol
67 per 1000167 per 1000

(34 to 529)
OR 2.8

(0.5 to

15.73)
60 (1 study)Very lowEvidence based on a single trial with lack of methodological detail and evidence of imprecision

Pandian 2010

GnRH a flare up versus GnRHa long protocol
286 per 100077 per 1000

(16 to 304)
OR 0.21

(0.04 to

1.09)
54 (1 study)Very lowEvidence based on a single trial with lack of methodological detail and evidence of imprecision

Pandian 2010

GnRH antagonist versus GnRH a flare up protocol
163 per 1000163 per 1000

(62 to 363)
OR 1

(0.34 to

2.92)
98 92

studies)
LowLack of methodological details and evidence of imprecision

Pandian 2010

Low dose GnRHa flare up protocol versus spontaneous natural cycle IVF
119 per 1000101 per 1000

(35 to 252)
OR 0.83

(0.27 to

2.5)
129 (1

study)
LowEvidence based on a single trial with evidence of imprecision

Pandian 2010

Multiple dose GnRH agonist versus mini dose long agonist protocol
244 per 1000227 per 1000

(99 to 439)
OR 0.91

(0.34 to

2.42)
89 (1 study)LowNo allocation concealment or blinding, evidence based on a single trial with evidence of imprecision

Pandian 2010

Flare up protocol versus modified long protocol
381 per 1000142 per 1000

(36 to 429)
OR 0.27

(0.06 to

1.22)
42 (1 study)LowEvidence based on a single trial with evidence of imprecision

Pandian 2010

Long protocol versus modified long protocol
381 per 1000105 per 1000

(18 to 398)
OR 0.19

(0.03 to

1.06)
40 (1 study)LowEvidence based on a single trial with evidence of imprecision

4.4 Natural cycle IVF

Allersma 2013112 per 100086 per 1000

(36 to 194)
OR 0.75

(0.3 to 1.91)
219

(3 studies)
Low1/3 studie did not report adequate allocaiton concealment, risk of performace bias, wide confidence intervals

5. Ovulation triggering

Youssef 2011a

GnRH agonist versus HCG
428 per 1000337 per 1000

(280 to 397)
OR 0.68

(0.52 to

0.88)
1090 (12

studies)
ModerateNo evidence of blinding in many of the trials

Youssef 2011

rHCG versus UhCG
312 per 1000367 per 1000

(312 to 428)
OR 1.28

(1 to 1.65)
1206 (8

studies)
HighOverall well designed trials included

Youssef 2011

rhLH versus uhCG
265 per 1000251 per 1000

(160 to 370)
OR 0.93

(0.53 to

1.63)
280 (2

studies)
LowOne of the trials lacked adequate methodological details and there was evidence of imprecision

6. Oocyte retrieval

Kwan 2013

Conscious sedation versus conscious sedation + electro-acupuncture (VAS)
241 per 1000594 per 1000 (326 to 815)OR 4.59 (1.52 to 13.87)61 (1 study)Very lowOne small study

Kwan 2013

Conscious sedation versus conscious sedation + acupuncture (VAS)
241 per 1000344 per 1000OR 1.65 (0.54 to 5.05)61 (1 study)Very lowOne small study

Kwan 2013

Conscious sedation and analgesia versus general anaesthesia
200 per 1000100 per 1000OR 1 (0.25 to 4)50 (1 study)Very lowOne small study

Kwan 2013

Conscious sedation+paracervical block versus general anaesthesia
375 per 1000296 per 1000OR 0.7 (0.22 to 1.2651 (1 study)Very lowOne small study

Kwan 2013

Conscious sedation+paracervical block versus spinal anaesthesia
375 per 1000358 per 1000OR 0.93 (0.24 to 3.65)38 (1 study)Very lowOne small study

Kwan 2013

Conscious sedation+ paracervical block versus paracervical block only
253 per 1000240 per 1000OR 0.93 (0.44 to 1.96)150 (1 study)Very lowOne small study

Kwan 2013

Conscious sedation+paracervical block versus electro-acupuncture+paracervical block
367 per 1000358 per 1000OR 0.96 (0.72 to 1.29)783 (4 studies)HighAdequate methodology, low heterogeneity

Kwan 2013

Conscious sedation and analgesia: pt controlled vs physician controlled
182 per 1000168 per 1000OR 0.91 (0.45 to 1.83)218 (2 studies)ModerateAdequate methodology, low heterogeneity, sample size suboptimal

Wongtra-ngan 2010

Follicular flushing versus no flushing
229 per 1000258 per 1000

(145 to 414)
OR 1.17

(0.57 to

2.38)
164 (3

studies)
ModerateTrials lacked sufficient methodological details

7. Sperm retrieval

Proctor 2008

Microsurgical epididymal sperm aspiration versus epididymal micropuncture with perivascular nerve stimulation
233 per 100055 per 1000 (12

to 202)
OR 0.19

(0.04 to 0.83)
59 (1 study)LowEvidence based on a single trial with insufficient methodological detail

8. Laboratory phase

Carney 2012

Assisted hatching versus no assisted hatching
332 per 1000360 per 1000

(334 to 387)
OR 1.13

(1.01 to 1.27)
5728
(31 studies)
ModerateThere were methodological limitations or missing information in most of the trials

Van Rumste 2003

Intracytoplasmic sperm injection versus in vitro fertilisation
252 per 1000329 per 1000

(243 to 429)
OR 1.45

(0.95 to

2.22)
415 (1

study)
LowDetails of blinding were unclear and the evidence is based on a single trial

Bontekoe 2012

Embryo culture with low oxygen concentrations versus atmospheric oxygen concentration
369 per 1000442 per 1000

(387 to 494)
OR 1.35

(1.08 to 1.67
1382 (4

studies)
ModerateIn one of the trials there was no allocation concealment and in another trial the method of allocation concealment was unclear

Twisk 2006

Preimplantation genetic screening versus no screening in women with advanced age
291 per 1000187 per 1000

(144 to 235)
OR 0.56

(0.41 to 0.75)
1000 (4

studies)
ModerateOnly one of the studies described an adequate method of allocation concealment.

Huang 2013

Brief co-incubation versus standard insemination
177 per 1000337 per 1000

(238 to 453)
OR 2.36

(1.45 to 3.85)
372
(3 studies)
LowOne trial lacked adequate explanation for methods of randomization. Allocation concealment not mentioned in any trial.

Teixeira 2013

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction
33 per 10043 per 100

(36 to 52)
RR 1.29

(1.06 to 1.55)
2014

(9 studies)
Very lowHigh risk of bias (differences within studies between number of oocytes transferred), inconsistency across studies, publication bias strongly suspected.

9. Embryo transfer

9.1 Developmental stage

Glujovsky 2012

Cleavage stage transfer versus blastocyst stage transfer
388 per 1000420 per 156)OR 1.14

(0.99 to 1.32)
3241 (23

studies)
ModerateSome methodological details were unclear or inadequate. Significant heterogeneity but I2 < 50%

9.2 Number of embryos

Pandian 2013

Double embryo transfer versus single embryo transfer (one cycle only)
357 per 1000553 per 1000

(500 to 605)
OR 2.23

(1.80 to 2.76)
1505

(7 studies)
ModerateMost studies do fully describe method of allocation concealment

Pandian 2013

Double embryo transfer versus repeated single embryo transfer
524 per 1000483 per 1000

(413 to 554)
OR 0.85

(0.64 to 1.13)
752

(2 studies)
LowMethod of allocation concealment not fully described in either trial, some inconsistency (I squared =47%)

Pandian 2013

Double embryo transfer versus three embryo transfers
273 per 1000305 per 1000

(107 to 614)
OR 1.17

(0.32 to 4.25)
45 (1 study)Very lowRandomisation and blinding were unclear, evidence is based on a single trial with evidence of imprecision

Pandian 2013

Double embryo transfer versus four embryo transfers
607 per 1000537 per 1000

(287 to 769)
OR 0.75

(0.26 to 2.16)
56 (1 study)Very lowRandomisation, allocation concealment and blinding were unclear, evidence is based on a single trial with evidence of imprecision

9.3 Transfer techniques

Gunby 2004

Day 2 versus Day 3 embryo transfer
404 per 1000392 per 1000

(363 to 423)
OR 0.95

(0.84 to 1.08)
3980 (13

studies)
LowHeterogeneity >60%, lack of details regarding blinding

Bontekoe 2010

Transfer medium enriched with hyaluronic acid versus medium devoid of hyaluronic acid
241 per 1000385 per 1000OR 1.97

(1.46 to 2.67)
886 (6 studies)ModerateEvidence of heterogeneity >50%

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer
279 per 1000336 per 1000

(313 to 361)
OR 1.31

(1.18 to 1.46)
6415 (17 studies)ModerateSubjects were unable to be blinded but no reporting of blinding of researchers or outcome assessors was reported

Kroon 2012

Antibiotics prior to embryo transfer versus no antibiotics
355 per 1000359 per 1000

(266 to 465)
1.02 (0.66 to 1.58)350 (1 study)HighNot all of the patients were followed up for one of the outcomes (bacterial contamination)

Derks 2009

Cervical dilatation versus no intervention
232 per 1000124 per 1000

(78 to 189)
OR 0.47

(0.28 to 0.77)
288 (1 study)ModerateEvidence based on a single study

Derks 2009

Straightening the endocervical angle versus no intervention
271 per 1000267 per 1000

(175 to 384)
OR 0.98

(0.57 to 1.68)
273 (2 studies)ModerateEvidence of imprecision

Derks 2009

Removal of cervical mucus versus no intervention
327 per 1000320 per 1000

(169 to 522)
OR 0.97

(0.42 to 2.25)
97 (1 study)LowLack of methodological details, evidence of imprecision and evidence based on a single trial

Derks 2009

Flushing the endocervical canal versus no intervention
413 per 1000445 per 1000

9360 to 533)
OR 1.14

(0.8 to 1.62)
537 (3 studies)LowLack of methodological details, heterogeneity >50%

Derks 2009

Flushing the endometrial cavity versus no intervention
519 per 1000584 per 1000

(437 to 718)
OR 1.3

(0.72 to 2.36)
181 (1 study)LowLack of methodological details, evidence of imprecision and evidence based on a single trial

Abou-Setta 2009

Mechanical pressure versus no intervention
478 per 1000637 per 1000

(561 to 706)
OR 1.92

(1.4 to 2.63)
639 (1 study)LowEvidence based on a single trial, method of randomisation was unclear and the trial was open label

Abou-Setta 2009

Fibrin sealant versus no intervention
291 per 1000287 per 1000

(181 to 422)
OR 0.98

(0.54 to 1.78)
211 (1 study)LowEvidence based on a single trial with inadequate allocation concealment

Abou-Setta 2009

Less bed rest versus more bed rest
277 per 1000303 per 1000

(228 to 391)
OR 1.13

(0.77 to 1.67)
542 (2 studies)ModerateOne of the trials was open label

10. Luteal phase support

van der Linden 2011

hCG versus placebo/no treatment
169 per 1000209 per 1000

(155 to 277)
OR 1.3

(0.9 to

1.88)
746 (5

study)
LowInsufficient methodological details provided. Evidence of imprecision.

van der Linden 2011

Progesterone versus placebo/no treatment
140 per 1000230 per 1000

(174 to 298)
OR 1.83

(1.29 to

2.61)
841 (7

study)
LowInsufficient methodological details provided. Evidence of imprecision.

Boomsma 2012

Peri-implantation glucocorticoids versus no glucocorticoids
290 per 1000320 per 1000

(275 to 369)
OR 1.15

(0.93 to

1.43)
1759 (13

studies)
ModerateMost of the studies lacked adequate blinding

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

D'Angelo 2007

Cryopreservation versus fresh embryo transfer
463 per 1000482 per 1000

(318 to 654)
OR1.08

(0.54 to

2.19)
125 (1

study)
LowEvidence based on a single open label study with insufficient methodological details provided. Evidence of imprecision

D'Angelo 2007

Cryopreservation versus intravenous albumin
385 per 100036 per 1000 (0

to 423)
OR 0.06

(0 to 1.17)
26 (1 study)LowEvidence based on a single, open label trial with evidence of imprecision

Youssef 2011b

Intravenous fluids for the prevention of OHSS versus placebo
69 per 100058 per 1000 (40

to 85)
OR 0.84

(0.56 to

1.26)
1522 (7

studies)
LowInsufficient methodological details provided and evidence of imprecision

D'Angelo 2011

Coasting versus no coasting
353 per 1000234 per 1000

(98 to 471)
OR 0.56

(0.2 to

1.63)
68 (1 study)Very lowEvidence based on a single trial. Insufficient methodological details provided and evidence of imprecision

Tang 2012

Cabergoline versus placebo/no treatment
429 per 1000403 per 1000

(240 to 682)
OR 0.94

(0.56 to

1.59)
230 (2

studies)
LowAllocation concealment inadequately reported in both trials. One trial provided insufficient details on blinding both trials had issues for incomplete outcome data reporting

12. Frozen embryo replacement cycles

Ghobara 2008

Oestrogen + progesterone frozen thawed embryo transfer (FET) versus natural cycle FET
205 per 1000214 per 1000

(93 to 419)
OR 1.06

(0.4 to

2.8)
100 (1

study)
Very lowEvidence based on a single trial, insufficient methodological details provided, open label and evidence of imprecision

Ghobara 2008

Oestrogen + progesterone frozen thawed embryo transfer (FET) versus GnRHa, oestrogen and progesterone preparations FET
215 per 1000173 per 1000

(125 to 232)
OR 0.76

(0.52 to

1.1)
725 (4

studies)
LowHeterogeneity >50%, included open label trials, some of the trials failed to provide adequate methodological details

Ghobara 2008

Oestrogen + progesterone frozen thawed embryo transfer (FET) versus FSH ovulation induction FET
128 per 1000109 per 1000

949 to 228)
OR 0.84

(0.35 to

2.02)
194 (1

study)
Very lowEvidence based on a single trial, there were insufficient methodological details provided and the trial was open label. There was also evidence of imprecision

Ghobara 2008

Clomiphene frozen thawed embryo transfer (FET) versus oestrogen and progesterone FET
96 per 100075 per 1000 (22

to 228)
OR 0.76

(0.21 to

2.77)
119 (1

study)
Very lowEvidence based on a single trial, there were insufficient methodological details provided. There was also evidence of imprecision

Ghobara 2008

Clomiphene frozen thawed embryo transfer (FET) versus GnRHa + oestrogen and progesterone FET
162 per 100075 per 1000 (23

to 221)
OR 0.42

(0.12 to

1.47)
104 (1

study)
Very lowEvidence based on a single trial, there were insufficient methodological details provided. There was also evidence of imprecision

Ghobara 2008

Clomiphene + HMG frozen thawed embryo transfer (FET) versus HMG FET
275 per 1000148 per 1000OR 0.46

(0.23 to

0.92)
209 (1

study)
LowEvidence based on a single trial, there were insufficient methodological details provided.

Glujovsky 2010

GnRH agonists versus control for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
215 per 1000246 per 1000

(167 to 347)
OR 1.19

(0.73 to

1.94)
778 (5

studies)
ModerateAll of the trials were open label and there was insufficient methodological details in many of the studies

Glujovsky 2010

Intramuscular progesterone versus vaginal progesterone for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
261 per 1000337 per 1000

(257 to 426)
OR 1.44

(0.98 to

2.1)
655 (4

studies)
ModerateAll of the trials were open label and there was insufficient methodological details in many of the studies

 
Table 6. OHSS per woman

Outcome

Intervention and comparison intervention
Assumed risk with ComparatorCorresponding risk with interventionRelative effect

(95%CI)
Number of participants

(Studies)
Quality of the evidence

(GRADE)
Comments

1. Indication for ART

Pandian 2012

IVF versus intra-uterine insemination + ovarian stimulation for unexplained subfertility (treatment naïve women
34 per 100051 per 1000 (9

to 250)
OR 1.53

(0.25 to

9.49)
118 (1

study)
LowEvidence lacked precision and there was a inadequate explanation of blinding.

2. Pre-ART and adjuvant strategies

Tso 2009

Metformin versus placebo or no treatment
207 per 100059 per 1000 (30

to 109)
OR 0.24

(0.12 to

0.47)
449 (5

studies)
ModerateThe trials had methodological limitations

3. Down-regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection
3 per 1002 per 100

(1 to 6)
OR 0.84

(0.29 to 2.42)
570
(5 studies)
lowMost of the studies were classified as at unclear risk of bias for all domains.
The total number of events was fewer than 300.
There were insufficient studies to assess publication bias.

Al-Inany 2011

GnRH antagonist versus long course GnRH agonist
66 per 100030 per 1000 (23

to 39)
OR 0.43

(0.33 to

0.57)
5417 (29

studies)
LowMethodological limitations including lack of blinding and heterogeneity was 68%

Al-Inany 2011

rhCG versus uhCG
27 per 100040 per 1000

(169 to 331)
OR 0.39

(0.25 to

0.61)
374 (3

studies)
ModerateOne of the trials lacked methodological details on randomisation, allocation concealment and blinding

Al-Inany 2011

rhLH versus uhCG
125 per 1000105 per 1000

(53 to 194)
OR 0.82

(0.39 to

1.69)
280 (2

studies)
LowOne of the trials lacked adequate methodological details and there was evidence of imprecision

Kwan 2008

Ultrasound + estradiol versus ultrasound only
36 per 100026 per 1000 (14

to 49)
RR 0.74

(0.4 to

1.37)
1233 (2

studies)
LowMethodological limitations in one of the trials and evidence of imprecision

Boomsma 2012

Peri-implantation glucocorticoids versus no glucocorticoids
194 per 1000159 per 1000

(64 to 392)
OR 0.82

(0.33 to

2.02)
151 (2

studies)
LowMethodological limitations and evidence of imprecision

4. Ovarian stimulation

4.1 Medication type

Gibreel 2012

Clomiphene citrate with gonadotropins (with or without mid-cycle GnRH antagonist) versus gonadotropins with GnRH agonists protocols in IVF and ICSI cycles
35 per 10008 per 1000

(4 to 19)
OR 0.23

(0.1 to 0.52)
1559
(5 studies)
lowFew participants. Small number of events in outcome.
Very wide 95% confidence interval crossing the threshold points of appreciable benefit or harm, which is 25%.

Pouwer 2012

Long acting FSH (low dose) versus daily FSH
42 per 100051 per 1000 (23

to 110)
OR 1.23

(0.54 to 2.82)
645 (3

studies)
LowOpen label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (medium dose) versus daily FSH
62 per 100066 per 1000 (45

to 95)
OR 1.07

(0.72 to

1.58)
1657 (3

studies)
LowOpen label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (high dose) versus daily FSH
0 per 10000 per 1000 (0 to

0)
OR 1.81

(0.08 to

41.62)
33 (1 study)Very lowOpen label trials included with evidence of imprecision due to low events and evidence based on a single trial

Mochtar 2007

Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) versus rFSH alone for controlled ovarian hyperstimulation
20 per 100027 per 1000 (12

to 59)
OR 1.34

(0.58 to

3.09)
986 (7

studies)
LowSome methodological details were unclear and there is evidence of imprecision

Martins 2013

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques
3 per 1001 per 100

(0 to 4)
OR 0.30

(0.06 to1.59)
351

(5 studies)
Very lowVery serious imprecision, inconsistency, high risk of bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus antagonist
17 per 100025 per 1000
(5 to 133)
OR 1.5
(0.26 to 8.8)
234
(1 study)
very lowSingle study. Wide confidence intervals which cross line of no effect.
High risk of attrition bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus agonist
55 per 100035 per 1000
(12 to 100)
OR 0.63
(0.21 to 1.92)
290
(2 studies)
very lowSingle study. Wide confidence intervals which cross line of no effect.

One study has high risk of attrition bias

4.4 Natural cycle IVF

Allersma 201367 per 100013 per 1000

(1 to 393)
OR 0.10

(0.01 to 4.06)
60

(1 study)
Very lowAllocation concealment method not reported, very serious imprecision

5. Ovulation triggering

Youssef 2011a

GnRH agonist versus HCG
90 per 10006 per 1000

(2 to 18)
OR 0.06

(0.02 to 0.19)
962

(10 studies)
ModerateNo evidence of blinding in many of the trials

Wongtra-ngan 2010

rFSH versus urinary gonadotrophins
19 per 100022 per 1000

(16 to 30)
OR 1.18

(0.86 to 1.61)
7740

(32 studies)
HighThere was a lack of blinding

Youssef 2011

rhCG versus uhCG
27 per 100040 per 1000

(169 to 331)
OR 0.39

(0.25 to 0.61)
374

(3 studies)
ModerateOne of the trials lacked methodological details on randomisation, allocation concealment and blinding

Youssef 2011

rhLH versus uhCG
125 per 1000105 per 1000

(53 to 194)
OR 0.82

(0.39 to 1.69)
280

(2 studies)
LowOne of the trials lacked adequate methodological details and there was evidence of imprecision

10. Luteal phase support

van der Linden 2011

hCG versus placebo/no treatment
41 per 1000134 per 1000

(73 to 232)
OR 3.62

(1.85 to 7.06)
387

(1 study)
LowEvidence is based on a single trial. Insufficient methodological details provided. Evidence of imprecision.

Akhtar 2013

Heparin versus placebo or no treatment
250 per 1000349 per 1000

(256 to 458)
OR 1.61

(1.03 to 2.53)
386

(3 studies)
Very lowSelection Bias found in one study. High Heterogeneity. Results sensitive to choice of statistical model

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

Tang 2012

Cabergoline versus placebo/no treatment
312 per 1000125 per 1000

(62 to 240)
OR 0.40

(0.20 to 0.77)
230 (2

studies)
LowLack of details for allocation concealment

D'Angelo 2007

Cryopreservation versus fresh embryo transfer
60per 10008 per 1000 (318

1 to 128)
OR1.12

(0.01 to 2.29)
125

(1 study)
LowEvidence based on a single open label study with insufficient methodological details provided. Evidence of imprecision

D'Angelo 2007

Cryopreservation versus intravenous albumin
77 per 1000308 per 1000

(41 to 824)
OR 5.33

(0.51 to 56.24)
26

(1 study)
Very lowEvidence based on a single, open label trial with evidence of imprecision

Youssef 2011b

Intravenous human albumin for prevention of OHSS versus placebo
83 per 100057 per 1000OR 0.67

(0.45 to 0.99)
1660

(8 studies)
LowInsufficient methodological details provided. Heterogeneity was >60% (I2)

Youssef 2011b

Intravenous hydroxyethyl starch for prevention of OHSS versus placebo
46 per 10006 per 1000

(2 to 19)
OR 0.12

(0.04 to 0.4)
487

(3 studies)
ModerateInsufficient methodological details provided in some of the trials

D'Angelo 2011

Coasting versus no coasting
265 per 100058 per 1000

(11 to 241)
OR 0.17

(0.03 to 0.88)
68 (1 study)Very lowEvidence is based on a single conference abstract. There are insufficient methodological details provided and there is evidence of imprecision

 
Table 7. Multiple pregnancy per woman

Outcome

Intervention and comparison intervention
Assumed risk with ComparatorCorresponding risk with interventionRelative effect

(95%CI)
Number of participants

(Studies)
Quality of the evidence

(GRADE)
Comments

1. Indication for ART

Pandian 2012

IVF versus intra-uterine insemination + ovarian stimulation for unexplained subfertility (treatment naïve women)
131 per 100088 per 1000

(45 to 163)
OR 0.64

(0.31 to 1.29)
351

(3 studies)
ModerateThe trials lacked adequate methodological details

2. Pre-ART and adjuvant strategies

Siristatidis 2011

Aspirin versus placebo or no treatment
59 per 100050 per 1000

(27 to 91)
RR 0.74

(0.38 to 1.46)
680

(2 studies)
ModerateThere were some methodological limitations in the two trials

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment
67 per 100048 per 1000

(29 to 80)
OR 0.7

(0.41 to 1.21)
1022

(2 studies)
Very lowImprecision, some methodological details were unclear

Duffy 2010

Growth hormone compared with placebo
195 per 1000131 per 1000

(42 to 342)
OR 0.62

(0.18 to 2.15)
80

(2 studies)
ModerateSome evidence of lack of precision

Cheong 2013

Acupuncture versus no acupuncture on or around the day of embryo transfer
56 per 100072 per 1000

(42 to 122)
OR 1.32

(0.74 to 2.35)
795

(2 studies)
LowOnly 1/2 studies described adequate allocation concealment, wide confidence intervals crossed line of no effect

Nastri 2011

Endometrial injury prior to ovulation induction (pipelle induced) versus no endometrial injury
278 per

1000
251 per 1000

(81 to 559)
OR 0.87

(0.23 to 3.3)
46 (1 study)Very lowEvidence based on a single trial with imprecision

3. Down-regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection
24 per 10025 per 100

(13 to 43)
OR 1.1

(0.49 to 2.46)
132
(4 studies)
LowMost of the studies were classified as at unclear risk of bias for all domains.
The total number of events was fewer than 300.
There were insufficient studies to assess publication bias.

Boomsma 2012

Peri-implantation glucocorticoids versus no glucocorticoids
38 per 100074 per 1000

(31 to 168)
OR 2.02

(0.8 to 5.11)
372

(4 studies)
ModerateLacked methodological details

4. Ovarian stimulation

4.1 Medication type

Gibreel 2012

Clomiphene citrate (± urinary or recombinant gonadotrophin) versus urinary or recombinant gonadotrophin in either long or short protocols
233 per

1000
211 per 1000

(109 to 372)
OR 0.88

(0.4 to 1.95)
160

(4 studies)
ModerateThe studies lacked methodological details

Smulders 2010

Combined oral contraceptive pill plus antagonist versus antagonist
42 per 100092 per 1000
(10 to 507)
OR 2.32
(0.23 to 23.65)
45
(1 study)
Very lowImprecision,high risk of attrition bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus agonist
67 per 100068 per 1000
(26 to 168)
OR 1.02
(0.37 to 2.82)
238
(2 studies)
lowImprecision

4.4 Natural cycle IVF

Allersma 201329 per 10006 per 1000

(0 to 117)
OR 0.21

(0.01 to 4.38)
132

(1 study)
Very lowMethod of sequence generatin and allocation concealment not stated, high risk of attrition bias, very serious imprecisikon

5. Ovulation triggering

Youssef 2011a

GnRH agonist versus HCG
82 per 1000134 per 1000

(71 to 238)
OR 1.74

(0.86 to

3.5)
342 (3

studies)
ModerateNo evidence of blinding in many of the trials

van Wely 2011

rFSH versus urinary gonadotrophins
85 per 100078 per 1000 (66

to 92)
OR 0.91

(0.76 to

1.09)
6329 (25

studies)
ModerateNo evidence of blinding in many of the trials

8. Laboratory phase

Twisk 2006

Preimplantation genetic screening versus no screening in women with advanced age
200 per

1000
206 per 1000

(113 to 347)
OR 1.04

(0.51 to

2.13)
199 (4

studies)
LowThere were methodological limitations that were not adequately explained and evidence of imprecision

Carney 2012

Assisted hatching versus no assisted hatching
102 per 1000136 per 1000

(112 to 162)
OR 1.38

(1.11 to 1.7)
3447
(14 studies)
LowThere were methodological limitations or missing information in most trials
There was inconsistency between the trials (I square statistic was 57%)

Bontekoe 2012

Embryo culture with low oxygen concentration versus atmospheric oxygen concentration
88 per 1000113 per 1000

(80 to 158)
OR 1.33

(0.91 to

1.95)
1382 (4

studies)
LowThere were methodological limitations that were not adequately explained and evidence of imprecision

9. Embryo transfer

9.1 Developmental stage

Glujovsky 2012

Cleavage stage transfer versus blastocyst stage transfer
109 per 1000101 per 1000

(80 to 127)
OR 0.92

(1.71 to

1.19)
2481 (16

studies)
ModerateSome methodological details were unclear or inadequate

9.2 Number of embryos

Pandian 2013

Double embryo transfer versus single embryo transfer (one cycle only)
293 per 100024 per 1000 (8

to 62)
OR 0.06

(0.02 to

0.16)
468 (8

studies)
ModerateSome methodological details such as randomisation and blinding were unclear

Pandian 2013

Double embryo transfer versus repeated single embryo transfer
17 per 1000130 per 1000

(81 to 203)
OR 8.47

(4.97 to 14.43)
1612

(10 studies)
HighHeterogeneity (I2 = 45%): attributable to 36% of women noncompliant with treatment allocation in one study.

Pandian 2013

Double embryo transfer versus three embryo transfers
91 per 100017 per 1000 (1

to 278)
OR 0.17

(0.01 to

3.85)
45 (1 study)Very lowRandomisation and blinding were unclear, evidence is based on a single trial with evidence of imprecision

Pandian 2013

Double embryo transfer versus four embryo transfers
214 per 1000107 per 1000

(27 to 349)
OR 0.44

(0.1 to

1.97)
56 (1 study)Very lowRandomisation, allocation concealment and blinding were unclear, evidence is based on a single trial with evidence of imprecision

9.3 Transfer techniques

Gunby 2004

Day 3 versus Day 2 embryo transfer
136 per 1000138 per 1000

9114 to 166)
OR 1.02

(0.82 to

1.27)
2780 (8

studies)
ModerateTrials lacked details on blinding

Bontekoe 2010

Transfer medium enriched with hyaluronic acid versus medium devoid of hyaluronic acid
67 per 1000184 per 1000

(76 to 383)
OR 3.14

(1.14 to

8.65)
181 (2

studies)
High-

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer
63 per 100079 per 1000 (59

to 105)
OR 1.27

(0.93 to

1.75)
2346 (6

studies)
LowStudies were open label and heterogeneity >60%

Abou-Setta 2009

Less bed rest versus more bed rest
73 per 1000113 per 1000

(25 to 383)
OR 1.62

(0.33 to

7.9)
542 (2

studies)
Very lowHeterogeneity >70%, wide confidence intervals indicating imprecision, one trial was open

Abou-Setta 2009

Mechanical pressure on cervix versus no intervention
121 per

1000
243 per 1000

(174 to 329)
OR 2.33

(1.53 to

3.56)
639 (1 study)Very lowEvidence based on a single trial, trial was open label and method of randomisation was unclear

12. Frozen embryo replacement cycles

Ghobara 2008

Oestrogen + progesterone frozen thawed embryo transfer (FET) versus natural cycle FET
0 per 10000 per 1000OR 2.48

(0.09 to

68.14)
21 (1 study)Very lowEvidence based on a single trial, evidence of imprecision, very small sample size, open label and insufficient methodological details provided

Ghobara 2008

Clomiphene + HMG frozen thawed embryo transfer (FET) versus HMG FET
143 per

1000
187 per 1000

(43 to 544)
OR 1.38

(0.27 to

7.15)
44 (1 study)Very lowEvidence based on a single trial, evidence of imprecision, very small sample size, open label and insufficient methodological details provided

Glujovsky 2010

Intramuscular progesterone versus vaginal progesterone for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
422 per

1000
414 per 1000

(271 to 574)
OR 0.97

(0.51 to

1.85)
153 (1 study)Very lowEvidence based on a single trial, evidence of imprecision, open label and insufficient methodological details provided

 
Table 8. Miscarriage per woman

Outcome

Intervention and comparison intervention
Assumed risk with ComparatorCorresponding risk with interventionRelative effect

(95%CI)
Number of participants

(Studies)
Quality of the evidence

(GRADE)
Comments

2. Pre-ART strategies

Cheong 2013

Acupuncture versus no acupuncture on or around the day of embryo transfer
207 per 1000233 per 1000

(160 to 303)
OR 1.1

(0.73 to 1.67)
616

(6 studies)
LowOnly 2/6 studies described adequate allocation concealment, imprecision

Cheong 2013

Acupuncture versus no acupuncture around the time of oocyte retrieval
242 per 1000201 per 1000

(118 to 319)
OR 0.79

(0.42 to 1.47)
262 (4 studies)LowOnly 1/4 studies described adequate allocation concealment, imprecision

Siristatidis 2011

Aspirin versus placebo or no treatment
41 per 100047 per 1000 (30

to 75)
RR 1.10

(0.68 to

1.77)
1497 (5

studies)
ModerateThere were some methodological limitations in some of the trials

Tso 2009

Metformin versus placebo or no treatment
125 per

1000
107 per 1000(

54 to 200)
OR 0.84

(0.4 to

1.75)
289 (4

studies)
LowTwo trials each lacked adequate information on allocation concealment and randomisation. Two trials were open labelled

Showell 2010

Antioxidant versus control
19 per 100029 per 1000 (6

to 124)
OR 1.54

(0.32 to

7.3)
242 (3

studies)
Very lowInadequate details of methodology, lack of head to head comparisons and evidence of heterogeneity

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment
63 per 100056 per 1000

(37 to 84)
OR 0.88

(0.57 to 1.36)
1456

(8 studies)
LowImprecision, some methodological details were unclear, types of subfertility and antioxidants used differed across trials.

Nastri 2011

Endometrial injury prior to ovulation induction (pipelle induced) versus no endometrial injury
286 per 100012 per 1000 (-

179 to 147)
OR 0.03 (-

0.38 to 0.43)
23 (1 study)Very lowEvidence of imprecision and evidence based on a single trial

Benschop 2010

Aspiration of endometrioma versus expectant management
100 per 100097 per 1000 (25

to 316)
OR 0.97

(0.23 to 4.15)
81

(1 study)
Very lowEvidence was based on a single trial, wide confidence intervals whcih cross line of no effect

Benschop 2010

GnRH agonist versus GnRH antagonist
30 per 100029 per 1000

(2 to 331)
OR 0.97

(0.06 to 15.85)
67

(1 study)
Very lowEvidence was based on a single trial, wide confidence intervals which cross line of no effect

Johnson 2010

Salpingectomy versus no surgical treatment
53 per 100046 per 1000 (17

to 117)
OR 0.86

(0.31 to

2.38)
329 (3

studies)
ModerateRandomisation methods not fully described. Imprecision: wide confidence intervals which cross line of no effect.

Johnson 2010

Tubal occlusion versus no surgical treatment
67 per 100060 per 1000 (6

to 399)
OR 0.89

(0.09 to

9.28)
65 (1 study)Very lowEvidence based on a single trial. Evidence of imprecision: wide confidence intervals which cross line of no effect.

Johnson 2010

Aspiration of hydro salpingeal fluid versus no surgical treatment
31 per 100063 per 1000 (6

to 436)
OR 2.07

(0.18 to

24.01)
64 (1 study)Very lowEvidence based on a single trial. Evidence of imprecision: wide confidence intervals which cross line of no effect.

3. Down-regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection
13 per 10014 per 100

(9 to 22)
OR 1.16

(0.7 to 1.94)
512
(9 studies)
lowMost of the studies were classified as at unclear risk of bias for all domains.
The total number of events was fewer than 300.
There were insufficient studies to assess publication bias

Al-Inany 2011

GnRH antagosist versus long course GnRH agonist
118 per

1000
113 per 1000

(85 to 149)
OR 0.96

(0.7 to 1.31)
1647 (27

studies)
LowMethodological limitations including lack of blinding and there was also evidence of imprecision

Boomsma 2012

Peri-implantation glucocorticoids versus no glucocorticoids
57 per 100080 per 1000 (47

to 132)
OR 1.44

(0.82 to

2.51)
832 (7

studies)
LowMethodological limitations including lack of blinding and there was also evidence of imprecision

4. Ovarian stimulation

4.1 Type of medication

Pandian 2010

Multiple dose GnRH agonist versus mini dose long agonist protocol
22 per 100046 per 1000 (4

to 353)
OR 2.1

(0.18 to

23.98)
89 (1 study)Very lowSingle trial with no allocation concealment or blinding and evidence of imprecision

Gibreel 2012

Clomiphene citrate (+/- urinary or recombinant gonadotrophin) versus urinary or recombinant gonadotrophin in either long or short protocols
184 per 1000199 per 1000

(107 to 337)
OR 1.1

(0.53 to

2.25)
201 (4

studies)
ModerateMost of the included trials lacked adequate methodological details

Gibreel 2012

Clomiphene citrate (+/- urinary or recombinant gonadotrophin) and mid cycle antagonists versus urinary or recombinant gonadotrophin in either long or short protocols
155 per 1000115 per 1000

(44 to 268)
OR 0.71

(0.25 to

1.99)
125 (3

studies)
ModerateMost of the included trials lacked adequate methodological details

Mochtar 2007

Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) versus rFSH alone for controlled ovarian hyperstimulation
66 per 100053 per 1000 (35

to 81)
OR 0.8

(0.51 to

1.26)
1330 (11

studies)
ModerateSome methodological details were unclear

Martins 2013

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques
16 per 10017 per 1000RR 1.08

(0.50 to 2.31)
127

(4 studies)
Very lowVery serious imprecision, high risk of bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus antagonist
68 per 100084 per 1000
(52 to 134)
OR 1.26
(0.76 to 2.12)
847
(4 studies)
LowImprecision, insufficient reporting of randomisation methods

Smulders 2010

Combined oral contraceptive pill plus antagonist versus agonist
80 per 100043 per 1000
(20 to 87)
OR 0.52
(0.24 to 1.1)
472
(3 studies)
LowImprecision, insufficient reporting of randomisation methods

5. Ovulation triggering

Youssef 2011a

GnRH agonist versus HCG
75 per 1000110 per 1000

(76 to 158)
OR 1.53

(1.01 to

2.31)
1090 (12

studies)
ModerateNo evidence of blinding in many of the trials

van Wely 2011

rFSH versus urinary gonadotrophins
50 per 100057 per 1000 (46

to 70)
OR 1.16

(0.93 to

1.44)
6663 (30

studies)
ModerateNo evidence of blinding in many of the trials

Youssef 2011

rhCG versus uhCG
63 per 100044 per 1000 (27

to 74)
OR 0.69

(0.41 to

1.18)
1106 (7

studies)
ModerateSome methodological detail was lacking in some of the trials

Youssef 2011

rhLH versus uhCG
66 per 100062 per 1000 (25

to 144)
OR 0.94

(0.37 to

2.38)
280 (2

studies)
LowOne of the trials lacked adequate methodological details and there was evidence of imprecision

8. Laboratory phase

Bontekoe 2012

Embryo culture with low oxygen concentration versus atmospheric oxygen concentration
75 per 100094 per 1000 (65

to 133)
OR 1.28

(0.86 to

1.9)
1291 (3

studies)
LowThere were methodological limitations and evidence of imprecision

Carney 2012

Assisted hatching versus no assisted hatching
45 per 100046 per 1000

(32 to 68)
OR 1.03

(0.69 to 1.54)
2131
(14 studies)
ModerateThere were methodological limitations or missing information in most of the trials

Twisk 2006

Preimplantation genetic screening versus no screening in women with advanced age
122 per 1000108 per 1000

(76 to 150)
OR 0.87

(0.59 to

1.27)
1062 (5

studies)
ModerateMost of the included trials lacked adequate methodological details

Twisk 2006

Preimplantation genetic screening versus no screening in women with good prognosis
89 per 1000103 per 1000

(54 to 183)
OR 1.17

(0.59 to

2.3)
388 (3

studies)
Very lowOpen label studies with evidence of imprecision. Heterogeneity was >60%

Huang 2013

Brief co-incubation versus standard insemination
24 per 100047 per 1000

(9 to 217)
OR 1.98

(0.35 to 11.09)
167
(1 study)
LowOne trial only and method of randomization or allocation concealment not stated

9. Embryo transfer

Glujovsky 2012

Cleavage stage transfer versus blastocyst stage transfer
80 per 100091 per 1000 (68

to 119)
OR 1.14

(0.84 to

1.55)
2127 (14

studies)
ModerateSome methodological details were unclear or inadequate

Pandian 2013

Double embryo transfer versus single embryo transfer (one cycle only)
67 per 100078 per 1000

(51 to 118)
OR 1.18

(0.75 to 1.86)
1097

(3 studies)
LowSome methodological details such as randomisation and blinding were unclear. INconsistency (I squared =61%)

Pandian 2013

Double embryo transfer versus repeated single embryo transfer
94 per 1000148 per 1000

(50 to 363)
OR 1.67

(0.51 to 5.48)
107

(1 study)
Very lowMethod ofallocation concealment not fully described, very serious imprecisoin

Gunby 2004

Day 3 versus Day 2 embryo transfer
63 per 100066 per 1000 (49

to 89)
OR 1.05

(0.76 to

1.44)
2452 (9

studies)
LowEvidence of imprecision and lack of details about blinding

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer
40 per 100038 per 1000 (26

to 54)
OR 0.95

(0.65 to

1.38)
2930 (8

studies)
LowStudies were open label and there was evidence of imprecision

Derks 2009

Straightening the utero-cervical angle versus no intervention
156 per 10000 per 1000 (0 to

0)
OR 0 (0 to

0)
131 (1 study)LowEvidence based on a single trial, evidence of imprecision and study lacked blinding

Derks 2009

Cervical dilatation versus no intervention
35 per 100023 per 1000OR 0.64

(0.21 to

1.93)
288 (1 study)ModerateEvidence of imprecision and evidence based on a single trial

Abou-Setta 2009

Less bed rest versus more bed rest
47 per 100075 per 1000 (38

to 143)
OR 1.63

(0.79 to

3.35)
542 (2

studies)
ModerateOpen label trial

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

Tang 2012

Cabergoline versus placebo or no treatment
38 per 100012 per 1000 (1

to 117)
RR 0.31

(0.03 to

3.07)
163 (1 study)LowLack of details for allocation concealment and evidence based on a single trial

D'Angelo 2011

Coasting versus no coasting
88 per 100059 per 1000 (10

to 285)
OR 0.65

(0.1 to

4.13)
68 (1 study)Very lowEvidence based on a single conference abstract. Insufficient methodological detail and evidence of imprecision

Frozen embryo transfer cycles

Ghobara 2008

Oestrogen + progesterone frozen thawed embryo transfer (FET) versus GnRHa, oestrogen and progesterone preparations FET
314 per 1000256 per 1000

(135 to 436)
OR 0.75

(0.34 to

1.69)
128 (3

studies)
Very lowInsufficient details on methodological detail in some trials, open label trials and heterogeneity >73% (I2)

Ghobara 2008

Clomiphene + HMG frozen thawed embryo transfer (FET) versus HMG FET
179 per 1000250 per 1000

(71 to 596)
OR 1.53

(0.35 to

6.79)
44 (1 study)Very lowInsufficient details on methodological detail in some trials, evidence based on a single trial with evidence of imprecision

Glujovsky 2010

GnRH agonists versus control for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
30 per 100028 per 1000 (9

to 84)
OR 0.92

(0.29 to

2.96)
415 (2

studies)
ModerateInsufficient details on methodological detail in some trials

Glujovsky 2010

Intramuscular progesterone versus vaginal progesterone for endometrial preparation for embryo transfer with frozen embryos or donor oocytes
65 per 100040 per 1000OR 0.6

(0.26 to 1.39)
579 (3

studies)
ModerateInsufficient details on methodological detail in some trials