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Table 1. Trial characteristics

Review ID

Date assessed as up to date

Number of included trials

Population

Intervention

Comparison intervention/control

Outcomes

Review limitations

1. Indication for ART

ZP672

Pandian 2012

In vitro fertilisation for unexplained subfertility

1/07/2011

6 RCTs

733 couples with unexplained subfertility

In vitro fertilisation

Expectant 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

15/05/2009

No RCTs

N/A

In vitro fertilisation

Tubal re‐anastamosis

Live 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 No longer being updated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

17/02/2011

No RCTs

N/A

In vitro maturation

In 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 No longer being updated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

18/11/2009

1 RCT

94 women who perceived that they may be infertile

Smoking cessation

advice

Standard clinical advice

Smoking 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

14/11/2011

5 RCTs

591 women undergoing ART

Endometrial injury

No 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 2014

Antioxidants for male subfertility

25/08/2014

48 RCTs

4179 male partners of couples undergoing ART.

Antioxidant

Placebo/no treatment

Antioxidant

Live birth

Pregnancy

Adverse events

DNA fragmentation Sperm parameters

Miscarriage

Lack of a clear description of trial methods and inconsistent, inadequate reporting of live births and clinical pregnancies.

JC1630

Showell 2013

Antioxidants for female subfertility

15/4/13

28 RCTs

3548 women attending an ART clinic

Antioxidant

Placebo/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

22/7/13

20 RCTs

4544 women undergoing ART

Acupuncture

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

01/07/2009

10 RCTs

440 couples undergoing IVF

Growth hormone

Placebo

Live 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

RBG1760

Gutarra‐Vilchez 2014

Vasodilators for women undergoing fertility treatment

25/2/2014

10 RCTs

797 women undergoing ART

Vasodilators

Other interventions, placebo or no treatment

Live birth

Clinical pregnancy

Multiple pregnancy

Miscarriage

The main limitations were imprecision and lack of clarity about study methods. Risk of publication bias could not be assessed because of the low number of identified studies.

VJP 951

Siristatidis 2011

Aspirin for in vitro fertilisation

15/06/2011

13 RCTs

2653 women undergoing IVF

Aspirin

Placebo

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

28/10/2009

5 RCTs

646 women due to undergo IVF

Surgical 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

26/11/2010

4 RCTs

312 women undergoing management of endometrioma prior to ART

Surgical or medical treatment prior to ART

Placebo/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 2014

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

syndrome

15/10/2014

9 RCTs

816 women with

polycystic ovary syndrome

Metformin

Placebo

No treatment

Live birth

Clinical pregnancy Miscarriage

OHSS

Adverse events Number of oocytes

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

SH1141

McDonnell 2014

Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility

24/4/14

3 RCTs

339 women with ovarian cysts undergoing ART

Ovarian cyst aspiration

Conservative treatment

Clinical pregnancy

Number of follicles recruited

Number of oocytes collected

Number of cancelled cycles

Live birth not reported by any of the studies

Poor reporting of study methods

Imprecision

Inconsistency

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

3/7/12

16 RCTs

963 women undergoing IVF

GnRHa depot

GnRHa daily

Clinical 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

01/03/2010

45 RCTs

7511 women undergoing ART

GnRH antagonist

Long course GnRH agonist

Live 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

20/05/2010

3 RCTs

165 women with endometriosis undergoing ART

GnRH agonist

No GnRH agonist

Clinical 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

24/01/2011

29 RCTs

Included women undergoing ART: total number of participants unclear from review

Long 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

23/3/2012

14 RCTs

2536 (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

10/10/2011

4 RCTs

2335 women with subfertility

Long acting FSH

Daily FSH

Live 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

14/06/2011

33 RCTs

5624 women with subfertility

Recombinant

luteinising 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

20/10/2010

42 RCTs

9606 women undergoing ART

Recombinant

follicle stimulating hormone

Urinary gonadotrophins

Live 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

5/2/13

5 RCTs

351 women undergoing COH for ART.

Low dose human chorionic gonadotrophin in the late follicular phase

Follicle stimulating hormone throughout controlled ovarian hyperstimulation

Live 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

16/11/2008

23 RCTs

2603 women with subfertility

Combined 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 attrition bias in some studies, poor precision due to low sample numbers for individual comparisons

4.2 Monitoring

IOK972

Kwan 2014

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

30/5/2014

6 RCTs

781 women undergoing ovarian stimulation with gonadotrophins in ART

Ultrasound plus

oestradiol

Ultrasound only

Clinical pregnancy

Number of oocytes

OHSS

No studies reported live birth

Study methods inadequately described, serious imprecision

4.3 Interventions for poor responders

RSS791

Pandian 2010

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

16/03/2009

10 RCTs

625 women considered to be 'poor responders' to COH in IVF treatment

Stop 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

5/3/13

5 RCTs

382 subfertile women and couples undertaking IVF treatment

Natural cycle IVF

Modified natural cycle IVF

Controlled ovarian hyperstimulation IVF

Live 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 criteria differed

5. Ovulation triggering

MM1690

Youssef 2014

Gonadotropin‐releasing hormone agonist versus HCG for oocyte triggering in antagonist‐assisted reproductive technology

8/9/2014

17 RCTs

1847 women undergoing ART

GnRH agonist

HCG

Live birth rate

Ongoing pregnancy rate

Clinical pregnancy rate

Multiple pregnancy rate

Miscarriage rate

OHSS

Risk of bias in included studies. Limitations included premature termination, failure to clearly report methods, and substantial heterogeneity.

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

20/1/2010

14 RCTs

2306 women undergoing ART

Recombinant hCG

Recombinant hLH

Urinary hCG

Live 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

31/1/13

21 RCTs

2974 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

pethidine

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

31/03/2010

4 RCTs

208 women undergoing ART

Follicular flushing

Aspiration alone

Clinical /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 RCT

59 men with obstructive or non‐obstructive azoospermia

Epididymal 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

SMD 1810

McDowell 2014

Advanced sperm selection techniques for assisted reproduction

26/5/2014

2 RCTS

581 couples undergoing ART

Sperm selection by hyaluronanic acid binding for ICSI

1.Conventional ICSI

2. Comparison of different hyaluronanic acid binding technique

Live birth

Pregnancy

Miscarriage

Only one study reported live birth

Poor reporting of study methods in one study

Data discrepancy in one study

Imprecision

8. Laboratory phase

DG1352

Glujovsky 2014

3/3/14

2 RCTs

106 women undergoing ART and wishing to preserve oocytes

Vitrification

Slow freezing

Clinical pregnancy

Ongiong pregnancy

Failure to report live birth

Imprecision

MWS391

Carney 2012

Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI))

8/8/12

31 RCTs

5728 women undergoing ART

Assisted hatching

No assisted hatching

Live 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 adequate 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 RCT

415 couples with non‐male factor subfertility

Intracytoplasmic

sperm injection

In vitro fertilisation

Clinical 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

4/11/2011

7 RCTs

2422 couples undergoing ART

Embryo 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

15/07/2010

9 RCTs

1589 women undergoing IVF or ICSI with and without PGS for all suggested indications

IVF/ICSI with preimplantation genetic screening

IVF/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

26/3/13

8 RCTs

733 women undergoing ART

Brief co‐incubation of gametes for women undergoing IVF

Standard 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

8/5/13

9RCTs

2014 couples undergoing ART

IMSI

ICSI

Live 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

21/02/2012

23 RCTs

3241 women undergoing ART

Cleavage stage transfer

Blastocyst stage transfer

Live 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

15/12/2003

16 trials

2691 (12 studies) couples undergoing ART

Day 3 embryo transfer

Day 2 embryo transfer

Live 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

17/07/2012

14 RCTs

2165 couples undergoing ART

Single 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 2014

Adherence compounds in embryo transfer media for assisted reproductive technologies

13/11/13

17RCTs

3898 women undergoing ART

Embryo 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

Live birth

Ongoing pregnancy

Clinical pregnancy

Multiple pregnancy Implantation rate

Adverse events

There were some methodological limitations and some imprecision

SV602

Derks 2009

Techniques for preparation prior to embryo transfer

18/03/2009

10 RCTs

1693 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 in most of the included trials

EN1382

Kroon 2012

Antibiotics prior to embryo transfer in ART

23/11/2011

1 RCT

350 women attending infertility clinic

Antibiotics

No treatment

Bacterial 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

9/11/2009

20 RCTs

6524 women with any form of infertility

Ultrasound guided

transfer

Clinical touch transfer

Live 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 2014

Post‐embryo transfer interventions for in vitro fertilisation and intra‐ cytoplasmic sperm injection patients

19/6/14

4 RCTs

1392 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

25/05/2011

69 RCTs

16,327 women with any cause of subfertility

Progesterone

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

20/09/2011

14 RCTs

1879 couples with any cause of subfertility

Glucocorticoids

No 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

6/5/13

3 RCTs

386 subfertile women undergoing ART

Heparin

Placebo

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

2/09/2011

2 RCTs

230 women at

high risk of OHSS

undergoing ART

Cabergoline

Placebo/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

19/07/2010

4 RCTs

340 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 RCTs

151 women

down‐regulated by GnRH‐a, undergoing superovulation in IVF and or ICSI cycles.

Cryopreservation

Fresh 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

02/11/2010

9 RCTs

2147 women

having controlled ovarian hyperstimulation and at risk of severe OHSS

Human albumin

Hydroxyethyl starch

Placebo

OHSS

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)

11/10/2007

7 RCTs

1120 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

7/10/2009

22 RCTs

3451 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

Figures and Tables -
Table 1. Trial characteristics
Table 2. AMSTAR assessment

Review no

First author

REVIEW TITLE

AMSTAR CRITERIA

Prespecified question and inclusion criteria

Duplicate study selection and data extraction

Comprehensive lit search

Grey lit included

Lists included and excluded studies

Describes characteristics of included studies

Study quality assessed

Studies combined using appropriate methods

Likelihood of publication bias considered/tested

Potential for conflict of interest addressed

AAS605

Abou‐Setta 2014

Post‐embryo transfer interventions for assisted reproduction technology cycles

ADA561

D'Angelo 2007

Embryo freezing for preventing ovarian hyperstimulation syndrome

ADA563

D'Angelo 2011

Coasting (withholding gonadotrophins) for preventing ovarian
hyperstimulation syndrome

AM1335

Gibreel 2012

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

AMVP611

Proctor 2008

Techniques for surgical retrieval of sperm prior to intra‐cytoplasmic sperm injection (ICSI) for azoospermia

AMY731

Yossry 2006

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

n/a

n/a

n/a

n/a

AWP1710

Pouwer 2012

Long‐acting FSH versus daily FSH for women undergoing assisted reproduction

CMB1261

Boomsma 2012

Peri‐implantation glucocorticoid administration for assisted reproductive
technology cycles

CO266

Gunby 2004

Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection

x

CS1400

Siristatidis 2009

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

n/a

n/a

n/a

n/a

DB551

Glujovsky 2012

Cleavage stage versus blastocyst stage embryo transfer in assisted
reproductive technology

DB552

Bontekoe 2014

Adherence compounds in embryo transfer media for assisted reproductive technologies

DG1351

Glujovsky 2010

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

DG1352

Glujovsky 2014

Vitrification versus slow freezing for women undergoing oocyte cryopreservation

DHH752

Smulders 2010

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

EN1382

Kroon 2012

Antibiotics prior to embryo transfer in ART

HA412

Al‐Inany 2011

Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology

x

HA413

Youssef 2011

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

HNS881

Sallam 2006

Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis

x

IOK971

Kwan 2013

Pain relief for women undergoing oocyte retrieval for assisted reproduction

IOK972

Kwan 2014

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

x

IOK973

van Wely 2011

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

IRS911

Cheong 2013

Acupuncture and assisted reproductive technology

JB604

Brown 2010

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

x

JC1630

Showell 2013

Antioxidants for female subfertility

KA992

Anderson 2010

Pre‐conception lifestyle advice for people with subfertility

KH291

Duffy 2010

Growth hormone for in vitro fertilization

x

LA541

Albuquerque 2013

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

LDT1201

Tso 2014

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

MA1441

Akhtar 2013

Heparin for assisted reproduction

MGS1510

Showell 2014

Antioxidants for male subfertility

MHM931

Mochtar 2007

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

x

MM1690

Youssef 2014

Gonadotropin‐releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

MV263

van der Linden 2011

Luteal phase support in ART cycles

MVR461

Van Rumste 2003

Intra‐cytoplasmic sperm injection versus conventional techniques for
oocyte insemination during in vitro fertilisation in patients with non‐male
subfertility

MWS391

Carney 2012

Assisted hatching on assisted conception (IVF and ICSI)

NJ472

Johnson 2010

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation

x

PMA481

Youssef 2011b

Intra‐venous fluids for the prevention of severe ovarian hyperstimulation syndrome

RBG1760

Gutarra‐Vilchez 2014

Vasodilators for women undergoing fertility treatment

RSS791

Pandian 2010

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

SB1283

Bontekoe 2012

Low oxygen concentrations for embryo culture in assisted reproductive technologies

SD265

Maheshwari 2011

Gonadotropin‐releasing hormone agonist protocols for pituitary suppression in assisted reproductive technology cycles

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology

SH1141

McDonnell 2014

Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility

SMA991

Twisk 2006

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

SMD1810

McDowell 2014

Advanced sperm selection techniques for assisted reproduction

SV602

Derks 2009

Techniques for preparation prior to embryo transfer

SW811

Wongtra‐ngan 2010

Follicular flushing during oocyte retrieval in assisted reproductive
techniques

TA1860

Allersma 2013

Natural cycle IVF for subfertile couples

TG691

Ghobara 2008

Cycle regimens for frozen‐thawed embryo transfer

TH1338

Tang 2012

Cabergoline for preventing ovarian hyperstimulation syndrome

VJP951

Siristatidis 2011

Aspirin for in vitro fertilisation

WM1504

Nastri 2011

Endometrial injury in women undergoing assisted reproductive techniques

WPM1780

Martins 2013

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

WPM1800

Teixeira 2013

Regular (ICSI) versus ultra‐high magnification (IMSI) sperm selection for assisted reproduction

ZH1093

Huang 2013

Brief co‐incubation of sperm and oocytes for in vitro fertilization techniques

ZP661

Pandian 2013

Number of embryos for transfer following in‐vitro fertilisation or intracytoplasmic sperm injection

ZP672

Pandian 2012

In vitro fertilisation for unexplained subfertility

x

Figures and Tables -
Table 2. AMSTAR assessment
Table 3. Latest search date assessment

Review no

First author

REVIEW TITLE

< 3 yrs since last search

(to Oct 2014) or deemed stable)

AAS605

Abou‐Setta 2014

Post‐embryo transfer interventions for assisted reproduction technology cycles

ADA561

D'Angelo 2007

Embryo freezing for preventing ovarian hyperstimulation syndrome

Stable

ADA56x3

D'Angelo 2011

Coasting (withholding gonadotrophins) for preventing ovarian
hyperstimulation syndrome

x

AM1335

Gibreel 2012

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

x

AMVP611

Proctor 2008

Techniques for surgical retrieval of sperm prior to intra‐cytoplasmic sperm injection (ICSI) for azoospermia

Stable

AMY731

Yossry 2006

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

AWP1710

Pouwer 2012

Long‐acting FSH versus daily FSH for women undergoing assisted reproduction

CMB1261

Boomsma 2012

Peri‐implantation glucocorticoid administration for assisted reproductive
technology cycles

CO266

Gunby 2004

Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection

x

CS1400

Siristatidis 2009

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

DB551

Glujovsky 2012

Cleavage stage versus blastocyst stage embryo transfer in assisted
reproductive technology

DB552

Bontekoe 2014

Adherence compounds in embryo transfer media for assisted reproductive technologies

DG1351

Glujovsky 2010

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

x

DG1352

Glujovsky 2014

Vitrification versus slow freezing for women undergoing oocyte cryopreservation

Review information

DHH752

Smulders 2010

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

x

EN1382

Kroon 2012

Antibiotics prior to embryo transfer in ART

x

HA412

Al‐Inany 2011

Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology

x

HA413

Youssef 2011

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

x

HNS881

Sallam 2006

Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis

x

IOK971

Kwan 2013

Pain relief for women undergoing oocyte retrieval for assisted reproduction

x

IOK972

Kwan 2014

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

IOK973

van Wely 2011

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

x

IRS911

Cheong 2013

Acupuncture and assisted reproductive technology

JB604

Brown 2010

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

JC1630

Showell 2013

Antioxidants for female subfertility

KA992

Anderson 2010

Pre‐conception lifestyle advice for people with subfertility

x

KH291

Duffy 2010

Growth hormone for in vitro fertilization

x

LA541

Albuquerque 2013

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

x

LDT1201

Tso 2014

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

MA1441

Akhtar 2013

Heparin for assisted reproduction

MGS1510

Showell 2014

Antioxidants for male subfertility

MHM931

Mochtar 2007

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

x

MM1690

Youssef 2014

Gonadotropin‐releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

WPM1800

Teixeira 2013

Regular (ICSI) versus ultra‐high magnification (IMSI) sperm selection for assisted reproduction

MV263

van der Linden 2011

Luteal phase support in ART cycles

x

MVR461

Van Rumste 2003

Intra‐cytoplasmic sperm injection versus conventional techniques for
oocyte insemination during in vitro fertilisation in patients with non‐male
subfertility

MWS391

Carney 2012

Assisted hatching on assisted conception (IVF and ICSI)

NJ472

Johnson 2010

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation

x

PMA481

Youssef 2011b

Intra‐venous fluids for the prevention of severe ovarian hyperstimulation syndrome

x

RBG1760

Gutarra‐Vilchez 2014

Vasodilators for women undergoing fertility treatment

RSS791

Pandian 2010

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

x

SB1283

Bontekoe 2012

Low oxygen concentrations for embryo culture in assisted reproductive technologies

SD265

Maheshwari 2011

Gonadotropin‐releasing hormone agonist protocols for pituitary suppression in assisted reproductive technology cycles

x

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology

x

SH1141

McDonnell 2014

Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility

SMA991

Twisk 2006

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

x

SMD1810

McDowell 2014

Advanced sperm selection techniques for assisted reproduction

SV602

Derks 2009

Techniques for preparation prior to embryo transfer

x

SW811

Wongtra‐ngan 2010

Follicular flushing during oocyte retrieval in assisted reproductive
techniques

x

TA1860

Allersma 2013

Natural cycle IVF for subfertile couples

TG691

Ghobara 2008

Cycle regimens for frozen‐thawed embryo transfer

x

TH1338

Tang 2012

Cabergoline for preventing ovarian hyperstimulation syndrome

x

VJP951

Siristatidis 2011

Aspirin for in vitro fertilisation

x

WM1504

Nastri 2011

Endometrial injury in women undergoing assisted reproductive techniques

WPM1780

Martins 2013

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

ZH1093

Huang 2013

Brief co‐incubation of sperm and oocytes for in vitro fertilization techniques

ZP661

Pandian 2013

Number of embryos for transfer following in‐vitro fertilisation or intracytoplasmic sperm injection

ZP672

Pandian 2012

In vitro fertilization for unexplained subfertility

x

Figures and Tables -
Table 3. Latest search date assessment
Table 4. Live birth per woman

Outcome

Intervention and comparison intervention

Assumed risk with Comparator

Corresponding risk with intervention

Relative 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 1000

458 per 1000 (90

to 879)

OR 22 (2.56

to 189.37)

51 (1 study)

Low

Evidence based on a single study

Pandian 2012

IVF versus intra‐ uterine insemination for unexplained subfertility

259 per 1000

407 per 1000 (235

to 604)

OR 1.96

(0.88 to

4.36)

113

(1 study)

Very low

Evidence 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 1000

317 per 1000

(215 to 462)

RR 1.09

(0.74 to 1.59)

234

(2 studies)

Moderate

Both 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 1000

332 per 1000 (206 to 489)

OR 2.46

(1.28 to 4.72)

200

(2 studies)

Moderate

Evidence of imprecision and some methodological details were unclear

Showell 2014

Antioxidant versus control

50 per 1000

181 per 1000

(99 to 309)

OR 4.21

(2.08 to 8.51)

277

(4 studies)

Low

Inadequate explanations of methodology, large unexplained dropouts in one study

No head to head comparisons: comparison in all these studies was placebo or no treatment

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment

367 per 1000

420 per 1000

(99 to 827)

OR 1.25

(0.19 to 8.26)

97

(2 studies)

Very low

Serious 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 1000

323 per 1000

(254 to 399)

OR 1.22

(0.87 to 1.7)

2505

(8 studies)

Low

Imprecision, inadequate explanation of methods, high statistical heterogeneity (I‐squared =69%)

Cheong 2013

Acupuncture versus no acupuncture around the time of oocyte retrieval

357 per 1000

326 per 1000

(247 to 418)

OR 0.87

(0.59 to 1.29)

464

(2 studies)

Low

Imprecision, inadequate explanation of methods, high statistical heterogeneity (I‐squared =69%)

Duffy 2010

Growth hormone versus placebo

146 per 1000

184 per 1000 (64

to 431)

OR 1.32 (0.4 to 4.43)

80

(2 studies)

Moderate

Some evidence of imprecision

Duffy 2010

Growth hormone versus placebo – poor responders

50 per 1000

221 per 1000

(90 to 447)

OR 5.39

(1.89 to 15.35)

165

(4 studies)

Moderate

Some of the studies did not provide adequate explanation of randomisation and/or allocation concealment

Gutarra‐Vilchez 2014

Vasodilator compared with placebo

236 per 1000

278 per 1000

(193 to 398)

RR 1.18

(0.82 to 1.69)

350

(3 studies)

Moderate

Studies had low or unclear risk of bias but serious imprecision.

Siristatidis 2011

Aspirin versus placebo or no treatment

227 per 1000

211 per 1000

(170 to 266)

RR 0.91

(0.72 to 1.15)

1053

(3

studies)

Moderate

Some evidence of methodological limitations

2.2 For selected populations

Tso 2014

Metformin versus placebo or no treatment

320 per 1000

395 per 1000

(276 to 530)

OR1.39

(0.81 to 2.40)

551

(5 studies)

Low

Inconsistency: unexplained heterogeneity (I2 = 52%)

Imprecision: total number of events is fewer than 300

There was a data discrepancy in one of these studies. Sensitivity analysis excluding this study yielded an OR of 1.48 (95% CI 0.72 to 3.02) for live birth

3. Down‐regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection

4 per 100

23 per 100

(181 to 292)

OR 0.95

(0.7 to 1.31)

873
(7 studies)

low

No 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 1000

282 per 1000

(240 to 331)

OR 0.86

(0.69 to 1.08)

1515

(9

studies)

Moderate

Lack 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 1000

218 per 1000

(124 to 351)

OR 1.8 (0.92 to 3.5)

251

(3 studies)

Very low

Serious 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 1000

198 per 1000

(91 to 376)

OR 1.78

(0.72 to 4.36)

150 (1 study)

Very low

Evidence 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 1000

215 per 1000

(169 to 268)

OR 0.93

(0.69 to 1.24)

1079
(5 studies)

low

Wide 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 1000

198 per 1000

(142 to 269)

OR 0.61

(0.41 to 0.91)

645

(3 studies)

Low

Open label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (medium dose) versus daily FSH

336 per 1000

343 per 1000

(298 to 391)

OR 1.03

(0.84 to 1.27)

1657 (3

studies)

Low

Open label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (high dose) versus daily FSH

375 per 1000

161 per 1000

(29 to 533)

OR 0.32

(0.05 to 1.9)

33 (1 study)

Very low

Open 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 1000

247 per 1000

(194 to 307)

OR 1.14

(0.84 to 1.54)

963 (5 studies)

Low

Some 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 1000

239 per 1000

(220 to 260)

OR 0.97

(0.87 to 1.08)

7339 (28

studies)

High

There 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 100

22 per 100

RR 1.56

(0.75 to 3.25)

130 (2 studies)

V ery low

Very serious imprecision, high risk of bias

Smulders 2010

Combined oral contraceptive plus antagonist versus antagonist

292 per 1000

150 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 1000

187 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 1000

86 per 1000

(26 to 245)

OR 1.01

(0.29 to 3.5)

129 (1 study)

Low

Evidence based on a single trial with evidence of imprecision

4.4 Natural cycle IVF

Allersma 2013

125 per 1000

28 per 1000

(1 to 393)

OR 0.20

(0.01 to 4.54)

30 (1 study)

Very low

High risk of performance bias. Very serious imprecision

5. Ovulation triggering

Youssef 2014

GnRH agonist versus HCG

313 per 1000

176 per 1000

(124 to 242)

OR 0.47

(0.31 to 0.70)

532

(5 studies)

Moderate

One of the studies at high risk of bias because of premature termination, substantial heterogeneity: I2 = 59% to 66%.

Youssef 2011

rhCG versus uhCG

400 per 1000

409 per 1000

(345 to 477)

OR 1.04

(0.79 to 1.37)

1019

(6 studies)

Moderate

2 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 1000

189 per 1000

(110 to 304)

OR 0.94

(0.5 to 1.76)

280

(2 studies)

Low

One 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 1000

334 per 1000 (184

to 601)

OR 2.35 (1.09 to 5.05)

149 (1 study)

Low

Evidence based on a single trial

7. Sperm retrieval

McDowell 2014

HA culture dish (PICSI) compared with viscous medium containing HA (SpermSlow) for infertility requiring intracytoplasmic sperm injection

300 per 1000

350 per 1000

(190 to 550)

RR 1.16

(0.65 to 2.05)

99

(1 study)

Low

Serious risk of bias: study methods not reported in adequate detail.

Serious imprecision: confidence intervals compatible with substantial benefit or harm from the intervention, or with no effect.

8. Laboratory phase

Carney 2012

Assisted hatching versus no assisted hatching

305 per 1000

311 per 1000 (271 to 356)

OR 1.03

(0.84 to 1.26)

1921 (9

studies)

Moderate

Many 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)

Moderate

In 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 1000

171 per 1000 (133 to 221)

OR 0.59

(0.44 to 0.81)

1062 (5 studies)

Moderate

Only 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 1000

263 per 1000 (130

to 461)

OR 0.5 (0.21 to 1.2)

388 (3 studies)

Very low

Methodological 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 100

44 per 100

(30 to 63)

RR 1.14

(0.79 to 1.64)

168

(1 study)

Low

Serious imprecision

9. Embryo transfer

9.1 Developmental stage

Glujovsky 2012

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology

312 per 1000

389 per 1000 (339

to 441)

OR 1.4 (1.13 to 1.74)

1510 (12

studies)

Moderate

Some methodological details were unclear or inadequate

Gunby 2004

Day 3 versus Day 2 embryo transfer

315 per 1000

330 per 1000 (279

to 387)

OR 1.07

(0.84 to 1.37)

1200 (3

studies)

Low

Heterogeneity >60% and evidence of imprecision

9.2 Number of embryos

Pandian 2013

Double embryo transfer versus single embryo transfer (one cycle only)

292 per 1000

460 per 1000

(409 to 514)

OR 2.07

(1.68 to 2.57)

1564

(9 studies)

High

36% 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 1000

421 per 1000

(354 to 492)

OR 1.22

(0.92 to 1.62)

811

(3 studies)

Low

None of studies describe adequate allocation concealment, imprecision

Pandian 2013

Double embryo transfer versus three embryo transfers

273 per 1000

130 per 1000 (33

to 410)

OR 0.4

(0.09 to 1.85)

45 (1 study)

Very low

Randomisation 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 1000

288 per 1000

(113 to 548)

OR 0.35

(0.11 to 1.05)

56 (1 study)

Very low

Randomisation, allocation concealment and blinding were unclear, evidence is based on a single trial with evidence of imprecision

9.3 Transfer techniques and procedures

Bontekoe 2014

Transfer medium enriched with high level of hyaluronic acid versus medium with low level or no hyaluronic acid

367 per 1000

450 per 1000

(404 to 495)

OR 1.41

(1.17 to 1.69)

1950

(6 studies)

Moderate

All studies except one at high risk of bias in one or more domains.

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer

213 per 1000

236 per 1000 (201

to 273)

OR 1.14

(0.93 to

1.39)

2264 (3

studies)

Low

No reporting of blinding and evidence of heterogeneity >60%

Derks 2009

Cervical dilatation versus no intervention

190 per 1000

97 per 1000 (60 to 155)

OR 0.46

(0.27 to 0.78)

288 (1 study)

Moderate

Evidence 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)

Low

Evidence is based on a single trial. Insufficient methodological details provided. Evidence of imprecision.

van der Linden 2011

Progesterone versus placebo/no treatment

38 per 1000

104 per 1000

(39 to 253)

OR 2.95

(1.02 to 8.56)

156 (1 study)

Low

Evidence is based on a single trial. Insufficient methodological details provided. Evidence of imprecision.

Boomsma 2012

Peri‐implantation glucocorticoids versus no glucocorticoids

115 per 1000

136 per 1000

(80 to 224)

OR 1.21

(0.67 to 2.19)

424

(3 studies)

Low

Lacked details around methodology and there was evidence of imprecision

Akhtar 2013

Heparin versus control or no heparin

173 per 1000

271 per 1000

(183 to 378)

OR 1.77

(1.07 to 2.90)

386

(3 studies)

Very low

Selection 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 1000

380 per 1000

(1 to 128)

OR1.03

(0.5 to 2.12)

125 (1 study)

Low

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

D'Angelo 2011

Coasting versus no coasting

265 per 1000

148 per 1000

(48 to 369)

OR 0.48

(0.14 to 1.62)

68 (1 study)

Very low

Evidence 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)

Low

Evidence 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 1000

197 per 1000

9100 to 351)

OR 2.62

(1.19 to

5.78)

234 (1 study)

Very low

Evidence 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 low

Evidence based on a single, open label trial. Insufficient methodological details provided. Evidence of imprecision.

Figures and Tables -
Table 4. Live birth per woman
Table 5. Clinical pregnancy per woman

Outcome

Intervention and comparison intervention

Assumed risk with Comparator

Corresponding risk with intervention

Relative 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 1000

310 per 1000

(129 to 576)

OR 3.24

(1.07 to

9.8)

86 (2

studies)

Very Low

Methodological 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 1000

241 per 1000

(148 to 370)

OR 1.1

(0.6 to

2.03)

232 (2

studies)

Moderate

The 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 1000

411 per 1000

(314 to 515)

OR 2.61

91.71 to

3.97)

435 (4

studies)

Moderate

Some evidence of imprecision and some methodological details were unclear

Showell 2014

Antioxidant versus control

59 per 1000

177 per 1000

(108 to 277)

3.43 (1.92 to 6.11)

522 (7 studies)

Low

Inadequate explanations of methodology, large unexplained dropouts in one study

No head to head comparisons: comparison in all these studies was placebo or no treatment

lack of head to head comparisons

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment

231 per 1000

281 per 1000

(217 to 357)

OR 1.30

(0.92 to 1.85)

2441

(13 studies)

Very low

Serious imprecision, some methodological details were unclear, types of subfertility and antioxidants used differed across trials.

Duffy 2010

Growth hormone compared with placebo

273 per 1000

401 per 1000

(155 to 709)

OR 1.78

(0.49 to

6.5)

42 (1 study)

Moderate

Evidence based on a single trial and some evidence of imprecision

Duffy 2010

Growth hormone compared with placebo – poor responders

122 per 1000

313 per 1000

(195 to 463)

OR 3.28

(1.74 to

6.2)

279 (8

studies)

High

Adequate description of methodology, no evidence of imprecision or heterogeneity

Gutarra‐Vilchez 2014

Vasodilator compared with placebo

274 per 1000

340 per 1000

(274 to 526)

RR 1.18

(1.00 to 1.92)

717

(8 studies)

Low

Studies had low or unclear risk of bias but very serious risk of imprecision.

Siristatidis 2011

Aspirin versus placebo or no treatment

299 per 1000

317 per 1000

(290 to 347)

RR 1.03

(0.91 to

1.17)

2142 (10

studies)

Low

All 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 1000

399 per 1000

(343 to 460)

OR 1.11

(0.87 to 1.42)

3632

(14 studies)

Very low

Only 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 1000

372 per 1000

(292 to 461)

OR 1.12

(0.78 to 1.62)

912

(6 studies)

Low

Inadequate description of study methods, serious imprecision

2.2 For selected populations

Johnson 2010

Salpingectomy versus no surgical treatment

189 per 1000

359 per 1000

(258 to 441)

OR 2.2

(1.26 to

3.82)

329

(3 studies)

Moderate

No evidence of blinding in any of the trials. Heterogeneity: I‐squared 52%

Johnson 2010

Tubal occlusion versus no surgical treatment

123 per 1000

396 per 1000

(234 to 585)

OR 4.66

(2.17 to

10.01)

209

(2 studies)

Moderate

Randomisation methods not fully described

Johnson 2010

Aspiration of hydro salpingeal fluid versus no surgical treatment

188 per 1000

313 per 1000

(125 to 592)

OR 1.97

(0.62 to

6.29)

64

(1 study)

Very low

Evidence based on a single trial with imprecision

Benschop 2010

Aspiration of endometrioma versus expectant management prior to ART

200 per 1000

244 per 1000

(101 to 476)

OR 1.29

(0.45 to

3.64)

81

(1 study)

Low

Evidence was based on a single trial, wide confidence intervals which cross line of no effect

Benschop 2010

Cystectomy of endometrioma versus expectant management prior to ART

317 per 1000

348 per 1000

(194 to 542)

OR 1.15

(0.52 to

2.55)

109

(1 study)

Low

Evidence was based on a single trial, wide confidence intervals which cross line of no effect

Benschop 2010

GnRH agonist versus GnRH antagonist prior to ART

242 per 1000

206 per 1000

(77 to 448)

OR 0.81

(0.26 to

2.54)

67

(1 study)

Low

Evidence 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 1000

293 per 1000

(126 to 545)

OR 0.72

(0.25 to 2.08)

65

(1 study)

Very low

Unclear risk of bias related to sequence generation. Single small study, wide confidence intervals cross line of no effect

Tso 2014

Metformin versus placebo or no treatment

in women with polycystic ovary

syndrome

307 per 1000

403 per 1000

(322 to 488)

OR 1.52

(1.07 to 2.15)

775

(8 studies)

Moderate

Imprecision: total number of events is fewer than 300

There was a data discrepancy in one of these studies.Sensitivity analysis excluding this study did not substantially change the findings.

McDonnell 2014

Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility

53 per 1000

72 per 1000

(36 to 140)

OR 1.40

(0.67 to 2.94)

339

(3 studies)

Low

None of the studies described their method of randomisation or allocation concealment
Imprecision: Low event rate (n=33)

3. Down‐regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection

30 per 100

29 per 100

(25 to 35)

OR 0.96

(0.75 to 1.23)

1259
(11 studies)

moderate

No 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 1000

279 per 1000

(257 to 302)

OR 0.84

(0.75 to

0.94)

6571

(41 studies)

Moderate

Lack 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 1000

516 per 1000

(340 to 687)

OR 1.63

(0.79 to 3.36)

149

(3 studies)

Very low

All 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 1000

244 per 1000

(200 to 293)

OR 1.5

(1.16 to 1.93)

1437

(20 studies)

Low

There 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 1000

220 per 1000

(127 to 354)

OR 1.55

(0.8 to

3.01)

230

(2 studies)

Low

There 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 1000

243 per 1000

(203 to 285)

OR 1.07

(0.85 to 1.33)

1864
(10 studies)

moderate

Method 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 1000

300 per 1000

(268 to 335)

OR 1.22

(1.04 to

1.43)

3209

(15 studies)

Moderate

Some of the trials lacked sufficient methodological details

van Wely 2011

rFSH versus urinary gonadotrophins

282 per 1000

280 per 1000

(263 to 299)

OR 0.99

(0.91 to

1.09)

9482

(41 studies)

Moderate

No 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 100

41 per 100

(32 to 54)

RR 1.19 (0.92 to 1.55

351

(5 studies)

Low

Imprecision, high risk of bias

Smulders 2010

Combined oral contraceptive plus agonist versus agonist

333 per 1000

373 per 1000
(209 to 571)

OR 1.19
(0.53 to 2.66)

102
(1 study)

very low

Single study. Wide confidence intervals which cross line of no effect.

Smulders 2010

Combined oral contraceptive plus antagonist versus antagonist

255 per 1000

191 per 1000
(146 to 248)

OR 0.69
(0.5 to 0.96)

847
(4 studies)

low

Imprecision, high risk of bias

Smulders 2010

Combined oral contraceptive plus antagonist versus agonist

245 per 1000

210 per 1000
(147 to 290)

OR 0.82
(0.53 to 1.26)

472
(3 studies)

low

Imprecision, 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 2014

Ultrasound + estradiol versus ultrasound only

358per 1000

380 per 1000

(306 to 462)

OR 1.1

(0.79 to 1.54)

647

(4 studies)

Low

Methods of allocation concealment inadequately described in the four trials; none of the trials adequately described blinding. Serious imprecision with wide confidence intervals

4.3 Interventions for poor responders

Pandian 2010

Cessation of GnRHa on stop protocol versus conventional GnRHa long protocol

176 per 1000

138 per 1000

(43 to 370)

OR 0.75

(0.21 to

2.74)

70 (1 study)

Low

Evidence based on a single trial with no blinding

Pandian 2010

GnRH antagonist versus conventional GnRHa long protocol

67 per 1000

167 per 1000

(34 to 529)

OR 2.8

(0.5 to

15.73)

60 (1 study)

Very low

Evidence 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 1000

77 per 1000

(16 to 304)

OR 0.21

(0.04 to

1.09)

54 (1 study)

Very low

Evidence 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 1000

163 per 1000

(62 to 363)

OR 1

(0.34 to

2.92)

98 92

studies)

Low

Lack of methodological details and evidence of imprecision

Pandian 2010

Low dose GnRHa flare up protocol versus spontaneous natural cycle IVF

119 per 1000

101 per 1000

(35 to 252)

OR 0.83

(0.27 to

2.5)

129 (1

study)

Low

Evidence based on a single trial with evidence of imprecision

Pandian 2010

Multiple dose GnRH agonist versus mini dose long agonist protocol

244 per 1000

227 per 1000

(99 to 439)

OR 0.91

(0.34 to

2.42)

89 (1 study)

Low

No 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 1000

142 per 1000

(36 to 429)

OR 0.27

(0.06 to

1.22)

42 (1 study)

Low

Evidence based on a single trial with evidence of imprecision

Pandian 2010

Long protocol versus modified long protocol

381 per 1000

105 per 1000

(18 to 398)

OR 0.19

(0.03 to

1.06)

40 (1 study)

Low

Evidence based on a single trial with evidence of imprecision

4.4 Natural cycle IVF

Allersma 2013

112 per 1000

86 per 1000

(36 to 194)

OR 0.75

(0.3 to 1.91)

219

(3 studies)

Low

1/3 studie did not report adequate allocaiton concealment, risk of performace bias, wide confidence intervals

5. Ovulation triggering

Youssef 2014

GnRH agonist versus HCG

256 per 1000

194 per 1000

(157 to 238)

OR 0.7 (0.54 to 0.91)

1198 (11 studies)

Low

Outcome = ongoing pregnancy rather than clinical pregnancy

Substantial heterogeneity: I2 = 59% to 66%.

5/11 studies at high risk of bias because of early termination and/or inadequate allocation concealment. None clearly reported blinded outcome assessment.

Youssef 2011

rHCG versus UhCG

312 per 1000

367 per 1000

(312 to 428)

OR 1.28

(1 to 1.65)

1206 (8

studies)

High

Overall well designed trials included

Youssef 2011

rhLH versus uhCG

265 per 1000

251 per 1000

(160 to 370)

OR 0.93

(0.53 to

1.63)

280 (2

studies)

Low

One 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 1000

594 per 1000 (326 to 815)

OR 4.59 (1.52 to 13.87)

61 (1 study)

Very low

One small study

Kwan 2013

Conscious sedation versus conscious sedation + acupuncture (VAS)

241 per 1000

344 per 1000

OR 1.65 (0.54 to 5.05)

61 (1 study)

Very low

One small study

Kwan 2013

Conscious sedation and analgesia versus general anaesthesia

200 per 1000

100 per 1000

OR 1 (0.25 to 4)

50 (1 study)

Very low

One small study

Kwan 2013

Conscious sedation+paracervical block versus general anaesthesia

375 per 1000

296 per 1000

OR 0.7 (0.22 to 1.26

51 (1 study)

Very low

One small study

Kwan 2013

Conscious sedation+paracervical block versus spinal anaesthesia

375 per 1000

358 per 1000

OR 0.93 (0.24 to 3.65)

38 (1 study)

Very low

One small study

Kwan 2013

Conscious sedation+ paracervical block versus paracervical block only

253 per 1000

240 per 1000

OR 0.93 (0.44 to 1.96)

150 (1 study)

Very low

One small study

Kwan 2013

Conscious sedation+paracervical block versus electro‐acupuncture+paracervical block

367 per 1000

358 per 1000

OR 0.96 (0.72 to 1.29)

783 (4 studies)

High

Adequate methodology, low heterogeneity

Kwan 2013

Conscious sedation and analgesia: pt controlled vs physician controlled

182 per 1000

168 per 1000

OR 0.91 (0.45 to 1.83)

218 (2 studies)

Moderate

Adequate methodology, low heterogeneity, sample size suboptimal

Wongtra‐ngan 2010

Follicular flushing versus no flushing

229 per 1000

258 per 1000

(145 to 414)

OR 1.17

(0.57 to

2.38)

164 (3

studies)

Moderate

Trials lacked sufficient methodological details

7. Sperm retrieval

Proctor 2008

Microsurgical epididymal sperm aspiration versus epididymal micropuncture with perivascular nerve stimulation

233 per 1000

55 per 1000 (12

to 202)

OR 0.19

(0.04 to 0.83)

59 (1 study)

Low

Evidence based on a single trial with insufficient methodological detail

McDowell 2014

Conventional sperm selection versus hyaluron sperm selection (HA‐ICSI)

470 per 1000

480 per 1000

(390 to 570)

RR 0.99

(0.82 to 1.20)

482

(1 study)

Low

Serious risk of bias: discrepancy in reporting of pregnancy losses.

Serious imprecision: confidence intervals compatible with substantial benefit or harm from the intervention, or with no effect.

McDowell 2014

HA culture dish (PICSI) compared with viscous medium containing HA (SpermSlow) for infertility requiring intracytoplasmic sperm injection

400 per 1000

430 per 1000

(250 to 620)

RR 1.07

(0.67 to 1.71)

99

(1 study)

Low

Serious risk of bias: study methods not reported in adequate detail.

Serious imprecision: confidence intervals compatible with substantial benefit or harm from the intervention, or with no effect.

8. Laboratory phase

Carney 2012

Assisted hatching versus no assisted hatching

332 per 1000

360 per 1000

(334 to 387)

OR 1.13

(1.01 to 1.27)

5728
(31 studies)

Moderate

There were methodological limitations or missing information in most of the trials

Glujovsky 2014

Vitrification versus slow freezing for women undergoing oocyte cryopreservation

116 per 1000

449 per 1000

RR 3.86

(0.86 to 9.11)

106

(2 studies)

Moderate

Live birth not reported, wide CIs

Van Rumste 2003

Intracytoplasmic sperm injection versus in vitro fertilisation

252 per 1000

329 per 1000

(243 to 429)

OR 1.45

(0.95 to

2.22)

415 (1

study)

Low

Details 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 1000

442 per 1000

(387 to 494)

OR 1.35

(1.08 to 1.67

1382 (4

studies)

Moderate

In 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 1000

187 per 1000

(144 to 235)

OR 0.56

(0.41 to 0.75)

1000 (4

studies)

Moderate

Only one of the studies described an adequate method of allocation concealment.

Huang 2013

Brief co‐incubation versus standard insemination

177 per 1000

337 per 1000

(238 to 453)

OR 2.36

(1.45 to 3.85)

372
(3 studies)

Low

One 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 100

43 per 100

(36 to 52)

RR 1.29

(1.06 to 1.55)

2014

(9 studies)

Very low

High 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 1000

420 per 156)

OR 1.14

(0.99 to 1.32)

3241 (23

studies)

Moderate

Some 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 1000

553 per 1000

(500 to 605)

OR 2.23

(1.80 to 2.76)

1505

(7 studies)

Moderate

Most studies do fully describe method of allocation concealment

Pandian 2013

Double embryo transfer versus repeated single embryo transfer

524 per 1000

483 per 1000

(413 to 554)

OR 0.85

(0.64 to 1.13)

752

(2 studies)

Low

Method 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 1000

305 per 1000

(107 to 614)

OR 1.17

(0.32 to 4.25)

45 (1 study)

Very low

Randomisation 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 1000

537 per 1000

(287 to 769)

OR 0.75

(0.26 to 2.16)

56 (1 study)

Very low

Randomisation, 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 1000

392 per 1000

(363 to 423)

OR 0.95

(0.84 to 1.08)

3980 (13

studies)

Low

Heterogeneity >60%, lack of details regarding blinding

Bontekoe 2014

Transfer medium enriched with high level of hyaluronic acid versus medium with low level or no hyaluronic acid

412 per 1000

493 per 1000

(459 to 528)

OR

1.39

(1.21 to 1.6)

3542 (14 studies)

Moderate

All studies except one were at high risk of bias in at least one domain, moderate heterogeneity I2=46%

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer

279 per 1000

336 per 1000

(313 to 361)

OR 1.31

(1.18 to 1.46)

6415 (17 studies)

Moderate

Subjects 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 1000

359 per 1000

(266 to 465)

1.02 (0.66 to 1.58)

350 (1 study)

High

Not all of the patients were followed up for one of the outcomes (bacterial contamination)

Derks 2009

Cervical dilatation versus no intervention

232 per 1000

124 per 1000

(78 to 189)

OR 0.47

(0.28 to 0.77)

288 (1 study)

Moderate

Evidence based on a single study

Derks 2009

Straightening the endocervical angle versus no intervention

271 per 1000

267 per 1000

(175 to 384)

OR 0.98

(0.57 to 1.68)

273 (2 studies)

Moderate

Evidence of imprecision

Derks 2009

Removal of cervical mucus versus no intervention

327 per 1000

320 per 1000

(169 to 522)

OR 0.97

(0.42 to 2.25)

97 (1 study)

Low

Lack of methodological details, evidence of imprecision and evidence based on a single trial

Derks 2009

Flushing the endocervical canal versus no intervention

413 per 1000

445 per 1000

9360 to 533)

OR 1.14

(0.8 to 1.62)

537 (3 studies)

Low

Lack of methodological details, heterogeneity >50%

Derks 2009

Flushing the endometrial cavity versus no intervention

519 per 1000

584 per 1000

(437 to 718)

OR 1.3

(0.72 to 2.36)

181 (1 study)

Low

Lack of methodological details, evidence of imprecision and evidence based on a single trial

Abou‐Setta 2014

Mechanical pressure versus no intervention

478 per 1000

637 per 1000

(561 to 706)

OR 1.92

(1.4 to 2.63)

639 (1 study)

Low

Evidence based on a single trial, method of randomisation was unclear and the trial was open label

Abou‐Setta 2014

Fibrin sealant versus no intervention

291 per 1000

287 per 1000

(181 to 422)

OR 0.98

(0.54 to 1.78)

211 (1 study)

Low

Evidence based on a single trial with inadequate allocation concealment

Abou‐Setta 2014

Less bed rest versus more bed rest

277 per 1000

303 per 1000

(228 to 391)

OR 1.13

(0.77 to 1.67)

542 (2 studies)

Moderate

One of the trials was open label

10. Luteal phase support

van der Linden 2011

hCG versus placebo/no treatment

169 per 1000

209 per 1000

(155 to 277)

OR 1.3

(0.9 to

1.88)

746 (5

study)

Low

Insufficient methodological details provided. Evidence of imprecision.

van der Linden 2011

Progesterone versus placebo/no treatment

140 per 1000

230 per 1000

(174 to 298)

OR 1.83

(1.29 to

2.61)

841 (7

study)

Low

Insufficient methodological details provided. Evidence of imprecision.

Boomsma 2012

Peri‐implantation glucocorticoids versus no glucocorticoids

290 per 1000

320 per 1000

(275 to 369)

OR 1.15

(0.93 to

1.43)

1759 (13

studies)

Moderate

Most of the studies lacked adequate blinding

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

D'Angelo 2007

Cryopreservation versus fresh embryo transfer

463 per 1000

482 per 1000

(318 to 654)

OR1.08

(0.54 to

2.19)

125 (1

study)

Low

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

D'Angelo 2007

Cryopreservation versus intravenous albumin

385 per 1000

36 per 1000 (0

to 423)

OR 0.06

(0 to 1.17)

26 (1 study)

Low

Evidence based on a single, open label trial with evidence of imprecision

Youssef 2011b

Intravenous fluids for the prevention of OHSS versus placebo

69 per 1000

58 per 1000 (40

to 85)

OR 0.84

(0.56 to

1.26)

1522 (7

studies)

Low

Insufficient methodological details provided and evidence of imprecision

D'Angelo 2011

Coasting versus no coasting

353 per 1000

234 per 1000

(98 to 471)

OR 0.56

(0.2 to

1.63)

68 (1 study)

Very low

Evidence based on a single trial. Insufficient methodological details provided and evidence of imprecision

Tang 2012

Cabergoline versus placebo/no treatment

429 per 1000

403 per 1000

(240 to 682)

OR 0.94

(0.56 to

1.59)

230 (2

studies)

Low

Allocation 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 1000

214 per 1000

(93 to 419)

OR 1.06

(0.4 to

2.8)

100 (1

study)

Very low

Evidence 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 1000

173 per 1000

(125 to 232)

OR 0.76

(0.52 to

1.1)

725 (4

studies)

Low

Heterogeneity >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 1000

109 per 1000

949 to 228)

OR 0.84

(0.35 to

2.02)

194 (1

study)

Very low

Evidence 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 1000

75 per 1000 (22

to 228)

OR 0.76

(0.21 to

2.77)

119 (1

study)

Very low

Evidence 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 1000

75 per 1000 (23

to 221)

OR 0.42

(0.12 to

1.47)

104 (1

study)

Very low

Evidence 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 1000

148 per 1000

OR 0.46

(0.23 to

0.92)

209 (1

study)

Low

Evidence 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 1000

246 per 1000

(167 to 347)

OR 1.19

(0.73 to

1.94)

778 (5

studies)

Moderate

All 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 1000

337 per 1000

(257 to 426)

OR 1.44

(0.98 to

2.1)

655 (4

studies)

Moderate

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

Figures and Tables -
Table 5. Clinical pregnancy per woman
Table 6. OHSS per woman

Outcome

Intervention and comparison intervention

Assumed risk with Comparator

Corresponding risk with intervention

Relative 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 1000

51 per 1000 (9

to 250)

OR 1.53

(0.25 to

9.49)

118 (1

study)

Low

Evidence lacked precision and there was a inadequate explanation of blinding.

2. Pre‐ART and adjuvant strategies

Tso 2014

Metformin versus placebo or no treatment

270 per 1000

97 per 1000

(62 to 153)

OR 0.29

(0.18 to

0.49)

798

(8 studies)

Moderate

Imprecision: total number of events is fewer than 300

3. Down‐regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection

3 per 100

2 per 100

(1 to 6)

OR 0.84

(0.29 to 2.42)

570
(5 studies)

low

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

66 per 1000

30 per 1000 (23

to 39)

OR 0.43

(0.33 to

0.57)

5417 (29

studies)

Low

Methodological limitations including lack of blinding and heterogeneity was 68%

Al‐Inany 2011

rhCG versus uhCG

27 per 1000

40 per 1000

(169 to 331)

OR 0.39

(0.25 to

0.61)

374 (3

studies)

Moderate

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

Al‐Inany 2011

rhLH versus uhCG

125 per 1000

105 per 1000

(53 to 194)

OR 0.82

(0.39 to

1.69)

280 (2

studies)

Low

One of the trials lacked adequate methodological details and there was evidence of imprecision

Boomsma 2012

Peri‐implantation glucocorticoids versus no glucocorticoids

194 per 1000

159 per 1000

(64 to 392)

OR 0.82

(0.33 to

2.02)

151 (2

studies)

Low

Methodological 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 1000

8 per 1000

(4 to 19)

OR 0.23

(0.1 to 0.52)

1559
(5 studies)

low

Few 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 1000

51 per 1000 (23

to 110)

OR 1.23

(0.54 to 2.82)

645 (3

studies)

Low

Open label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (medium dose) versus daily FSH

62 per 1000

66 per 1000 (45

to 95)

OR 1.07

(0.72 to

1.58)

1657 (3

studies)

Low

Open label trials included with evidence of imprecision due to low events

Pouwer 2012

Long acting FSH (high dose) versus daily FSH

0 per 1000

0 per 1000 (0 to

0)

OR 1.81

(0.08 to

41.62)

33 (1 study)

Very low

Open 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 1000

27 per 1000 (12

to 59)

OR 1.34

(0.58 to

3.09)

986 (7

studies)

Low

Some 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 100

1 per 100

(0 to 4)

OR 0.30

(0.06 to1.59)

351

(5 studies)

Very low

Very serious imprecision, inconsistency, high risk of bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus antagonist

17 per 1000

25 per 1000
(5 to 133)

OR 1.5
(0.26 to 8.8)

234
(1 study)

very low

Single 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 1000

35 per 1000
(12 to 100)

OR 0.63
(0.21 to 1.92)

290
(2 studies)

very low

Single study. Wide confidence intervals which cross line of no effect.

One study has high risk of attrition bias

4.2 Monitoring

Kwan 2014

Ultrasound + estradiol versus ultrasound only

37 per 1000

38 per 1000

(18 to 78)

OR 1.03

(0.48 to 2.20)

781 (6 studies)

Low

Methods of randomisation inadequately described in three of the six trials, allocation concealment inadequately described in all the six trials and blinding inadequately described in five of the six trials
No definition of OHSS provided by authors of these 6 studies

Serious imprecision with wide confidence intervals

4.4 Natural cycle IVF

Allersma 2013

67 per 1000

13 per 1000

(1 to 393)

OR 0.10

(0.01 to 4.06)

60

(1 study)

Very low

Allocation concealment method not reported, very serious imprecision

5. Ovulation triggering

Youssef 2014

GnRH agonist versus HCG

5 per 1000

1 per 1000

(0 to 2)

OR 0.15

(0.05 to 0.47)

989

(9 studies)

Moderate

All studies at high risk of bias in 1 or more domains. None clearly reported blinded outcome assessment.

Wongtra‐ngan 2010

rFSH versus urinary gonadotrophins

19 per 1000

22 per 1000

(16 to 30)

OR 1.18

(0.86 to 1.61)

7740

(32 studies)

High

There was a lack of blinding

Youssef 2011

rhCG versus uhCG

27 per 1000

40 per 1000

(169 to 331)

OR 0.39

(0.25 to 0.61)

374

(3 studies)

Moderate

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

Youssef 2011

rhLH versus uhCG

125 per 1000

105 per 1000

(53 to 194)

OR 0.82

(0.39 to 1.69)

280

(2 studies)

Low

One 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 1000

134 per 1000

(73 to 232)

OR 3.62

(1.85 to 7.06)

387

(1 study)

Low

Evidence is based on a single trial. Insufficient methodological details provided. Evidence of imprecision.

Akhtar 2013

Heparin versus placebo or no treatment

250 per 1000

349 per 1000

(256 to 458)

OR 1.61

(1.03 to 2.53)

386

(3 studies)

Very low

Selection 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 1000

125 per 1000

(62 to 240)

OR 0.40

(0.20 to 0.77)

230 (2

studies)

Low

Lack of details for allocation concealment

D'Angelo 2007

Cryopreservation versus fresh embryo transfer

60per 1000

8 per 1000 (318

1 to 128)

OR1.12

(0.01 to 2.29)

125

(1 study)

Low

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

D'Angelo 2007

Cryopreservation versus intravenous albumin

77 per 1000

308 per 1000

(41 to 824)

OR 5.33

(0.51 to 56.24)

26

(1 study)

Very low

Evidence based on a single, open label trial with evidence of imprecision

Youssef 2011b

Intravenous human albumin for prevention of OHSS versus placebo

83 per 1000

57 per 1000

OR 0.67

(0.45 to 0.99)

1660

(8 studies)

Low

Insufficient methodological details provided. Heterogeneity was >60% (I2)

Youssef 2011b

Intravenous hydroxyethyl starch for prevention of OHSS versus placebo

46 per 1000

6 per 1000

(2 to 19)

OR 0.12

(0.04 to 0.4)

487

(3 studies)

Moderate

Insufficient methodological details provided in some of the trials

D'Angelo 2011

Coasting versus no coasting

265 per 1000

58 per 1000

(11 to 241)

OR 0.17

(0.03 to 0.88)

68 (1 study)

Very low

Evidence is based on a single conference abstract. There are insufficient methodological details provided and there is evidence of imprecision

Figures and Tables -
Table 6. OHSS per woman
Table 7. Multiple pregnancy per woman

Outcome

Intervention and comparison intervention

Assumed risk with Comparator

Corresponding risk with intervention

Relative 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 1000

88 per 1000

(45 to 163)

OR 0.64

(0.31 to 1.29)

351

(3 studies)

Moderate

The trials lacked adequate methodological details

2. Pre‐ART and adjuvant strategies

Siristatidis 2011

Aspirin versus placebo or no treatment

59 per 1000

50 per 1000

(27 to 91)

RR 0.74

(0.38 to 1.46)

680

(2 studies)

Moderate

There were some methodological limitations in the two trials

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment

67 per 1000

48 per 1000

(29 to 80)

OR 0.7

(0.41 to 1.21)

1022

(2 studies)

Very low

Imprecision, some methodological details were unclear

Duffy 2010

Growth hormone compared with placebo

195 per 1000

131 per 1000

(42 to 342)

OR 0.62

(0.18 to 2.15)

80

(2 studies)

Moderate

Some evidence of lack of precision

Cheong 2013

Acupuncture versus no acupuncture on or around the day of embryo transfer

56 per 1000

72 per 1000

(42 to 122)

OR 1.32

(0.74 to 2.35)

795

(2 studies)

Low

Only 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 low

Evidence based on a single trial with imprecision

Gutarra‐Vilchez 2014

Vasodilator compared with placebo

89 per 1000

79 per 1000

(35 to 180)

RR 0.89

(0.39 to 2.03)

250

(2 studies)

Moderate

Studies had low or unclear risk of bias but serious imprecision.

3. Down‐regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection

24 per 100

25 per 100

(13 to 43)

OR 1.1

(0.49 to 2.46)

132
(4 studies)

Low

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.

Boomsma 2012

Peri‐implantation glucocorticoids versus no glucocorticoids

38 per 1000

74 per 1000

(31 to 168)

OR 2.02

(0.8 to 5.11)

372

(4 studies)

Moderate

Lacked 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)

Moderate

The studies lacked methodological details

Smulders 2010

Combined oral contraceptive pill plus antagonist versus antagonist

42 per 1000

92 per 1000
(10 to 507)

OR 2.32
(0.23 to 23.65)

45
(1 study)

Very low

Imprecision,high risk of attrition bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus agonist

67 per 1000

68 per 1000
(26 to 168)

OR 1.02
(0.37 to 2.82)

238
(2 studies)

low

Imprecision

4.4 Natural cycle IVF

Allersma 2013

29 per 1000

6 per 1000

(0 to 117)

OR 0.21

(0.01 to 4.38)

132

(1 study)

Very low

Method of sequence generatin and allocation concealment not stated, high risk of attrition bias, very serious imprecisikon

5. Ovulation triggering

Youssef 2014

GnRH agonist versus HCG

82 per 1000

134 per 1000

(71 to 238)

OR 1.74

(0.86 to

3.5)

342 (3

studies)

Moderate

No evidence of blinding in many of the trials

van Wely 2011

rFSH versus urinary gonadotrophins

85 per 1000

78 per 1000 (66

to 92)

OR 0.91

(0.76 to

1.09)

6329 (25

studies)

Moderate

No 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)

Low

There were methodological limitations that were not adequately explained and evidence of imprecision

Carney 2012

Assisted hatching versus no assisted hatching

102 per 1000

136 per 1000

(112 to 162)

OR 1.38

(1.11 to 1.7)

3447
(14 studies)

Low

There 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 1000

113 per 1000

(80 to 158)

OR 1.33

(0.91 to

1.95)

1382 (4

studies)

Low

There 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 1000

101 per 1000

(80 to 127)

OR 0.92

(1.71 to

1.19)

2481 (16

studies)

Moderate

Some 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 1000

24 per 1000 (8

to 62)

OR 0.06

(0.02 to

0.16)

468 (8

studies)

Moderate

Some methodological details such as randomisation and blinding were unclear

Pandian 2013

Double embryo transfer versus repeated single embryo transfer

17 per 1000

130 per 1000

(81 to 203)

OR 8.47

(4.97 to 14.43)

1612

(10 studies)

High

Heterogeneity (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 1000

17 per 1000 (1

to 278)

OR 0.17

(0.01 to

3.85)

45 (1 study)

Very low

Randomisation 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 1000

107 per 1000

(27 to 349)

OR 0.44

(0.1 to

1.97)

56 (1 study)

Very low

Randomisation, 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 1000

138 per 1000

9114 to 166)

OR 1.02

(0.82 to

1.27)

2780 (8

studies)

Moderate

Trials lacked details on blinding

Bontekoe 2014

Transfer medium enriched with high level of hyaluronic acid versus medium with low level or no hyaluronic acid

175 per 1000

282 per 1000

(240 to 328)

OR 1.86

(1.49 to 2.31)

1951

(5 studies)

Moderate

All studies except one at high risk of bias in one or more domains

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer

63 per 1000

79 per 1000 (59

to 105)

OR 1.27

(0.93 to

1.75)

2346 (6

studies)

Low

Studies were open label and heterogeneity >60%

Abou‐Setta 2014

Less bed rest versus more bed rest

73 per 1000

113 per 1000

(25 to 383)

OR 1.62

(0.33 to

7.9)

542 (2

studies)

Very low

Heterogeneity >70%, wide confidence intervals indicating imprecision, one trial was open

Abou‐Setta 2014

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 low

Evidence 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 1000

0 per 1000

OR 2.48

(0.09 to

68.14)

21 (1 study)

Very low

Evidence 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 low

Evidence 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 low

Evidence based on a single trial, evidence of imprecision, open label and insufficient methodological details provided

Figures and Tables -
Table 7. Multiple pregnancy per woman
Table 8. Miscarriage per woman

Outcome

Intervention and comparison intervention

Assumed risk with Comparator

Corresponding risk with intervention

Relative 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 1000

233 per 1000

(160 to 303)

OR 1.1

(0.73 to 1.67)

616

(6 studies)

Low

Only 2/6 studies described adequate allocation concealment, imprecision

Cheong 2013

Acupuncture versus no acupuncture around the time of oocyte retrieval

242 per 1000

201 per 1000

(118 to 319)

OR 0.79

(0.42 to 1.47)

262 (4 studies)

Low

Only 1/4 studies described adequate allocation concealment, imprecision

Siristatidis 2011

Aspirin versus placebo or no treatment

41 per 1000

47 per 1000 (30

to 75)

RR 1.10

(0.68 to

1.77)

1497 (5

studies)

Moderate

There were some methodological limitations in some of the trials

Tso 2014

Metformin versus placebo or no treatment

139 per

1000

110 per 1000

(65 to 182)

OR 0.76

(0.43 to 1.37)

521

(6 studies)

Moderate

Imprecision: total number of events low

Showell 2014

Antioxidant versus control

19 per 1000

33 per 1000

(8 to 29)

OR 1.74

(0.

40 to 7.60)

247 (3

studies)

Very low

Inadequate explanations of methodology, large unexplained dropouts in one study, low event rate

No head to head comparisons: comparison in all these studies was placebo or no treatment

Showell 2013

Antioxidant versus placebo or no treatment/standard treatment

63 per 1000

56 per 1000

(37 to 84)

OR 0.88

(0.57 to 1.36)

1456

(8 studies)

Low

Imprecision, 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 1000

12 per 1000 (‐

179 to 147)

OR 0.03 (‐

0.38 to 0.43)

23 (1 study)

Very low

Evidence of imprecision and evidence based on a single trial

Benschop 2010

Aspiration of endometrioma versus expectant management

100 per 1000

97 per 1000 (25

to 316)

OR 0.97

(0.23 to 4.15)

81

(1 study)

Very low

Evidence was based on a single trial, wide confidence intervals which cross line of no effect

Benschop 2010

GnRH agonist versus GnRH antagonist

30 per 1000

29 per 1000

(2 to 331)

OR 0.97

(0.06 to 15.85)

67

(1 study)

Very low

Evidence was based on a single trial, wide confidence intervals which cross line of no effect

Johnson 2010

Salpingectomy versus no surgical treatment

53 per 1000

46 per 1000 (17

to 117)

OR 0.86

(0.31 to

2.38)

329 (3

studies)

Moderate

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

Johnson 2010

Tubal occlusion versus no surgical treatment

67 per 1000

60 per 1000 (6

to 399)

OR 0.89

(0.09 to

9.28)

65 (1 study)

Very low

Evidence 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 1000

63 per 1000 (6

to 436)

OR 2.07

(0.18 to

24.01)

64 (1 study)

Very low

Evidence based on a single trial. Evidence of imprecision: wide confidence intervals which cross line of no effect.

Gutarra‐Vilchez 2014

Vasodilator compared with placebo

69 per 1000

58 per 1000

(26 to 132)

RR 0.84

(0.37 to 1.91)

350

(2 studies)

Moderate

Studies had low or unclear risk of bias but serious imprecision.

3. Down‐regulation with agonists or antagonists

Albuquerque 2013

GnRHa depot versus daily injection

13 per 100

14 per 100

(9 to 22)

OR 1.16

(0.7 to 1.94)

512
(9 studies)

low

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

118 per

1000

113 per 1000

(85 to 149)

OR 0.96

(0.7 to 1.31)

1647 (27

studies)

Low

Methodological limitations including lack of blinding and there was also evidence of imprecision

Boomsma 2012

Peri‐implantation glucocorticoids versus no glucocorticoids

57 per 1000

80 per 1000 (47

to 132)

OR 1.44

(0.82 to

2.51)

832 (7

studies)

Low

Methodological 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 1000

46 per 1000 (4

to 353)

OR 2.1

(0.18 to

23.98)

89 (1 study)

Very low

Single 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 1000

199 per 1000

(107 to 337)

OR 1.1

(0.53 to

2.25)

201 (4

studies)

Moderate

Most 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 1000

115 per 1000

(44 to 268)

OR 0.71

(0.25 to

1.99)

125 (3

studies)

Moderate

Most 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 1000

53 per 1000 (35

to 81)

OR 0.8

(0.51 to

1.26)

1330 (11

studies)

Moderate

Some 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 100

17 per 1000

RR 1.08

(0.50 to 2.31)

127

(4 studies)

Very low

Very serious imprecision, high risk of bias

Smulders 2010

Combined oral contraceptive pill plus antagonist versus antagonist

68 per 1000

84 per 1000
(52 to 134)

OR 1.26
(0.76 to 2.12)

847
(4 studies)

Low

Imprecision, insufficient reporting of randomisation methods

Smulders 2010

Combined oral contraceptive pill plus antagonist versus agonist

80 per 1000

43 per 1000
(20 to 87)

OR 0.52
(0.24 to 1.1)

472
(3 studies)

Low

Imprecision, insufficient reporting of randomisation methods

5. Ovulation triggering

Youssef 2014

GnRH agonist versus HCG

67 per 1000

111per 1000

(73 to 165)

OR 1.74

(1.10 to 2.75)

1198 (11 studies)

Moderate

5/11 studies at high risk of bias because of early termination and/or inadequate allocation concealment. None clearly reported blinded outcome assessment.

van Wely 2011

rFSH versus urinary gonadotrophins

50 per 1000

57 per 1000 (46

to 70)

OR 1.16

(0.93 to

1.44)

6663 (30

studies)

Moderate

No evidence of blinding in many of the trials

Youssef 2011

rhCG versus uhCG

63 per 1000

44 per 1000 (27

to 74)

OR 0.69

(0.41 to

1.18)

1106 (7

studies)

Moderate

Some methodological detail was lacking in some of the trials

Youssef 2011

rhLH versus uhCG

66 per 1000

62 per 1000 (25

to 144)

OR 0.94

(0.37 to

2.38)

280 (2

studies)

Low

One of the trials lacked adequate methodological details and there was evidence of imprecision

7. Sperm selection

McDowell 2014

HA culture dish (PICSI) compared with viscous medium containing HA (SpermSlow) for infertility requiring intracytoplasmic sperm injection

250 per 1000‐

190 per 1000

(50 to 510)

RR 0.76

(0.24 to 2.44)

41 pregnancies

(1 study)

Low

Serious risk of bias: study methods not reported in adequate detail.

Serious imprecision: confidence intervals compatible with substantial benefit or harm from the intervention, or with no effect.

8. Laboratory phase

Bontekoe 2012

Embryo culture with low oxygen concentration versus atmospheric oxygen concentration

75 per 1000

94 per 1000 (65

to 133)

OR 1.28

(0.86 to

1.9)

1291 (3

studies)

Low

There were methodological limitations and evidence of imprecision

Carney 2012

Assisted hatching versus no assisted hatching

45 per 1000

46 per 1000

(32 to 68)

OR 1.03

(0.69 to 1.54)

2131
(14 studies)

Moderate

There 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 1000

108 per 1000

(76 to 150)

OR 0.87

(0.59 to

1.27)

1062 (5

studies)

Moderate

Most of the included trials lacked adequate methodological details

Twisk 2006

Preimplantation genetic screening versus no screening in women with good prognosis

89 per 1000

103 per 1000

(54 to 183)

OR 1.17

(0.59 to

2.3)

388 (3

studies)

Very low

Open label studies with evidence of imprecision. Heterogeneity was >60%

Huang 2013

Brief co‐incubation versus standard insemination

24 per 1000

47 per 1000

(9 to 217)

OR 1.98

(0.35 to 11.09)

167
(1 study)

Low

One 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 1000

91 per 1000 (68

to 119)

OR 1.14

(0.84 to

1.55)

2127 (14

studies)

Moderate

Some methodological details were unclear or inadequate

Pandian 2013

Double embryo transfer versus single embryo transfer (one cycle only)

67 per 1000

78 per 1000

(51 to 118)

OR 1.18

(0.75 to 1.86)

1097

(3 studies)

Low

Some 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 1000

148 per 1000

(50 to 363)

OR 1.67

(0.51 to 5.48)

107

(1 study)

Very low

Method of allocation concealment not fully described, very serious imprecision

Gunby 2004

Day 3 versus Day 2 embryo transfer

63 per 1000

66 per 1000 (49

to 89)

OR 1.05

(0.76 to

1.44)

2452 (9

studies)

Low

Evidence of imprecision and lack of details about blinding

Brown 2010

Ultrasound guidance versus clinical touch for embryo transfer

40 per 1000

38 per 1000 (26

to 54)

OR 0.95

(0.65 to

1.38)

2930 (8

studies)

Low

Studies were open label and there was evidence of imprecision

Derks 2009

Straightening the utero‐cervical angle versus no intervention

156 per 1000

0 per 1000 (0 to

0)

OR 0 (0 to

0)

131 (1 study)

Low

Evidence based on a single trial, evidence of imprecision and study lacked blinding

Derks 2009

Cervical dilatation versus no intervention

35 per 1000

23 per 1000

OR 0.64

(0.21 to

1.93)

288 (1 study)

Moderate

Evidence of imprecision and evidence based on a single trial

Abou‐Setta 2014

Less bed rest versus more bed rest

47 per 1000

75 per 1000 (38

to 143)

OR 1.63

(0.79 to

3.35)

542 (2

studies)

Moderate

Open label trial

11. Prevention of ovarian hyperstimulation syndrome (OHSS)

Tang 2012

Cabergoline versus placebo or no treatment

38 per 1000

12 per 1000 (1

to 117)

RR 0.31

(0.03 to

3.07)

163 (1 study)

Low

Lack of details for allocation concealment and evidence based on a single trial

D'Angelo 2011

Coasting versus no coasting

88 per 1000

59 per 1000 (10

to 285)

OR 0.65

(0.1 to

4.13)

68 (1 study)

Very low

Evidence 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 1000

256 per 1000

(135 to 436)

OR 0.75

(0.34 to

1.69)

128 (3

studies)

Very low

Insufficient 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 1000

250 per 1000

(71 to 596)

OR 1.53

(0.35 to

6.79)

44 (1 study)

Very low

Insufficient 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 1000

28 per 1000 (9

to 84)

OR 0.92

(0.29 to

2.96)

415 (2

studies)

Moderate

Insufficient 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 1000

40 per 1000

OR 0.6

(0.26 to 1.39)

579 (3

studies)

Moderate

Insufficient details on methodological detail in some trials

Figures and Tables -
Table 8. Miscarriage per woman