Abstract
Background
As many as one in six couples will encounter problems with fertility, defined as failure to achieve a clinical pregnancy after regular intercourse for 12 months. Increasingly, couples are turning to assisted reproductive technology (ART) for help with conceiving and ultimately giving birth to a healthy live baby of their own. Fertility treatments are complex, and each ART cycle consists of several steps. If one of these steps is incorrectly applied, the stakes are high as conception may not occur. With this in mind, it is important that each step of the ART cycle is supported by good evidence from well‐designed studies.
Objectives
To summarise the evidence from Cochrane systematic reviews on procedures and treatment options available to couples with subfertility undergoing assisted reproductive technology (ART) procedures.
Methods
Published Cochrane systematic reviews of couples undergoing ART procedures (in vitro fertilisation or intracytoplasmic sperm injection) were eligible for inclusion in the overview. We also identified Cochrane reviews in preparation, for future inclusion.
The primary outcome of the overview was live birth or the composite outcome live birth or ongoing pregnancy, as reported by the included reviews. Our secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage, and ovarian hyperstimulation syndrome. We excluded studies of intrauterine insemination and ovulation induction.
We undertook selection of systematic reviews, data extraction, and quality assessment in duplicate. We assessed review quality by using the AMSTAR tool. We organised reviews by their relevance to specific stages in the ART cycle. We summarised their findings in the text and reported data for each outcome in 'Additional tables'.
Main results
We included 68 systematic reviews published in the Cochrane Library up to May 2018. All were of high quality. These reviews identified 38 interventions that were effective (n = 23) or promising (n = 15), and they identified 19 interventions that were ineffective (n = 2) or possibly ineffective (n = 17). For 15 interventions, review authors were unable to draw conclusions owing to lack of evidence.
We identified an additional 11 protocols and four titles for future inclusion in this overview.
Authors' conclusions
This overview provides the most up‐to‐date evidence on ART cycles from systematic reviews of randomised controlled trials. Fertility treatments are costly, and the stakes are high. Using the best available evidence to optimise outcomes is best practice. Evidence from this overview could be used to develop clinical practice guidelines and protocols that can be applied in daily clinical practice to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation, and ovarian hyperstimulation syndrome.
Plain language summary
Assisted reproductive technology: an overview of Cochrane Reviews
Review question
What is the evidence on effectiveness and safety of procedures and treatment options available to couples with subfertility undergoing assisted reproductive technology (ART) procedures.
Background
As many as one in six couples encounter problems with fertility, defined as failure to achieve a clinical pregnancy after regular intercourse for 12 months. Increasingly, couples are turning to assisted reproductive technology (ART) for help with conceiving and ultimately giving birth to a healthy live baby of their own. Fertility treatments are complex and costly, and each assisted reproduction cycle consists of several steps. If one of the steps is incorrectly applied, the stakes are high as conception may not occur. With this in mind, it is important that each step involved in ART is supported by good evidence from well‐designed studies. Cochrane reviewers examined the evidence from Cochrane systematic reviews on ART published in the Cochrane Library.
Study characteristics
We included 68 Cochrane systematic reviews on various stages of the ART cycle. All were of high quality. We included in the overview reviews of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). We did not include reviews of intrauterine insemination (placing sperm inside a woman's uterus to facilitate fertilisation) or ovulation induction (stimulation of ovulation by medication). This overview provides the most up‐to‐date evidence from randomised controlled trials on ART cycles. The overview is up‐to‐date to May 2018.
Key results
The reviews identified 38 interventions that were effective (n = 23) or promising (n = 15), and they identified 19 interventions that were ineffective (n = 2) or possibly ineffective (n = 17). For 15 interventions, the reviews were unable to draw conclusions owing to lack of evidence. Use of evidence from this overview to guide clinical practice should help to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation, and ovarian hyperstimulation syndrome.
Quality of the evidence
All included reviews were of high quality. The quality of the evidence for specific comparisons ranged from very low to high.
Background
Description of the condition
As many as one in six couples will encounter problems with fertility, defined as failure to achieve a clinical pregnancy after regular intercourse for 12 months (Boivin 2007; Zegers‐Hochschild 2009). Increasingly, couples are turning to assisted reproductive technology (ART) for help with conceiving and ultimately giving birth to a healthy live baby of their own. Fertility treatments are complex, and each assisted reproduction cycle consists of several steps. If one of the steps is incorrectly applied, the stakes are high as conception may not occur. With this in mind, it is important that each step involved in assisted fertility treatment is supported by good evidence from well‐designed studies.
This review summarises the evidence for the different steps of an ART cycle.
Description of the interventions
Assisted reproductive technology (ART) consists of procedures that involve the in vitro handling of both human oocytes and sperm, or of embryos, with the objective of establishing a pregnancy (Zegers‐Hochschild 2009).
Once couples have been prepared for treatment, the following the steps make up an ART cycle.
Drugs are initiated to stimulate growth of multiple ovarian follicles, while at the same time other medications are given to suppress the natural menstrual cycle and down‐regulate the pituitary gland.
After ovarian stimulatory drugs are initiated, monitoring is undertaken at intervals to assess the growth of follicles.
When the follicles have reached an appropriate size, the next step involves giving a drug to bring about final maturation of the eggs (known as ovulation triggering).
The next step involves egg collection (usually with a transvaginal ultrasound probe to guide the pickup) and, in some cases of male infertility, sperm retrieval.
Next is the fertilisation process, which usually is completed by in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).
Laboratory procedures follow for embryo culture: culture media, oxygen concentration, co‐culture, assisted hatching, etc.
Embryos are then placed into the uterus. Issues of importance here include endometrial preparation, the best timing for embryo transfer, how many embryos to transfer, what type of catheter to use, the use of ultrasound guidance, need for bed rest, etc.
Then comes luteal phase support, for which several options are available, including administration of progesterone, oestrogen (E2), and human chorionic gonadotrophin (hCG).
Finally, adverse effects, such as ovarian hyperstimulation syndrome, can be associated with the assisted reproduction process.
How the intervention might work
Assisted reproductive technology (ART) is applied to treat a variety of causes of infertility by collecting gametes, creating embryos from these in the laboratory, and transferring the most viable embryo into the uterus.
Why it is important to do this overview
The significance of this process of reviewing reviews on ART is that it highlights evidence indicating the best methods for each step in the ART cycle, which can lead to simplifying and improving the process. The outcome should be an increase in live birth rates from assisted reproduction, along with a reduction in adverse events, such as ovarian hyperstimulation syndrome and multiple pregnancy.
Objectives
To summarise the evidence from Cochrane systematic reviews on procedures and treatment options available to couples with subfertility undergoing ART procedures.
Methods
Criteria for considering reviews for inclusion
Only published Cochrane systematic reviews were considered in this overview. Cochrane reviews in preparation (published protocols and titles) were identified for future inclusion.
Participants
Participants in eligible studies were couples with subfertility seeking a pregnancy and undergoing ART. Specifically, participants included women with endometriosis, women with a previous poor response or recurrent pregnancy losses, and couples undergoing frozen embryo replacement cycles, oocyte donation cycles or both.
Interventions
Reviews of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) were considered. Reviews of intrauterine insemination and ovulation induction were excluded from the overview.
Outcomes
The primary outcome of this overview was live birth, or the composite outcome of live birth or ongoing pregnancy, as reported by the individual reviews.
Secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage, and ovarian hyperstimulation syndrome.
Search methods for identification of reviews
The Cochrane Database of Systematic Reviews was searched on 4h May 2018, using the term 'Assisted Reproductive Technology'. The search term was limited to title, abstract, or keywords. No other databases were searched.
Data collection and analysis
Selection of reviews
We selected reviews addressing the stages or steps of ART interventions. One review author identified these reviews and a second review author confirmed them. We resolved disagreements by consensus or by discussion with a third party.
We separated reviews according to the following topics (discussed under these headings).
1. Indication for ART
2. Pre‐ART and adjuvant strategies
2.1. Strategies for unselected populations
2.1.1. Lifestyle advice
2.1.2. Surgical therapy
2.1.3. Medical therapy
2.1.4. Alternative therapy
2.2. Strategies for selected populations
2.2.1. Tubal pathology
2.2.2. Endometriosis
2.2.3. Polycystic ovary syndrome (PCOS)
2.2.4. Ovarian cysts
3. Down‐regulation with agonists or antagonists
4. Ovarian stimulation
4.1 Medication type
4.2. Monitoring
4.3. Interventions for poor responders
4.4. Natural cycle IVF
5. Ovulation triggering
6. Oocyte retrieval
7. Sperm retrieval
8. Laboratory phase
9. Embryo transfer
9.1. Developmental stage
9.2. Number of embryos
9.3. Transfer techniques and procedures
9.4 Interventions for recurrent implantation failure
10. Luteal phase support
11. Prevention of ovarian hyperstimulation syndrome (OHSS)
12. Frozen embryo replacement cycles
Data extraction and management
For the 2018 update, two review authors (JM and CF) independently extracted data on the above outcomes. We resolved disagreements by consensus. When significant data were missing, we contacted the original review authors for assistance. We extracted and reported in additional tables information concerning the following.
Population demographics: participant characteristics.
Review characteristics: the number of included trials; the number of participants; the date the review was assessed as up‐to‐date; interventions and comparisons; all outcomes; and limitations of the review.
Statistical summary: summary effects from relevant comparisons and outcomes.
We used the same effect measures as were used in the original reviews, in most cases odds ratios. Problems can arise if the odds ratio is misinterpreted as a risk ratio. For interventions that increase the chance of events, the odds ratio is larger than the risk ratio, so misinterpretation will tend to overestimate the intervention effect, especially when events are common (with, say, risk of events > 20%). For interventions that reduce the chance of events, the odds ratio is smaller than the risk ratio, so that again, misinterpretation overestimates the effect of the intervention (Higgins 2011).
Assessment of methodological quality of included reviews
Quality of included reviews
We assessed the quality of the included reviews using the AMSTAR tool (Shea 2007). We noted in each case whether the literature search had been conducted or updated within the past three years.
Quality of evidence from primary studies in included reviews
We used the GRADEPro 'Summary of findings' tables from each review (or, if necessary, we constructed such a table) to indicate the quality of evidence for the main comparisons. We took into account the following criteria: study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness, and publication bias.
Data synthesis
We prepared a narrative description of the included trials and did not conduct a network meta‐analysis.
We summarised the main results of the included reviews by categorising their findings within the following framework, organised by topic.
Effective interventions: indicating that the review found evidence of effectiveness for an intervention.
Promising interventions (more evidence needed): indicating that the review found some evidence of effectiveness for an intervention, but that more evidence is needed.
Ineffective interventions: indicating that the review found evidence of lack of effectiveness for an intervention.
Probably ineffective interventions (more evidence needed): indicating that the review found evidence suggesting lack of effectiveness for an intervention, but that more evidence is needed.
No conclusions possible due to lack of evidence: indicating that the review found insufficient evidence for review authors to comment on the effectiveness of an intervention.
Authors of the overview determined that the choice of category reflected the conclusions of the original review authors. We resolved disagreements by discussion between overview authors to reach a consensus.
This approach to summarising the evidence was based on a Cochrane Overview of pain management in labour, which categorises interventions as "What works", “What may work”, and “Insufficient evidence to make a judgement" (Jones 2012).
Results
Description of included reviews
As of May 2018, we included in this review 68 systematic reviews published in the Cochrane Library (over 175,055 participants). See Table 1 for a summary of characteristics of the 68 included reviews (review title and author, when the review was last assessed as up‐to‐date, how many randomised controlled trials and participants were included, and interventions and comparisons, outcomes, and main limitations of each review). We added 9 of the 68 reviews to the 2018 update (Ata 2018; Craciunas 2016; Kalampokas 2017; Lensen 2018, Nagels 2015; Reavey 2016; Siristatidis 2018; Wong 2017; Youssef 2015).
1. Review 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 2015 In vitro fertilisation for unexplained subfertility |
4/5/2015 | 8 RCTs | 1774 couples with unexplained subfertility | In vitro fertilisation | Expectant management Intrauterine insemination Intrauterine insemination + ovarian stimulation |
Live birth Clinical pregnancy Multiple pregnancy OHSS |
Serious imprecision resulting from small study numbers and low event rates |
| 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‐anastomosis | Live birth Clinical pregnancy Multiple pregnancy 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 |
1/5/2013 Review is considered to be stable, with no update planned |
No RCTs | N/A | In vitro maturation | In vitro fertilisation Intracytoplasmic sperm injection |
Live birth Cycle cancellation Oocyte fertilisation OHSS Miscarriage 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 Pre‐conception 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 |
Trial did not report on fertility outcomes. Evidence was based on a single trial |
| WM1504 Nastri 2015 Endometrial injury in women undergoing assisted reproductive techniques |
19/1/2015 | 14 RCTs | 1063 women undergoing ART | Endometrial injury | No endometrial injury Mock procedure |
Live birth rate Clinical pregnancy Multiple pregnancy Miscarriage Ongoing pregnancy Pain/bleeding Implantation |
Serious imprecision for most outcomes..Adverse events such as miscarriage and multiple pregnancy were poorly reported |
| MGS1510 Showell 2014 Antioxidants for male subfertility |
31/1/14 | 3 RCTs* | 111 male partners of couples undergoing ART | Antioxidant | Placebo/no treatment Antioxidant Pentoxifylline |
Live birth Pregnancy Adverse events DNA fragmentation Sperm parameters Miscarriage |
* A further 45 RCTs in this review included subfertile couples not undergoing ART Lack of a clear description of trial methods and inconsistent, inadequate reporting of live births and clinical pregnancies |
| MGS1630 Showell 2017 Antioxidants for female subfertility |
27/9/2016 | 27 RCTs | Over 3000 women undergoing ART (not all studies reported sample size) | Antioxidant | Placebo/no treatment Antioxidant |
Live birth Pregnancy Multiple pregnancy Miscarriage |
A further 23 RCTs in this review included subfertile couples not undergoing ART The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision, and inconsistency |
| 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% of studies failing to describe an adequate method of allocation concealment |
| KH291 Duffy 2010 Growth hormone for in vitro fertilization |
01/07/2009 | 10 RCTs | 440 couples undergoing IVF | Growth hormone | Placebo | Live birth Pregnancy Number of women with ≥ 1 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 |
Main limitations were imprecision and lack of clarity about study methods |
| VJP951 Siristatidis 2016 Aspirin for in vitro fertilisation |
9/05/16 Review is considered to be stable, with no update planned |
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 |
Poor reporting of study methods, suspected publication bias |
| HEN1730 Nagels 2015 Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction |
12/03/2015 | 17 RCTs | 1496 women, most (15/17 RCTs) identified as poor responders | Testosterone Dehydroepiandrosterone |
Placebo or no treatment Oestradiol |
Live birth or ongoing pregnancy Clinical pregnancy Multiple pregnancy Miscarriage |
Main limitations were lack of blinding, inadequate reporting of study methods, and low event and sample sizes in some trials |
| 2.2. For selected populations | |||||||
| SG1241 Benschop 2010 Interventions for women with endometrioma prior to assisted reproductive technology |
26/11/2010 | 4 RCTs | 312 women undergoing management of endometrioma before ART | Surgical or medical treatment before ART | Placebo/no treatment Other surgical or medical treatment before ART |
Live birth Clinical pregnancy Adverse events Quality of life Pain Recurrence Oestradiol levels Number of mature oocytes |
No live birth rates reported Two trials were open‐label |
| LDT1201 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 Serum E2 level |
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 procedures | 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 RCTs; poor reporting of study methods; serious imprecision and inconsistent data in 1 study publication |
| 3. Down‐regulation with agonists or antagonists | |||||||
| LA541 Albuquerque 2013 Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles |
3/7/2012 | 16 RCTs | 1811 women undergoing IVF1811 | GnRHa depot | GnRHa daily | Clinical pregnancy Pregnancy per oocyte retrieval procedure Pregnancy per embryo transferred Number of ampoules of gonadotrophin employed Number of days of gonadotrophin treatment Number of oocytes retrieved Abortion Ongoing/delivered pregnancy rates per cycle started Multiple pregnancy rates OHSS |
Study quality was unclear owing to poor reporting. Only 4 RCTs reported live births as an outcome, and only 5 described adequate methods for concealment of allocation |
| HA412 Al‐Inany 2016 Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology |
28/4/2016 | 73 RCTs | 12,212 women undergoing ART procedures | GnRH antagonist | Long course GnRH agonist | Live birth Ongoing pregnancy Clinical pregnancy Miscarriage OHSS Cycle cancellation |
Poor reporting of study methods |
| HNS881 Sallam 2006 Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis |
17/10/2005 | 3 RCTs | 228 women with endometriosis undergoing ART procedures | 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 births. Possible unit of analysis error ‐ review being updated |
| SD265 Siristatidis 2015 Gonadotropin‐releasing hormone agonist protocols for pituitary suppression in assisted reproductive technology cycles |
23/4/2015 | 37 RCTs | 3872 women undergoing ART procedures | Long protocol (various regimens compared) Short protocol |
Short protocol Ultra‐short protocol Stop short protocol |
Live birth Clinical pregnancy Ongoing pregnancy Number of oocytes Dose of gonadotrophins Cycle cancellation |
Poor reporting of methods in primary studies and imprecise findings due to lack of data |
| 4. Ovarian stimulation | |||||||
| 4.1. Medication type | |||||||
| AM1335 Kamath 2017 Oral medications including clomiphene citrate or aromatase inhibitors with gonadotrophins for controlled ovarian stimulation in women undergoing in vitro fertilisation |
10/1/2017 | 27 RCTs | 3599 (22 trials) Subfertile women undergoing ART |
Regimens including oral induction medication (e.g. clomiphene citrate, aromatase inhibitors such as letrozole) | Gonadotrophin‐only regimens for controlled ovarian hyperstimulation |
Live birth Miscarriage Ectopic pregnancy Foetal abnormality Ongoing pregnancy Cancellation OHSS |
Live birth reported in only 5 trials. Most RCTs had suboptimal methods and poor reporting |
| AWP1710 Pouwer 2015 Long‐acting FSH versus daily FSH for women undergoing assisted reproduction |
8/6/15 | 6 RCTs | 3753 women with subfertility | Long‐acting FSH | Daily FSH | Live birth Ongoing pregnancy Clinical pregnancy OHSS Multiple pregnancy Miscarriage Adverse events Satisfaction |
Some RCTs limited by attrition bias and serious imprecision |
| MHM931 Mochtar 2017 Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles |
9/06/2016 | 36 RCTs | 8125 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 oestradiol used Number of oocytes retrieved |
Main limitations were risk of bias (associated with poor reporting of methods) and imprecision |
| IOK973 van Wely 2011 Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproduction 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 |
Most trials were open‐label |
| WPM1780 Martins 2013 FSH replaced by low‐dose hCG in the late follicular phase versus FSH alone 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 2 studies reported live births; both were at high risk of attrition bias. Imprecision was due to small overall sample size |
| DHH752 Farquhar 2017 Oral contraceptive pill, progestogen or oestrogen pre‐ treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques |
16/1/2017 | 29 RCTs | 4701 women with subfertility | COCP Progesterone oestrogen |
Placebo or no treatment COCP Progesterone Oestrogen |
Live birth Ongoing pregnancy Clinical/ongoing pregnancy Oocytes retrieved Gonadotrophin treatment Pregnancy loss Ovarian cyst formation Multiple pregnancies OHSS |
Main limitations were risk of bias and imprecision. Most studies did not describe their methods in adequate detail |
| BKT841 Kalampokas 2017 Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI |
10/10/2016 | 4 RCTs | 416 women with subfertility undergoing IVF or ICSI | Systemic glucocorticoids | Placebo or no treatment | Live birth Clinical pregnancy Miscarrige OHSS Steroidal side effects |
Risk of bias and imprecision, with small sample sizes and few events |
| SL1977 Lensen 2018 Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI) |
27/7/17 | 20 RCTs | 6088 women undergoing IVF/ICSI | Higher dose of FSH in women with predicted level of response ORT algorithm for FSH dose selection |
Lower dose of FSH in women with predicted level of response No ORT algorithm (use of standard dose) |
Live birth or ongoing pregnancy Severe OHSS Moderate or severe OHSS |
Clinical heterogeneity, imprecision, and risk of bias associated with lack of blinding |
| 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 births, study methods were inadequately described, and serious imprecision was noted |
| 4.3. Interventions for poor responders | |||||||
| RSS791 Pandian 2010 Interventions for 'poor responders' to controlled ovarian hyperstimulation (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 GnRHa 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 per woman Clinical pregnancy per woman Ongoing pregnancy per woman Miscarriage Ectopic pregnancy Cancellation Oocytes retrieved Dose of gonadotrophins Total FSH used |
Live birth was reported in only 1 trial. Methodological limitations included limited blinding and poor reporting as to how missing data were addressed |
| 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 Multiple pregnancy Lack of embryos for cryopreservation Cycle cancellation Gestational abnormalities Cancellation of treatment Cost‐effectiveness |
Few studies, live birth reported in only 1 very small trial. Clinical heterogeneity, as study inclusion criteria differed |
| 5. Ovulation triggering | |||||||
| MM1690 Youssef 2014 Gonadotropin‐releasing hormone agonist versus hCG for oocyte triggering in antagonist assisted reproductive technology cycles |
8/9/2014 | 17 RCTs | 1847 women undergoing ART | GnRHa | hCG | Live birth Ongoing pregnancy Clinical pregnancy Multiple pregnancy Miscarriage OHSS |
Poor reporting of study methods, serious imprecision |
| HA413 Youssef 2016a Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF/ICSI cycles |
23/4/2015 | 18 RCTs | 2952 women undergoing ART | Recombinant hCG Recombinant hLH |
Urinary hCG | Live birth OHSS Clinical pregnancy Miscarriage Oocytes retrieved Tolerance |
Only 6 of 14 trials reported live birth. Four trials lacked adequate description of allocation concealment, randomisation, and blinding |
| 6. Oocyte retrieval | |||||||
| IG1250 Reavey 2016 Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation |
29/8/2016 | 4 RCTs | 522 women undergoing in vitro maturation for subfertility | Human chorionic gonadotrophin (hCG) priming before immature oocyte retrieval | Placebo or no intervention | Live birth Miscarriage Clinical pregnancy Drug reaction Adverse events Mature oocytes retrieved/fertilised Embryos cleaved/implanted |
Lack of blinding, serious imprecision |
| IOK971 Kwan 2018 Pain relief for women undergoing oocyte retrieval for assisted reproduction |
9/11/2017 | 24 RCTs | 3160 women undergoing transvaginal oocyte retrieval during IVF treatment | Conscious sedation and analgesia (CSA) CSA + paracervical block (PCB) Patient‐controlled CSA |
Placebo CSA + acupuncture CSA + electroacupuncture General anaesthesia Spinal anaesthesia Electroacupuncture + PCB PCB alone Physician‐controlled CSA Differing doses of CSA |
Pain Patient satisfaction Live birth Ongoing pregnancy Clinical pregnancy |
Evidence was generally of low quality, mainly because of poor reporting of methods, small sample sizes, and inconsistency between trials. Only 1 study reported live birth |
| SW811 Georgiou 2018 Follicular flushing during oocyte retrieval in assisted reproductive techniques |
18/7/2017 | 10 RCTs | 928 women undergoing ART | Follicular flushing | Aspiration alone | Live birth Clinical pregnancy Ongoing pregnancy Oocyte retrieval Adverse events Duration of procedure Pain |
Quality of evidence ranged from moderate to very low. Limitations were associated with risk of bias, imprecision, and inconsistency |
| 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 azo‐ospermia | Epididymal or testicular techniques for sperm retrieval |
Epidydymal or testicular techniques for sperm retrieval |
Pregnancy Sperm parameters Fertilisation |
No live birth reported. Based on single RCT with poor methods |
| SMD1810 McDowell 2014 Advanced sperm selection techniques for assisted reproduction |
26/5/2014 | 2 RCTS | 581 couples undergoing ART | Sperm selection by hyaluronic acid binding for ICSI | Conventional ICSI Comparison of different hyaluronic acid binding techniques |
Live birth Pregnancy Miscarriage |
Only 1 study reported live birth. Poor reporting of study methods in 1 study, data discrepancy and serious imprecision in 1 study |
| 8. Laboratory phase | |||||||
| DG1352 Glujovsky 2014 Vitrification versus slow freezing for women undergoing oocyte cryopreservation |
3/3/14 | 2 RCTs | 106 women undergoing ART and wishing to preserve oocytes | Vitrification | Slow freezing | Clinical pregnancy Ongoing pregnancy |
Failure to report live birth, serious 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 blastocyst development |
Few studies described adequate allocation concealment, and 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 Embryo development Cryopreservation |
Only 3 trials reported on live birth outcomes, and methodological details were unclear in 6 trials |
| SMA991 Twisk 2006 Preimplantation genetic screening for abnormal number 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 pre‐implantation genetic screening | IVF/ICSI with no pre‐implantation genetic screening |
Live birth Clinical pregnancy Multiple pregnancy Miscarriage Ongoing pregnancy Congenital abnormalities |
Six of the 9 trials were open‐label and provided other methodological details that 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 |
Only 3 of 8 trials gave information on how randomisation was achieved, and all described 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 | 9 RCTs | 2014 couples undergoing ART | IMSI | ICSI | Live birth Clinical pregnancy Miscarriage Congenital abnormalities |
Only 1 trial reported live birth. Issues such as risk of bias (differences between numbers of oocytes transferred), imprecision, and strong suspicion of publication bias |
| SCA1950 Armstrong 2015 Time‐lapse systems for embryo incubation and assessment in assisted reproduction |
17/11/14 | 3 RCTs | 994 women undergoing ART | TIme‐lapse systems | Conventional embryo incubation | Live birth Miscarriage Clinical pregnancy Cumulative clinical pregnancy |
Evidence limited by methodological weaknesses, imprecision, and indirectness |
| MM1610 Youssef 2015 Culture media for human pre‐implantation embryos in assisted reproductive technology cycles |
27/3/2015 | 32 RCTs | Over 3666 women undergoing ART | Specific culture medium | Alternative culture medium | Live birth Health of babies born Clinical pregnancy Multiple pregnancy Miscarriage Implantation Cryopreservation Embryo quality Fertilisation |
Imprecision and risk of bias, with poor reporting of study methods |
| CS1968 Siristatidis 2018 Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies |
24/11/2016 | 4 RCTs | 802 women undergoing ART | Metabolomic assessment of endometrium, oocytes, or embryos | Other type of assessment (e.g. morphology grading) | Live birth or ongoing pregnancy Miscarriage Clinical pregnancy Other adverse events |
Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials |
| 9. Embryo transfer | |||||||
| 9.1. Developmental stage | |||||||
| DB551 Glujovsky 2016 Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology |
4/4/2016 | 27 RCTs | 4031 women undergoing ART | Cleavage‐stage transfer | Blastocyst‐stage transfer | Live birth Clinical pregnancy Multiple pregnancy Miscarriage Embryo freezing Failure to have a transfer Cumulative pregnancy |
Main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation and unclear or high risk of attrition bias |
| 9.2. Number of embryos | |||||||
| CO266 Brown 2016 Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection |
26/4/2016 Review is considered to be stable, with no update planned |
15 RCTs | 2894 (14 RCTs) couples undergoing ART | Day 3 embryo transfer | Day 2 embryo transfer | Live birth Ongoing pregnancy Clinical pregnancy Complications Multiple pregnancy Miscarriage Ectopic pregnancy Foetal abnormalities Women's evaluation |
Main limitations were poor methodological reporting, selective reporting, inconsistency, and imprecision |
| ZP661 Pandian 2013 Number of embryos for transfer following in‐vitro fertilisation or intracytoplasmic 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 Pregnancy Multiple pregnancy Miscarriage |
Many of the included studies were small, with half enroling fewer than 60 participants. Clinical heterogeneity between studies was considerable, but evidence of statistical heterogeneity was scant for most analyses. Methodological quality of the studies was mixed |
| 9.3. Transfer techniques and procedures | |||||||
| BA1920 Ata 2018 Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI, and frozen embryo transfer) |
10/10/2017 | 11 RCTs | 3215 women undergoing ART | Seminal plasma to genital tract during the period starting 5 days before embryo transfer and ending 2 days after it | No seminal plasma application | Live birth Miscarriage Live birth or ongoing pregnancy Clinical pregnancy Multiple pregnancy Ectopic pregnancy Infection Adverse events |
Quality of the evidence ranged from very low to low. Main limitations were risk of bias (associated with poor reporting of allocation concealment and other methods) and imprecision for the primary outcome of live birth rate |
| DB552 Bontekoe 2014 Adherence compounds in embryo transfer media for assisted reproductive technologies |
13/11/2013 | 17 RCTs | 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 Adverse events |
Some methodological limitations and serious imprecision were noted |
| SV602 Derks 2009 Techniques for preparation prior to embryo transfer |
18/03/2009 | 10 RCTs | 1693 women (9 RCTs) undergoing IVF |
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 1 trial reported live birth, and most included trials inadequately explained methodological procedures |
| EN1382 Kroon 2012 Antibiotics prior to embryo transfer in ART |
23/11/2011 | 1 RCT | 350 women undergoing ART | Antibiotics | No treatment | Bacterial contamination of catheter Clinical pregnancy |
Analysis of bacterial contamination was not performed for all participants |
| JB604 Brown 2016a Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women |
6/5/2015 | 21 RCTs | 6711 women with any form of infertility undergoing ART | Ultrasound‐guided transfer |
Clinical touch transfer | Live birth Ongoing pregnancy Clinical pregnancy Multiple pregnancy Miscarriage Ectopic pregnancy Foetal abnormalities Complications Ease of transfer |
High heterogeneity and poor reporting of methodological detail |
| AAS605 Abou‐Setta 2014 Post‐embryo transfer interventions for assisted reproduction technology cycles |
19/6/14 | 4 RCTs | 1392 women with subfertility of any cause |
Bed rest Bladder emptying Mechanical pressure on cervix Fibrin sealant |
Different duration of bed rest No intervention |
Live birth Ongoing pregnancy Clinical pregnancy Multiple pregnancy Miscarriage Ectopic pregnancy Adverse events – pain Subjective experience |
Live birth not reported, lack of blinding |
| LC1966 Craciunas 2016 Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction |
10/11/2015 | 12 RCTs | 4038 subfertile women | Intra‐cavity hCG before embryo transfer | Placebo or no intervention Alternative intervention |
Live birth Miscarriage Clinical pregnancy Complications |
High risk of bias, serious imprecision |
| 10. Luteal phase support | |||||||
| MV263 van der Linden 2015 Luteal phase support for ART cycles |
25/11/2014 | 94 RCTs | 26,198 women with any cause of subfertility undergoing ART | Progesterone hCG |
Placebo or no treatment hCG Progesterone + oestrogen Progesterone + GnRH agonist |
Live birth Clinical pregnancy Ongoing pregnancy Miscarriage OHSS Multiple pregnancy |
Poor reporting of study methods and imprecision due to small sample sizes |
| CMB1261 Boomsma 2012 Peri‐implantation glucocorticoid administration for assisted reproductive technology cycles |
20/09/2011 | 14 RCTs | 1879 couples with subfertility of any cause undergoing ART | Glucocorticoids | No glucocorticoids Placebo |
Live birth Ongoing pregnancy Pregnancy Multiple pregnancy Miscarriage Ectopic pregnancy OHSS Implantation |
Only 3 trials reported live birth, lack of blinding, and poor reporting |
| MA1441 Akhtar 2013 Heparin for assisted reproduction |
6/5/2013 | 3 RCTs | 386 subfertile women undergoing ART | Heparin | Placebo No treatment |
Live birth Adverse effects Clinical pregnancy Multiple pregnancy Maternal complications Foetal complications |
Only 3 small RCTs, 1 of which did not adequately describe allocation concealment. High heterogeneity reflecting differing participant inclusion criteria |
| 11. Prevention of ovarian hyperstimulation syndrome (OHSS) | |||||||
| TH1338 Tang 2016 Dopamine agonists for preventing ovarian hyperstimulation syndrome |
15/8/2016 | 16 RCTs | 2091 women at high risk of OHSS undergoing ART |
Cabergoline Quinagolide Bromocriptine |
Placebo/no treatment Other treatment |
OHSS Live birth Miscarriage Clinical pregnancy Multiple miscarriage Adverse events |
Poor reporting of study methods (mostly lack of details on randomisation or blinding) and serious imprecision for some comparisons |
| ADA56 D'Angelo 2017 Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome |
6/07/2016 Review is considered to be stable, with no update planned |
8 RCTs | 702 women at high risk of OHSS |
Coasting when oestradiol levels were > 2500 pg/mL or > 9000 pmol/L |
No coasting Early unilateral follicular aspiration Gonadotrophin‐releasing hormone antagonist Follicle‐stimulating hormone co‐trigger Cabergoline |
OHSS Live birth Clinical pregnancy Multiple pregnancy Miscarriage Number of oocytes retrieved |
Main limitations were failure to report live birth, risk of bias due to lack of information about study methods, and imprecision due to low event rates and lack of data. Four of the studies were published only as abstracts and provided limited data |
| 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 GnRHa, undergoing superovulation in IVF and or ICSI cycles |
Cryopreservation | Fresh embryo transfer Intravenous albumin |
OHSS Clinical pregnancy Live birth Admissions |
Evidence based on 2 trials, 1 for each comparison Live birth reported in only 1 trial Seriouis risk of bias in both trials |
| PMA481 Youssef 2016 Volume expanders for the prevention of ovarian hyperstimulation syndrome |
2/11/15 | 9 RCTs | 1867 women with controlled ovarian hyperstimulation and at risk of severe OHSS |
Human albumin Hydroxyethyl starch Mannitol |
Placebo | OHSS Clinical pregnancy |
Imprecision, poor reporting of study methods, and failure to blind outcome assessment |
| 12. Frozen embryo replacement cycles | |||||||
| KMW1790 Wong 2017 Fresh versus frozen embryo transfers in assisted reproduction |
14/11/2016 | 4 RCTs | 1892 women undergoing IVF or ICSI | Freeze‐all strategy | Conventional IVF/ICSI strategy with transfer of fresh and subsequently frozen‐thawed embryos | Cumulative live birth OHSS Clinical pregnancy Time to pregnancy Multiple pregnancy Miscarriage Pregnancy complications Birth weight Congenital disorders |
Serious risk of bias: unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules Serious imprecision for some outcomes |
| TG691 Ghobara 2017 Cycle regimens for frozen‐ thawed embryo transfer (FET) |
13/12/2016 | 18 RCTs | 3815 women with a range of causes of subfertility | Natural cycle FET Modified natural cycle FET HT FET Subtypes of ovulation induction FET using clomiphene, hMG, and/or FSH |
Other regimens | Live birth per woman Clinical pregnancy per woman Ongoing pregnancy per woman Multiple pregnancy Cycle cancellation Miscarriage Endometrial thickness |
Failure to report important clinical outcomes, poor reporting of study methods, imprecision due to low event rates. No data were specific to non‐ovulatory women |
| 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 No detail on causes of infertility was provided |
Corticosteroids Low‐dose aspirin GnRHa Intramuscular progesterone Day of start of progesterone Artificial cycle hCG before retrieval |
No treatment GnRHa Vaginal progesterone Day of start of progesterone Non‐artificial cycle Placebo |
Live birth Clinical pregnancy Multiple pregnancy Cancelled cycle rates Endometrial thickness Pregnancy loss |
Only 8 trials reported adequate details of allocation concealment. Only 1 trial reported on blinding |
ART: assisted reproduction technology.
COCP: combined oral contraceptive pill.
COH: controlled ovarian hyperstimulation.
CSA: conscious sedation and analgesia.
E2: oestrogen.
FET: frozen‐thawed embryo transfer.
FSH: follicle‐stimulating hormone.
GnRH: gonadotrophin‐releasing hormone.
GnRHa: gonadotrophin‐releasing hormone agonist.
hCG: human chorionic gonadotrophin.
hLH: human luteinising hormone.
hMG: human menopausal gonadotrophin.
HT: hormone therapy.
ICSI: intracytoplasmic sperm injection.
IMSI: ultra‐high magnification sperm selection.
IVF: in vitro fertilisation.
IU: international units.
N/A: not applicable.
OHHS: ovarian hyperstimulation syndrome.
ORT: ovarian reserve test.
PCB: paracervical block.
PGS: pre‐implantation genetic screening.
RCT: randomised controlled trial.
rFSH: recombinant follicle‐stimulating hormone.
rLH: recombinant luteinising hormone.
Currently, we have identified an additional 10 protocols and four active titles in progress that will be added to the overview when they are published as full reviews and the overview is next updated. For details, see Appendix 1.
We have withdrawn one protocol identified in the previous version of this overview, as the topic is now covered by other reviews (ElDaly 2006).
Methodological quality of included reviews
Quality of systematic reviews
We rated the quality of the included reviews by using the AMSTAR tool (Shea 2007).
All reviews had pre‐specified their clinical question and inclusion criteria.
All reviews conducted study selection and data extraction in duplicate.
All reviews conducted a comprehensive literature search.
All reviews included searches of grey literature.
All reviews listed included and excluded studies.
All reviews described the characteristics of included studies.
All reviews assessed study quality.
All reviews combined studies using appropriate methods.
A total of 65 of the 67 reviews addressed the risk of reporting bias, using a statistical test when appropriate.
All reviews addressed the potential for conflict of interest.
Only 30 of the 68 reviews (44%) had conducted a literature search within the past three years (to May 2018) or had been deemed stable (i.e. search not to be updated unless we become aware of new evidence).
See Table 2 and Table 3 for details.
2. AMSTAR assessment.
| Review no. | First review author | Review title | AMSTAR criteria | |||||||||
| Pre‐specified question and inclusion criteria | Duplicate study selection and data extraction | Comprehensive lit search | Grey lit included | Lists of included and excluded studies | Characteristics of included studies described | Study quality assessed | Studies combined by 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 2017 | Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| AM1335 | Kamath 2017 | Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| 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 2015 | Long‐acting FSH versus daily FSH for women undergoing assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| BA1920 | Ata 2018 | Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI, and frozen embryo transfer) | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| BKT841 | Kalampokas 2017 | Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| CMB1261 | Boomsma 2012 | Peri‐implantation glucocorticoid administration for assisted reproductive technology cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| CO266 | Brown 2016 | Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| CS1400 | Siristatidis 2009 | In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | N/A | N/A | N/A | N/A | ✔ |
| CS1968 | Siristatidis 2018 | Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| DB551 | Glujovsky 2016 | 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 | Farquhar 2017 | 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 2016 | Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| HA413 | Youssef 2016a | Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF/ICSI cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| HEN1730 | Nagels 2015 | Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| HNS881 | Sallam 2006 | Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | x | ✔ |
| IG1250 | Reavey 2016 | Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| IOK971 | Kwan 2018 | Pain relief for women undergoing oocyte retrieval for assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| 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 | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| IRS911 | Cheong 2013 | Acupuncture and assisted reproductive technology | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| JB604 | Brown 2016a | Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| KA992 | Anderson 2010 | Pre‐conception lifestyle advice for people with subfertility | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| KH291 | Duffy 2010 | Growth hormone for in vitro fertilization | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | x | ✔ |
| KMW1790 | Wong 2017 | Fresh versus frozen embryo transfers in assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| LA541 | Albuquerque 2013 | Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| LC1966 | Craciunas 2016 | Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| LDT1201 | Tso 2014 | Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MA1441 | Akhtar 2013 | Heparin for assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MM1610 | Youssef 2015 | Culture media for human pre‐implantation embryos in assisted reproductive technology cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MGS1510 | Showell 2014 | Antioxidants for male subfertility | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MGS1630 | Showell 2017 | Antioxidants for female subfertility | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MHM931 | Mochtar 2017 | Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MM1690 | Youssef 2014 | Gonadotropin‐releasing hormone agonist versus hCG for oocyte triggering in antagonist assisted reproductive technology cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| MV263 | van der Linden 2015 | 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 | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| PMA481 | Youssef 2016 | Volume expanders for the prevention of ovarian hyperstimulation syndrome | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| RBG1760 | Gutarra‐Vilchez 2014 | Vasodilators for women undergoing fertility treatment | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| RSS791 | Pandian 2010 | Interventions for 'poor responders' to controlled ovarian hyperstimulation (COH) in in‐vitro fertilisation (IVF) | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| SB1283 | Bontekoe 2012 | Low oxygen concentrations for embryo culture in assisted reproductive technologies | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| SCA1950 | Armstrong 2015 | Time‐lapse systems for embryo incubation and assessment in assisted reproduction | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | x | ✔ |
| SD265 | Siristatidis 2015 | 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 | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| SL1977 | Lensen 2018 | Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI) | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | |
| 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 | Georgiou 2018 | Follicular flushing during oocyte retrieval in assisted reproductive techniques | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| TA1860 | Allersma 2013 | Natural cycle IVF for subfertile couples | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| TG691 | Ghobara 2017 | Cycle regimens for frozen‐thawed embryo transfer | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| TH1338 | Tang 2016 | Dopamine agonists for preventing ovarian hyperstimulation syndrome | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| VJP951 | Siristatidis 2016 | Aspirin for in vitro fertilisation | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| WM1504 | Nastri 2015 | 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 2015 | In vitro fertilisation for unexplained subfertility | ✔ | x | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
ART: assisted reproduction techniques.
COH: controlled ovarian hyperstimulation.
FSH: follicle‐stimulating hormone.
hCG: human chorionic gonadotrophin.
ICSI: intracytoplasmic sperm injection.
IVF: in vitro fertilisation.
IMSI: ultra‐high magnification sperm selection.
N/A: not applicable.
rFSH: recombinant follicle‐stimulating hormone.
rLH: recombinant luteinising hormone.
3. Latest search date assessment.
| Review no. | First review author | Review title | < 3 years since last search (to May 2018) or deemed stable |
| AAS605 | Abou‐Setta 2014 | Post‐embryo transfer interventions for assisted reproduction technology cycles | x |
| ADA561 | D'Angelo 2007 | Embryo freezing for preventing ovarian hyperstimulation syndrome | Stable |
| ADA563 | D'Angelo 2017 | Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome | Stable |
| AM1335 | Kamath 2017 | 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 | Stable |
| AMY731 | Yossry 2006 | In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation | Stable |
| AWP1710 | Pouwer 2015 | Long‐acting FSH versus daily FSH for women undergoing assisted reproduction | ✔ |
| BA1920 | Ata 2018 | Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI, and frozen embryo transfer) | ✔ |
| BKT841 | Kalampokas 2017 | Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI | ✔ |
| CMB1261 | Boomsma 2012 | Peri‐implantation glucocorticoid administration for assisted reproductive technology cycles | x |
| CO266 | Brown 2016 | Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection | Stable |
| CS1400 | Siristatidis 2009 | In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction | Stable |
| CS1968 | Siristatidis 2018 | Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies | ✔ |
| DB551 | Glujovsky 2016 | Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology | ✔ |
| DB552 | Bontekoe 2014 | Adherence compounds in embryo transfer media for assisted reproductive technologies | x |
| 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 | x |
| DHH752 | Farquhar 2017 | Oral contraceptive pill, progestogen or oestrogen pre‐treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques | ✔ |
| EN1382 | Kroon 2012 | Antibiotics prior to embryo transfer in ART | x |
| HA412 | Al‐Inany 2016 | Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology | x |
| HA413 | Youssef 2016a | Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF/ICSI cycles | x |
| HEN1730 | Nagels 2015 | Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction | x |
| HNS881 | Sallam 2006 | Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis | x |
| IG1250 | Reavey 2016 | Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation | ✔ |
| IOK971 | Kwan 2018 | 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 | x |
| IRS911 | Cheong 2013 | Acupuncture and assisted reproductive technology | x |
| JB604 | Brown 2016a | Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women | ✔ |
| KA992 | Anderson 2010 | Pre‐conception lifestyle advice for people with subfertility | x |
| KH291 | Duffy 2010 | Growth hormone for in vitro fertilization | x |
| KMW1790 | Wong 2017 | Fresh versus frozen embryo transfers in assisted reproduction | ✔ |
| LA541 | Albuquerque 2013 | Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles | x |
| LC1966 | Craciunas 2016 | Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction | ✔ |
| LDT1201 | Tso 2014 | Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. | x |
| MA1441 | Akhtar 2013 | Heparin for assisted reproduction | x |
| MGS1510 | Showell 2014 | Antioxidants for male subfertility | x |
| MGS1630 | Showell 2017 | Antioxidants for female subfertility | ✔ |
| MHM931 | Mochtar 2017 | Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles | ✔ |
| MM1610 | Youssef 2015 | Culture media for human pre‐implantation embryos in assisted reproductive technology cycles | x |
| MM1690 | Youssef 2014 | Gonadotropin‐releasing hormone agonist versus hCG for oocyte triggering in antagonist assisted reproductive technology cycles | x |
| MV263 | van der Linden 2015 | 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 | Stable |
| MWS391 | Carney 2012 | Assisted hatching on assisted conception (IVF and ICSI) | x |
| NJ472 | Johnson 2010 | Surgical treatment for tubal disease in women due to undergo in vitro fertilisation | x |
| PMA481 | Youssef 2016 | Volume expanders for the prevention of ovarian hyperstimulation syndrome | Stable |
| RBG1760 | Gutarra‐Vilchez 2014 | Vasodilators for women undergoing fertility treatment | x |
| RSS791 | Pandian 2010 | Interventions for 'poor responders' to controlled ovarian hyperstimulation (COH) in in‐vitro fertilisation (IVF) | x |
| SB1283 | Bontekoe 2012 | Low oxygen concentrations for embryo culture in assisted reproductive technologies | x |
| SCA1950 | Armstrong 2015 | Time‐lapse systems for embryo incubation and assessment in assisted reproduction | x |
| SD265 | Siristatidis 2015 | Gonadotrophin‐releasing hormone agonist protocols for pituitary suppression in assisted reproduction | 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 | x |
| SL1977 | Lensen 2018 | Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI) | ✔ |
| 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 | x |
| SV602 | Derks 2009 | Techniques for preparation prior to embryo transfer | x |
| SW811 | Georgiou 2018 | Follicular flushing during oocyte retrieval in assisted reproductive techniques | ✔ |
| TA1860 | Allersma 2013 | Natural cycle IVF for subfertile couples | x |
| TG691 | Ghobara 2017 | Cycle regimens for frozen‐thawed embryo transfer | ✔ |
| TH1338 | Tang 2016 | Dopamine agonists for preventing ovarian hyperstimulation syndrome | ✔ |
| VJP951 | Siristatidis 2016 | Aspirin for in vitro fertilisation | Stable |
| WM1504 | Nastri 2015 | 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 | x |
| WPM1800 | Teixeira 2013 | Regular (ICSI) versus ultra‐high magnification (IMSI) sperm selection for assisted reproduction | x |
| ZH1093 | Huang 2013 | Brief co‐incubation of sperm and oocytes for in vitro fertilization techniques | x |
| ZP661 | Pandian 2013 | Number of embryos for transfer following in‐vitro fertilisation or intracytoplasmic sperm injection | x |
| ZP672 | Pandian 2015 | In vitro fertilization for unexplained subfertility | ✔ |
ART: assisted reproduction techniques.
COH: controlled ovarian hyperstimulation.
FSH: follicle‐stimulating hormone.
hCG: human chorionic gonadotrophin.
ICSI: intracytoplasmic sperm injection.
IVF: in vitro fertilisation.
IMSI: ultra‐high magnification sperm selection.
N/A: not applicable.
rFSH: recombinant follicle‐stimulating hormone.
rLH: recombinant luteinising hormone.
Quality of evidence from primary studies in included reviews
We rated the quality of evidence reported by primary studies in the included reviews by using GRADE methods. The quality of the evidence varied widely (by review and also by outcome) and ranged from very low to high. See Table 1Table 4Table 5Table 6Table 7 and Table 8 for details.
4. Live birth or live birth/ongoing pregnancy per woman.
| Outcome Intervention and comparison intervention |
Assumed risk with comparator | Corresponding risk with intervention | Relative effect (95% CI) |
No. of participants (studies) |
Quality of the evidence (GRADE) |
Comments | |
| 1. Indication for ART | |||||||
|
Pandian 2015 IVF vs expectant management for unexplained subfertility Live birth |
37 per 1000 | 458 per 1000 (90 to 879) |
OR 22 (2.56 to 189.37) | 51 (1 RCT) | Very low | Very serious imprecision, questionable applicability, and (for the analysis of clinical pregnancy) serious inconsistency | |
|
Pandian 2015 IVF vs unstimulated intra‐uterine insemination for unexplained subfertility Live birth |
160 per 1000 | 320 per 1000 (185 to 494) | OR 2.47 (1.19 to 5.12) | 156 (2 RCTs) | Low | Very serious imprecision | |
|
Pandian 2015 IVF vs intra‐uterine insemination + ovarian stimulation with gonadotrophins for unexplained subfertility (treatment naïve women ) Live birth |
273 per 1000 | 308 per 1000 (264 to 360) | OR 1.27 (0.94 to 1.73) |
745 (4 RCTs) | Moderate | Serious imprecision with wide confidence interval | |
|
Pandian 2015 IVF vs intra‐uterine insemination + ovarian stimulation with gonadotrophins for unexplained subfertility (pre‐treated women) Live birth |
219 per 1000 | 523 per 1000 (374 to 731) | OR 3.90 (2.32 to 6.57) |
280 (1 RCT) |
Moderate | Serious imprecision (only 9 events) | |
| 2. Pre‐ART and adjuvant strategies | |||||||
| 2.1. For unselected populations | |||||||
|
Nastri 2015 *See comment Endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle vs no injury Live birth or ongoing pregnancy |
260 per 1000 | 342 per 1000 (281 to 481) | RR 1.42 (1.08 to 1.85 |
1496 (9 RCTs) |
Moderate | Serious imprecision | |
|
Nastri 2015 *See comment Endometrial injury on the day of oocyte retrieval vs no injury Live birth or ongoing pregnancy |
290 per 1000 | 90 per 1000 | RR 0.31 (0.14 to 0.69) |
156 (1 RCT) |
Low | Very serious imprecision | |
|
Showell 2014 Antioxidant vs placebo or no treatment for men Live birth |
100 per 1000 | 286 per 1000 (124 to 533) |
Peto OR 3.61 (1.27 to 10.29) |
90 (2 RCTs) |
Low | Very serious imprecision, with only 90 participants and 25 events | |
|
Showell 2017 Antioxidant vs placebo or no treatment for women Live birth |
305 per 1000 | 347 per 1000 (232to 481) |
OR 1.21 (0.69 to 2.11) |
230 (4 RCTs) |
Very low | Very serious risk of bias and very serious imprecision | |
|
Cheong 2013 Acupuncture vs no acupuncture on the day of embryo transfer Live birth |
281 per 1000 | 323 per 1000 (254 to 399) |
OR 1.22 (0.87 to 1.7) |
2505 (8 RCTs) |
Low | Imprecision, inadequate explanation of methods, high statistical heterogeneity (I2 = 69%) | |
|
Cheong 2013 Acupuncture vs no acupuncture around the time of oocyte retrieval Live birth |
357 per 1000 | 326 per 1000 (247 to 418) |
OR 0.87 (0.59 to 1.29) |
464 (2 RCTs) |
Low | Imprecision, inadequate explanation of methods, high statistical heterogeneity (I2 = 69%) | |
|
Duffy 2010 Growth hormone vs placebo Live birth |
146 per 1000 | 184 per 1000 (64 to 431) |
OR 1.32 (0.4 to 4.43) | 80 (2 RCTs) |
Moderate | Serious imprecision | |
|
Duffy 2010 Growth hormone vs placebo – poor responders Live birth |
50 per 1000 | 221 per 1000 (90 to 447) |
OR 5.39 (1.89 to 15.35) |
165 (4 RCTs) |
Moderate | Some studies did not provide an adequate explanation of randomisation and/or allocation concealment | |
|
Gutarra‐Vilchez 2014 Vasodilator compared with placebo Live birth |
236 per 1000 | 278 per 1000 (193 to 398) |
RR 1.18 (0.82 to 1.69) |
350 (3 RCTs) |
Moderate | Studies had low or unclear risk of bias but serious imprecision | |
|
Siristatidis 2016 Aspirin vs placebo or no treatment Live birth |
225 per 1000 | 204 per 1000 (162 to 258) | RR 0.91 (0.72 to 1.15) |
1053 (3 RCTs) |
Moderate | Serious imprecision with low event rates | |
|
Nagels 2015 DHEA vs placebo or no treatment Live birth or ongoing pregnancy |
116 per 1000 | 192 per 1000 (141 to 256) | OR 1.81 (1.25 to 2.62) | 878 (8 RCTs) | Moderate | Serious imprecision with low event rates | |
|
Nagels 2015 Testosterone vs placebo or no treatment Live birth or ongoing pregnancy |
82 per 1000 | 188 per 1000 (104 to 317) | OR 2.6 (1.3 to 5.2) | 345 (4 RCTs) | Moderate | Serious imprecision with low event rates | |
| 2.2. For selected populations | |||||||
|
Tso 2014 Metformin vs placebo or no treatment Live birth |
320 per 1000 | 395 per 1000 (276 to 530) |
OR 1.39 (0.81 to 2.40) |
551 (5 RCTs) |
Low | Serious inconsistency with unexplained heterogeneity (I2 = 52%). Serious imprecision, as total events are fewer than 300. Data discrepancy in 1 study: sensitivity analysis excluding this RCT 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 vs daily injection Live birth or ongoing pregnancy |
24 per 100 | 23 per 100 (181 to 292) |
OR 0.95 (0.7 to 1.31) |
873 (7 RCTs) | Low | Most studies were classified as at unclear risk of bias for all domains. Serious imprecision, as total events were fewer than 300 | |
|
Al‐Inany 2016 GnRH antagonist vs long course GnRH agonist Live birth |
286 per 1000 | 290 per 1000 (254 to 330) | OR 1.02 (0.85 to 1.23) | 2303 (12 RCTs) | Moderate | Asymmetrical funnel plot with small study effects in favour of GnRH antagonist | |
|
Siristatidis 2015 Long vs short protocol for pituitary suppression Live birth or ongoing pregnancy |
138 per 1000 | 172 per 1000 (131 to 225) | OR 1.3 (0.94 to 1.81) | 976 (12 RCTs) | Low | Poor reporting of methods and serious imprecision, with wide confidence intervals | |
|
Siristatidis 2015 Long vs ultra‐short protocol for pituitary suppression Live birth or ongoing pregnancy |
122 per 1000 | 198 per 1000 (91 to 376) | OR 1.78 (0.72 to 4.36) | 150 (1 RCT) | Low | Poor reporting of methods and serious imprecision, with wide confidence intervals | |
|
Siristatidis 2015 Long luteal phase protocol vs long follicular phase protocol for pituitary suppression Live birth or ongoing pregnancy |
102 per 1000 | 177 per 1000 (90 to 319) | OR 1.89 (0.87 to 4.1) | 223 (1 study) | Low | Poor reporting of methods and serious imprecision, with wide confidence intervals | |
|
Siristatidis 2015 Long protocol continued GnRH agonist vs long protocol stop GnRH agonist for pituitary suppression Live birth or ongoing pregnancy |
76 per 1000 | 222 per 1000 (138 to 336) | OR 0.75 (0.42 to 1.33) | 290 (3 studies) | Low | Poor reporting of methods and serious imprecision, with wide confidence intervals | |
|
Siristatidis 2015 Long protocol (GnRHa until hCG) compared with long protocol (extend GnRHa 12 days after hCG) for pituitary suppression Live birth or ongoing pregnancy |
378 per 1000 | 351 per 1000 (229 to 499) | OR 0.89 (0.49 to 1.64) | 181 (1 study) | Low | Very serious imprecision: small number of events and wide confidence intervals | |
| 4. Ovarian stimulation | |||||||
| 4.1. Medication type | |||||||
|
Kamath 2017 Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population Live birth |
235 per 1000 | 216 per 1000 (155 to 299) |
RR 0.92 (0.66 to 1.27) | 493 (4 RCTs) |
Low | Serious imprecision with wide confidence intervals. Method of allocation concealment inadequately reported in some trials | |
|
Kamath 2017 Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in poor responders Live birth |
49 per 1000 | 57 per 1000 (24 to 137) | RR 1.16 (0.49 to 2.79) | 357 (2 RCTs) | Low | Serious imprecision with wide confidence intervals. Method of allocation concealment inadequately reported in some trials | |
|
Pouwer 2015 Long acting FSH (any dose) vs daily FSH Live birth |
347 per 1000 | 330 per 1000 (273 to 348) |
RR 0.95 (0.84 to 1.07) |
2363 (5 RCTs) |
Moderate | Two studies at high risk of attrition bias | |
|
Pouwer 2015 Long‐acting FSH (low dose) vs daily FSH Live birth |
352 per 1000 | 246 per 1000 (183 to 327) |
RR 0.70 (0.52 to 0.93) |
645 (4 RCTs) |
Moderate | Serious imprecision, with low event rate | |
|
Pouwer 2015 Long‐acting FSH (medium dose) vs daily FSH Live birth |
255 per 1000 | 263 per 1000 (229 to 301) |
RR 1.03 (0.9 to 1.18) |
1685 (3 RCTs) |
Moderate | Two studies at high risk of attrition bias | |
|
Pouwer 2015 Long‐acting FSH (high dose) vs daily FSH Live birth |
375 per 1000 | 161 per 1000 (45 to 570) |
RR 0.43 (0.12 to 1.52) |
33 (1 RCT) |
Very low | Serious imprecision due to very low event rate, plus high risk of attrition bias | |
|
Mochtar 2017 Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) vs rFSH alone for controlled ovarian hyperstimulation Live birth |
173 per 1000 | 217 per 1000 (151 to 302) |
OR 1.32 (0.85 to 2.06) |
499 (4 RCTs) |
Very low | Imprecision, with wide confidence intervals. Serious risk of bias in certain domains such as random sequence generation and allocation concealment. Serious inconsistency (I2 > 50%) | |
|
van Wely 2011 rFSH vs urinary gonadotrophins Live birth or ongoing pregnancy |
237 per 1000 | 232 per 1000 (213 to 251) |
OR 0.97 (0.87 to 1.08) |
7339 (28 RCTs) |
High | Lack of blinding | |
|
Martins 2013 FSH replaced by low‐dose hCG in the late follicular phase vs continued FSH for assisted reproductive techniques Live birth |
140 per 1000 | 220 per 1000 (100 to 450) |
RR 1.56 (0.75 to 3.25) |
130 (2 RCTs) |
Very low | Very serious imprecision and high risk of bias | |
|
Farquhar 2017 Combined oral contraceptive plus antagonist vs antagonist Live birth or ongoing pregnancy |
270 per 1000 | 215 per 1000 (177 to 260) | OR 0.74 (0.58 to 0.95) | 1335 (6 RCTs) | Moderate | Poor reporting of sequence generation and allocation concealment | |
|
Farquhar 2017 Combined oral contraceptive plus antagonist vs agonist Live birth or ongoing pregnancy |
296 per 1000 | 273 per 1000 (212 to 345) | OR 0.89 (0.64 to 1.25) | 724 (4 RCTs) | Moderate | Serious imprecision with wide confidence intervals | |
|
Farquhar 2017 Progestogen plus agonist vs agonist Live birth or ongoing pregnancy |
170 per 1000 | 217 per 1000 (124 to 352) | OR 1.35 (0.69 to 2.65) | 222 (2 RCTs) | Low | Very serious imprecision with wide confidence intervals | |
|
Farquhar 2017 Progestogen plus antagonist vs antagonist Live birth or ongoing pregnancy |
292 per 1000 | 217 per 1000 (69 to 512) | OR 0.67 (0.18 to 2.54) | 47 (1 RCT) | Low | Very serious imprecision with wide confidence intervals | |
|
Farquhar 2017 Oestrogen plus antagonist vs antagonist Live birth or ongoing pregnancy |
299 per 1000 | 252 per 1000 (184 to 333) | OR 0.79 (0.53 to 1.17) | 502 (2 RCTs) | Moderate | Serious imprecision with wide confidence intervals | |
|
Farquhar 2017 Oestrogen plus antagonist vs agonist Live birth or ongoing pregnancy |
350 per 1000 | 322 per 1000 (215 to 447) | OR 0.88 (0.51 to 1.5) | 242 (2 RCTs) | Very low | Poor reporting of methods; very serious imprecision with wide confidence intervals | |
|
Kalampokas 2017 Glucocorticoid supplementation vs placebo Live birth |
147 per 1000 | 157 per 1000 (72 to 308) | OR 1.08 (0.45 to 2.58) | 212 (2 RCTs) | Low | Very serious imprecision with few events and wide confidence intervals | |
|
Lensen 2018 ORT‐based algorithm vs standard dose FSH Live birth or ongoing pregnancy |
258 per 1000 | 266 per 1000 (235 to 300) | OR 1.04 (0.88 to 1.23) | 2823 (4 RCTs) | Moderate | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting | |
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated low responders Live birth or ongoing pregnancy 1. 300/450 IU vs 150 IU 2. 400/450 IU vs 300 IU 3. 600 IU vs 450 IU |
1. 109 per 1000 | 80 per 1000 (38 to 162) | OR 0.71 (0.32 to 1.58) | 286 (2 RCTs) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events | |
| 2. 161 per 1000 | 129 per 1000 (35 to 380) | OR 0.77 (0.19 to 3.19) | 62 (1 RCT) | ||||
| 3. 108 per 1000 | 139 per 1000 (79 to 234) | OR 1.33 (0.71 to 2.52) | 356 (1 RCT) | ||||
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated normal responders Live birth or ongoing pregnancy 1. 200 IU vs 100 IU 2. 225/200 IU vs 150 IU 3. 300 IU vs 225 IU |
1. 204 per 1000 | 184 per 1000 (127 to 258) | OR 0.88 (0.57 to 1.36) | 522 (2 RCTs) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events | |
| 2. 193 per 1000 | 198 per 1000 (120 to 308) | OR 1.03 (0.57 to 1.86) | 277 (1 RCT) | ||||
| 3. 397 per 1000 | 300 per 1000 (174 to 465) | OR 0.65 (0.32 to 1.32) | 135 (1 RCT) | ||||
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated high responders Live birth or ongoing pregnancy 150 IU vs 100 IU |
255 per 1000 | 251 per 1000 (184 to 333) | OR 0.98 (0.66 to 1.46) | 521 (1 RCT) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events | |
| 4.3. Interventions for poor responders | |||||||
|
Pandian 2010 Low‐dose GnRHa flare‐up vs spontaneous natural cycle IVF Live birth |
85 per 1000 | 86 per 1000 (26 to 245) |
OR 1.01 (0.29 to 3.5) |
129 (1 RCT) | Low | Serious imprecision, evidence based on a single trial | |
| 4.4. Natural cycle IVF | |||||||
|
Allersma 2013 Natural cycle vs standard IVF Live birth |
125 per 1000 | 28 per 1000 (1 to 393) |
OR 0.20 (0.01 to 4.54) |
30 (1 RCT) | Very low | High risk of performance bias and very serious imprecision | |
| 5. Ovulation triggering | |||||||
|
Youssef 2014 GnRH agonist vs hCG Live birth |
313 per 1000 | 176 per 1000 (124 to 242) |
OR 0.47 (0.31 to 0.70) |
532 (5 RCTs) |
Moderate | One study at high risk of bias because of premature termination, substantial heterogeneity, with I2 = 56% | |
|
Youssef 2016a rhCG vs uhCG Live birth or ongoing pregnancy |
367 per 1000 | 396 per 1000 (344 to 454) | OR 1.15 (0.89 to 1.49) | 1136 (7 RCTs) | Moderate | Serious imprecision | |
|
Youssef 2016a rhLH vs uhCG Live birth or ongoing pregnancy |
371 per 1000 | 359 per 1000 (231 to 512) | OR 0.95 (0.51 to 1.78) | 289 (2 studies) | Very low | Poor reporting of study methods, very serious imprecision | |
| 6. Oocyte retrieval | |||||||
|
Reavey 2016 hCG priming vs no priming Live birth |
310 per 1000 | 226 per 1000 (97 to 439) | OR 0.65 (0.24 to 1.74) | 82 (1 RCT) | Low | Serious risk of bias, serious imprecision | |
|
Kwan 2018 Conscious sedation and analgesia plus paracervical block vs electroacupuncture plus paracervical block Live birth |
176 per 1000 | 334 per 1000 (184 to 601) |
OR 2.35 (1.09 to 5.05) | 149 (1 RCT) |
Low | Evidence based on a single trial, serious imprecision | |
|
Georgiou 2018 Follicular flushing vs aspiration alone Live birth |
414 per 1000 | 401 per 1000 (290 to 524) |
OR 0.95 (0.58 to 1.56) |
303 (3 RCTs) |
Moderate | Serious risk of bias: includes at least 1 open‐label study | |
| 7. Sperm retrieval | |||||||
|
McDowell 2014 HA culture dish (PICSI) compared with viscous medium containing HA (SpermSlow) for infertility requiring intracytoplasmic sperm injection Live birth |
300 per 1000 | 350 per 1000 (190 to 550) |
RR 1.16 (0.65 to 2.05) |
99 (1 RCT) |
Low | Serious risk of bias, as RCT methods not reported in adequate detail Serious imprecision, as confidence intervals compatible with substantial benefit or harm from the intervention, or with no effect | |
| 8. Laboratory phase | |||||||
|
Carney 2012 Assisted hatching vs no assisted hatching Live birth |
305 per 1000 | 311 per 1000 (271 to 356) |
OR 1.03 (0.85 to 1.26) |
1921 (9 RCTs) |
Moderate | Many trials had some methodological limitations or missing information | |
|
Bontekoe 2012 Embryo culture with low oxygen concentrations vs atmospheric oxygen concentration Live birth |
309 per 1000 | 383 per 1000 (332 to 440) |
OR 1.39 (1.11 to 1.76) |
1291 (3 RCTs) |
Moderate | One trial reported no allocation concealment, and another trial was unclear about the method of allocation concealment | |
|
Twisk 2006 Pre‐implantation genetic screening vs no screening in women with advanced age Live birth |
259 per 1000 | 171 per 1000 (133 to 221) | OR 0.59 (0.44 to 0.81) |
1062 (5 RCTs) |
Moderate | Only 1 study described an adequate method of allocation concealment | |
|
Twisk 2006 Pre‐implantation genetic screening vs no screening in women with repeated IVF failure Live birth |
Not calculated | OR 0.41 (0.20 to 0.88) |
139 (1 RCT) |
Very low | No allocation concealment, serious imprecision with few events | ||
|
Twisk 2006 Pre‐implantation genetic screening vs no screening in women with good prognosis Live birth |
416 per 1000 | 263 per 1000 (130 to 461) |
OR 0.5 (0.21 to 1.2) | 388 (3 RCTs) |
Very low | Methodological details unclear or inadequate; high heterogeneity, with I2 > 60% and serious imprecision | |
|
Teixeira 2013 Regular (ICSI) vs ultra‐high magnification (IMSI) sperm selection Live birth |
380 per 1000 | 440 per 1000 (300 to 630) |
RR 1.14 (0.79 to 1.64) |
168 (1 RCT) |
Low | Serious imprecision | |
|
Armstrong 2015 TLS with or without cell‐tracking algorithms vs conventional incubation for embryo incubation in assisted reproduction Live birth |
500 per 1000 | 526 per 1000 (310 to 732) |
OR 1.11 (0.45 to 2.73) |
76 (1 RCT) |
Moderate | Serious imprecision with small sample size and wide confidence intervals | |
|
Youssef 2015 Early embryo transfer ‐ GM501 vs ISMI Live birth |
264 per 1000 | 270 per 1000 (160 to 422) | OR 1.03 (0.53 to 2.03) | 172 (1 RCT) | Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Youssef 2015 Early embryo transfer ‐ GM501 vs Sydney IVF Live birth |
188 per 1000 | 167 per 1000 (81 to 311) | OR 0.87 (0.38 to 1.96) | 158 (1 RCT) | Low | Serious risk of bias with poor reporting of study methods, serious imprecision | |
|
Youssef 2015 Early embryo transfer ‐ G2 vs Universal IVF Live birth |
194 per 1000 | 269 per 1000 (139 to 457) | OR 1.53 (0.67 to 3.51) | 129 (1 RCT) | Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Youssef 2015 Early embryo transfer ‐ Cook (K‐SIFM or K‐SICM) vs Vitrolife (IVF or G3) Live birth |
220 per 1000 | 216 per 1000 (151 to 302) |
OR 0.98 (0.63 to 1.54) |
449 (1 RCT) |
Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Youssef 2015 Early embryo transfer ‐ G2 vs Ham's F10 Live birth |
579 per 1000 | 676 per 1000 (444 to 846) |
OR 1.52 (0.58 to 3.99) |
72 (1 RCT) |
Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Youssef 2015 Late embryo transfer ‐ GM501 vs Sydney IVF Live birth |
200 per 1000 | 143 per 1000 (7 to 778) | OR 0.67 (0.03 to 14.03) | 12 (1 RCT) | Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Youssef 2015 Late embryo transfer ‐ G2 vs Universal IVF Live birth |
148 per 1000 | 250 per 1000 (71 to 591) | OR 1.92 (0.44 to 8.31) | 47 (1 RCT) | Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Youssef 2015 Late embryo transfer ‐ ECM/Multiblast vs Global Live birth |
700 per 1000 | 538 per 1000 (318 to 746) |
OR 0.50 (0.20 to 1.26) |
79 (1 RCT) |
Very low | Serious risk of bias with poor reporting of study methods, very serious imprecision | |
|
Siristatidis 2018 Metabolomic vs non‐metabolomic assessment Live birth |
296 per 1,000 | 294 per 1,000 (225 to 377) | OR 0.99 (0.69 to 1.44) | 597 (3 RCTs) | Low | Serious risk of bias and serious imprecision | |
| 9. Embryo transfer | |||||||
| 9.1. Developmental stage | |||||||
|
Glujovsky 2016 Blastocyst stage vs cleavage stage embryo transfer in assisted reproductive technology Live birth |
286 per 1000 | 372 per 1000 (324 to 421) |
OR 1.48 (1.20 to 1.82) | 1630 (13 RCTs) |
Low | Several studies did not describe acceptable methods of sequence generation and/or allocation concealment, several were at unclear or high risk of attrition bias, and none clearly reported blinded outcome assessment. Sensitivity analysis restricted to 5 studies with clear description of allocation concealment results in a non‐significant effect (OR 1.38, 95% CI 0.96 to 1.99) | |
|
Brown 2016 Day 3 vs Day 2 embryo transfer Live birth |
315 per 1000 | 331 per 1000 (280 to 387) | RR 1.05 (0.89 to 1.23) |
1200 (3 RCTs) |
Very low | All studies lacked details about blinding of participants, researchers, and outcome assessors, serious inconsistency. Only 3 of the 15 included studies reported live birth | |
| 9.2. Number of embryos | |||||||
|
Pandian 2013 Single‐embryo transfer vs double (1 cycle only) Live birth |
450 per 1000 | 282 per 1000 (242 to 329)) |
OR 0.48 (0.39 to 0.60) | 1564 (9 RCTs) |
High | 36% of women were non‐compliant with treatment allocation in 1 RCT: however no heterogeneity was detected (I2 = 0%) | |
|
Pandian 2013 Repeated single‐embryo transfer vs double‐embryo transfer Live birth |
420 per 1000 | 373 per 1000 (310 to 441) |
OR 0.82 (0.62 to 1.09) |
811 (3 RCTs) |
Low | No studies described adequate allocation concealment, imprecision | |
|
Pandian 2013 Double‐embryo transfer vs 3 embryo transfers Live birth |
273 per 1000 | 130 per 1000 (33 to 410) |
OR 0.4 (0.09 to 1.85) |
45 (1 RCT) |
Very low | Methods of randomisation and blinding unclear, evidence based on a single trial with very serious imprecision | |
|
Pandian 2013 Double‐embryo transfer vs 4 embryo transfers Live birth |
536 per 1000 | 288 per 1000 (113 to 548) |
OR 0.35 (0.11 to 1.05) |
56 (1 RCT) |
Very low | Methods of randomisation and blinding unclear, evidence based on a single trial with very serious imprecision | |
| 9.3. Transfer techniques and procedures | |||||||
|
Ata 2018 Seminal plasma to genital tract vs no seminal plasma Live birth |
191 per 1000 | 210 per 1000 (164 to 273) | RR 1.10 (0.86 to 1.43) | 948 (3 RCTs) | Low | Serious risk of bias: method of allocation concealment unclear in all included trials, serious imprecision | |
|
Bontekoe 2014 Transfer medium enriched with high level of hyaluronic acid vs medium with low level or no hyaluronic acid Live birth |
374 per 1000 | 458 per 1000 (412 to 503) |
OR 1.41 (1.17 to 1.69) |
1950 (6 RCTs) |
Moderate | All studies except 1 at high risk of bias in 1 or more domains | |
|
Brown 2016a Ultrasound guidance vs clinical touch for embryo transfer Live birth |
210 per 1000 | 290 per 1000 (256 to 324) | OR 1.53 (1.29 to 1.80) | 3117 (4 RCTs) | Low | Poor reporting of study methods, high inconsistency | |
|
Derks 2009 Cervical dilatation vs no intervention Live birth |
190 per 1000 | 97 per 1000 (60 to 155) | OR 0.46 (0.27 to 0.78) |
288 (1 RCT) |
Moderate | Evidence based on a single trial | |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG; cleavage stage hCG < 500 IU Live birth |
495 per 1000 | 376 per 1000 (287 to 500) | RR 0.76 (0.58 to 1.01) | 280 (1 RCT) | Very low | Very serious risk of bias with poor reporting of methods and premature termination of study, imprecision | |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG; cleavage stage hCG ⋟ 500 IU Live birth |
247 per 1000 | 388 per 1000 (326 to 462) | RR 1.57 (1.32 to 1.87) | 914 (3 RCTs) | Moderate | Serious risk of bias: poor reporting of methods, lack of blinding | |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG; blastocyst stage hCG ⋟ 500 IU Live birth |
366 per 1000 | 337 per 1000 (293 to 381) | RR 0.92 (0.80 to 1.04) | 1666 (2 RCTs) | Moderate | Serious risk of bias: poor reporting of methods, lack of blinding | |
| 10. Luteal phase support | |||||||
|
van der Linden 2015 hCG vs placebo/no treatment Live birth or ongoing pregnancy |
120 per 1000 | 194 per 1000 (128 to 281) | OR 1.76 (1.08 to 2.86) | 527 (3 RCTs) | Very low | Serious imprecision, inadequate reporting of methods, findings no longer significant when random‐effects model used | |
|
van der Linden 2015 Progesterone vs placebo/no treatment Live birth or ongoing pregnancy |
39 per 1000 | 66 per 1000 (42 to 103) | OR 1.77 (1.09 to 2.86) | 642 (5 RCTs) | Very low | Serious imprecision, inadequate reporting of methods, findings no longer significant when restricted to live births | |
|
van der Linden 2015 Progesterone vs hCG regimens Live birth or ongoing pregnancy |
198 per 1000 | 190 per 1000 (138 to 254) | OR 0.95 (0.65 to 1.38) | 833 (5 RCTs) | Low | Serious imprecision, inadequate reporting of methods | |
|
van der Linden 2015 Progesterone vs progesterone + oestrogen Live birth or ongoing pregnancy |
367 per 1000 | 393 per 1000 (345 to 444) | OR 1.12 (0.91 to 1.38) | 1651 (9 RCTs) | Low | Serious imprecision, inadequate reporting of methods | |
|
van der Linden 2015 Progesterone vs progesterone + GnRH agonist Live birth or ongoing pregnancy |
356 per 1000 | 255 per 1000 (209 to 309) | OR 0.62 (0.48 to 0.81) | 2861 (9 RCTs) | Very low | Inadequate reporting of methods, serious inconsistency (I2 = 69%). Only 3 studies reported live birth | |
|
Boomsma 2012 Peri‐implantation glucocorticoids vs no glucocorticoids Live birth |
115 per 1000 | 136 per 1000 (80 to 222) |
OR 1.21 (0.67 to 2.19) |
424 (3 RCTs) |
Low | Lacked details around methods, serious imprecision | |
|
Akhtar 2013 Heparin vs control or no heparin Live birth |
173 per 1000 | 271 per 1000 (183 to 378) |
OR 1.77 (1.07 to 2.90) |
386 (3 RCTs) |
Very low | Selection bias found in 1 RCT, high heterogeneity, results sensitive to choice of statistical model | |
| 11. Prevention of ovarian hyperstimulation syndrome (OHSS) | |||||||
|
D'Angelo 2007 Cryopreservation vs fresh embryo transfer Live birth |
373 per 1000 | 380 per 1000 (229 to 558) |
OR 1.03 (0.5 to 2.12) |
125 (1 RCT) |
Low | Evidence based on a single open‐label RCT with insufficient methodological details provided, serious imprecision | |
|
D'Angelo 2017 Coasting vs no coasting Live birth |
265 per 1000 | 148 per 1000 (48 to 369) |
OR 0.48 (0.14 to 1.62) |
68 (1 RCT) |
Very low | Evidence based on a single conference abstract, serious imprecision, insufficient methodological details provided | |
|
Tang 2016 Dopamine agonist vs placebo or no intervention Live birth |
509 per 1000 |
512 per 1000 (355 to 665) |
OR 1.01 (0.53 to 1.91) |
182 (1 RCT) | Low | Poor reporting of study methods, serious imprecision with wide confidence interval. | |
| 12. Frozen embryo replacement cycles | |||||||
|
Wong 2017 Frozen vs fresh and frozen transfer Cumulative live birth rate |
579 per 1000 | 600 per 1000 (556 to 643) | OR 1.09 (0.91 to 1.31) | 1892 (4 RCTs) | Moderate | Serious risk of bias associated with lack of power calculation (unclear what determined end of study) and/or use of interim analysis that was calculated per transfer (unit of analysis error) with absence of adequate stopping rules (possible overestimation of treatment effect) | |
|
Ghobara 2017 Natural cycle FET vs hormone therapy plus GnRHa suppression FET Live birth |
316 per 1000 | 262 per 1000 (153 to 414) | OR 0.77 (0.39 to 1.53) | 159 (1 RCT) | Low | Very serious imprecision: single study, few events, wide confidence intervals | |
|
Ghobara 2017 Natural cycle FET vs modified natural cycle FET (hCG trigger) Live birth |
267 per 1000 | 167 per 1000 (55 to 413) | OR 0.55 (0.16 to 1.93) | 60 (1 RCT) | Very low | High attrition rate, baseline characteristics unequal, very serious imprecision, with few events and wide confidence intervals | |
|
Ghobara 2017 Modified natural cycle FET (hCG trigger) vs hormone therapy FET Live birth |
88 per 1000 | 114 per 1000 (78 to 165) | OR 1.34 (0.88 to 2.05) | 959 (1 RCT) |
Low | High attrition rate, unclear report of allocation concealment, serious imprecision with wide confidence interval | |
|
Ghobara 2017 Modified natural cycle FET (hCG trigger) vs hormone therapy + GnRHa FET Live birth |
98 per 1000 | 423 per 1000 (304 to 553) | OR 1.11 (0.66 to 1.87) | 236 (1 RCT) | Low | Unclear risk of bias in most domains, serious imprecision, wide confidence interval | |
|
Ghobara 2017 Hormone therapy FET vs hormone therapy + GnRHa FET Live birth |
742 per 1000 | 223 per 1000 (103 to 463) | OR 0.10 (0.04 to 0.30) | 75 (1 RCT) | Low | Serious imprecision, serious inconsistency (clinical pregnancy rate in this study higher than in 6 other studies in the same analysis, none of which reported live births) | |
|
Ghobara 2017 hMG FET vs clomiphene + hMG FET Live birth |
84 per 1000 | 186 per 1000 (89 to 347) | OR 2.49 (1.07 to 5.80) | 209 (1 RCT) | Very low | Unclear risk of bias in all domains, very serious imprecision, few events, confidence interval compatible with benefit in the hMG‐only group or with no clinically meaningful effect | |
ART: assisted reproduction techniques.
CI: confidence interval.
COH: controlled ovarian hyperstimulation.
DHEA: dehydroepiandrosterone.
ET: embryo transfer.
FET: frozen embryo transfer.
FSH: follicle‐stimulating hormone.
GnRH: gonadotrophin‐releasing hormone.
GnRHa: gonadotrophin‐releasing hormone agonist.
HA: hyaluronic acid.
hCG: human chorionic gonadotrophin.
hLH: human luteinising hormone.
hMG: human menopausal gonadotrophin.
HT: hormone therapy.
ICSI: intracytoplasmic sperm injection.
IU: international units.
IV: intravenous.
IVF: in vitro fertilisation.
N/A: not applicable.
OHSS: ovarian hyperstimulation syndrome.
OR: odds ratio.
ORT: ovarian reserve test.
PCB: paracervical block.
PICSI: physiological intracytoplasmic sperm injection.
RCT: randomised controlled trial.
rFSH: recombinant follicle‐stimulating hormone.
rhCG: recombinant human chorionic gonadotrophin.
rhLH: recombinant human luteinising hormone.
RR: risk ratio.
TLS: time‐lapse imaging.
uhCG: urinary human chorionic gonadotrophin.
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 2015 IVF vs expectant management for unexplained subfertility |
127 per 1000 | 320 per 1000 (135 to 588) | OR 3.24 (1.07 to 9.8) | 86 (2 RCTs) | Very low | Very serious imprecision, questionable applicability, and serious inconsistency |
|
Pandian 2015 IVF vs intrauterine 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 RCTs) |
Moderate | Trials lacked adequate methodological details |
| 2. Pre‐ART and adjuvant strategies | ||||||
| 2.1. For unselected populations | ||||||
|
Nastri 2015 Endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle vs no injury |
211 per 1000 | 298 per 1000 (386 to 480) |
RR 1.34 (1.12 to 1.61) |
1972 (13 RCTs) |
Moderate | Serious imprecision |
|
Nastri 201 Endometrial injury on the day of oocyte retrieval vs no injury |
330 per 1000 | 120 per 1000 | RR 0.36 (0.18 to 0.71) |
156 (1 RCT) |
Low | Very serious imprecision |
|
Showell 2014 Antioxidant vs placebo or no treatment for men |
150 per 1000 | 318 per 1000 (142 to 567) |
2.64 (0.94 to 7.41) |
90 (2 RCTs) |
Low | Very serious imprecision with only 90 participants and 28 events, confidence intervals cross line of no effect |
|
Showell 2017 Antioxidant vs placebo or no treatment for women |
316 per 1000 | 355 per 1000 (312 to 398) |
OR 1.19 (0.98 to 1.43) |
2263 (15 RCTs) | Very low | Very serious risk of bias, serious imprecision |
|
Showell 2017 Pentoxifylline vs placebo or no treatment for women |
393 per 1000 | 571 per 1000 (386 to 739) |
OR 2.06 (0.97 to 4.38) |
112 (1 RCT) | Very low | Questionable applicability: study table refers to male infertility in 51 of 112 participants, very serious imprecision |
|
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 RCT) |
Moderate | Evidence based on a single trial, serious 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 RCTs) |
High | Adequate description of methods, no evidence of imprecision or heterogeneity |
|
Gutarra‐Vilchez 2014 Vasodilator compared with placebo |
274 per 1000 | 340 per 1000 (274 to 526) |
RR 1.38 (1.00 to 1.92) |
717 (8 RCTs) |
Low | Low or unclear risk of bias but very serious risk of imprecision |
|
Siristatidis 2016 Aspirin vs placebo or no treatment |
337 per 1000 | 347 per 1000 (307 to 395) | RR 1.03 (0.91 to 1.17) |
2142 (10 RCTs) |
Low | Half of studies failed to report sufficient detail about study methods |
|
Cheong 2013 Acupuncture vs 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 RCTs) |
Very low | Only 3/14 studies described adequate allocation concealment, serious heterogeneity (I2 = 66%), and serious imprecision |
|
Cheong 2013 Acupuncture vs 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 RCTs) |
Low | Inadequate description of study methods, serious imprecision |
|
Nagels 2015 DHEA vs placebo or no treatment |
208 per 1000 | 260 per 1000 (210 to 316) | OR 1.34 (1.01 to 1.76) | 1246 (12 RCTs) | Moderate | Serious imprecision with low event rates |
|
Nagels 2015 DHEA vs placebo or no treatment |
115 per 1000 | 247 per 1000 (150 to 378) | OR 2.52 (1.36 to 4.68) | 345 (4 RCTs) | Moderate | Serious imprecision with low event rates |
| 2.2. For selected populations | ||||||
|
Johnson 2010 Salpingectomy vs no surgical treatment |
189 per 1000 | 359 per 1000 (258 to 441) |
OR 2.2 (1.26 to 3.82) |
329 (3 RCTs) |
Moderate | No evidence of blinding in any trials. Heterogeneity: I2 = 52% |
|
Johnson 2010 Tubal occlusion vs no surgical treatment |
123 per 1000 | 396 per 1000 (234 to 585) |
OR 4.66 (2.17 to 10.01) |
209 (2 RCTs) |
Moderate | Randomisation methods not fully described |
|
Johnson 2010 Aspiration of hydrosalpingeal fluid vs no surgical treatment |
188 per 1000 | 313 per 1000 (125 to 592) |
OR 1.97 (0.62 to 6.29) |
64 (1 RCT) |
Very low | Evidence based on a single trial with serious imprecision |
|
Benschop 2010 Aspiration of endometrioma vs expectant management before ART |
200 per 1000 | 244 per 1000 (101 to 476) |
Peto OR 1.29 (0.45 to 3.64) |
81 (1 RCT) |
Low | Serious imprecision: evidence based on a single trial; wide confidence intervals cross line of no effect |
|
Benschop 2010 Cystectomy of endometrioma vs expectant management before ART |
317 per 1000 | 348 per 1000 (194 to 542) |
Peto OR 1.15 (0.52 to 2.55) |
109 (1 RCT) |
Low | Serious imprecision: evidence based on a single trial; wide confidence intervals cross line of no effect |
|
Benschop 2010 GnRH antagonist vs GnRH before ART |
242 per 1000 | 206 per 1000 (77 to 448) |
Peto OR 0.81 (0.26 to 2.54) |
67 (1 RCT) |
Low | Serious imprecision: evidence based on a single trial; wide confidence intervals cross line of no effect |
|
Benschop 2010 Ablation vs cystectomy before ART |
366 per 1000 | 293 per 1000 (126 to 545) |
Peto OR 0.72 (0.25 to 2.08) |
65 (1 RCT) |
Very low | Unclear risk of bias related to sequence generation Serious imprecision: single small RCT, wide confidence intervals cross line of no effect |
|
Tso 2014 Metformin vs 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 RCTs) |
Moderate | Serious imprecision: total events fewer than 300. Data discrepancy in 1 study. However, sensitivity analysis excluding this study did not substantially change findings |
|
McDonnell 2014 Ovarian cyst aspiration before in vitro fertilisation treatment for subfertility |
62 per 1000 | 72 per 1000 (21 to 220) |
OR 1.19 (0.33 to 4.29) |
159 (2 RCTs) | Very low | Neither of the studies adequately described methods of randomisation and allocation concealment Very serious imprecision, with wide confidence intervals and very low event rates |
| 3. Down‐regulation with agonists or antagonists | ||||||
|
Albuquerque 2013 GnRHa depot vs daily injection |
30 per 1000 | 29 per 1000 (25 to 35) |
OR 0.96 (0.75 to 1.23) |
1259 (11 RCTs) | Moderate | Most studies classified as at unclear risk of bias for all domains |
|
Al‐Inany 2016 GnRH antagonist vs long course GnRH agonist |
303 per 1000 | 283 per 1000 (267 to 303) | OR 0.91 (0.83 to 1) | 9959 (54 RCTs) | Moderate | Serious risk of bias |
|
Sallam 2006 Ultra‐long GnRH agonist vs conventional stimulation protocols |
Not calculated | Not calculated | OR 4.28 (2.00 to 9.15) |
149 (3 RCTs) |
Very low | All trials subject to methodological limitations; outcome was an intermediate outcome; evidence of lack of precision Possible unit of analysis error; review being updated |
|
Siristatidis 2015 Long vs short protocol for pituitary suppression |
137 per 1000 | 192 per 1000 (158 to 232) | OR 1.5 (1.18 to 1.9) | 1643 (20 studies) | Moderate | Poor reporting of methods |
|
Siristatidis 2015 Long vs ultra‐short protocol for pituitary suppression |
161 per 1000 | 230 per 1000 (133 to 370) | OR 1.56 (0.8 to 3.06) | 230 (2 RCTs) | Low | Poor reporting of methods, serious imprecision with wide confidence intervals |
|
Siristatidis 2015 Short vs ultra‐short protocol for pituitary suppression |
195 per 1000 | 244 per 1000 (102 to 480) |
OR 1.33 (0.47 to 3.81) |
82 (1 RCT) | Very low | Unclear applicability (participants were poor responders), very serious imprecision with few events and wide confidence intervals |
|
Siristatidis 2015 Long luteal phase vs long follicular phase protocol for pituitary suppression |
269 per 1000 | 281 per 1000 (219 to 351) | OR 1.06 (0.76 to 1.47) | 750 (5 studies) | Low | Poor reporting of methods, serious imprecision with wide confidence intervals |
|
Siristatidis 2015 Long protocol continued GnRH agonist vs long protocol stop GnRH agonist for pituitary suppression |
235 per 1000 | 207 per 1000 (135 to 302) | OR 0.85 (0.51 to 1.41) | 360 (4 studies) | Low | Poor reporting of methods, serious imprecision with wide confidence intervals |
|
Siristatidis 2015 Long protocol (continued same vs reduced dose GnRHa) for pituitary suppression |
377 per 1000 | 382 per 1000 (292 to 479) | OR 1.02 (0.68 to 1.52) | 407 (4 studies) | Low | Poor reporting of methods, imprecision with wide confidence intervals |
|
Siristatidis 2015 Long protocol (GnRHa until hCG) compared with long protocol (extend GnRHa 12 days after hCG) for pituitary suppression |
489 per 1000 | 494 per 1000 (353 to 636) | OR 1.02 (0.57 to 1.83) | 181 (1 study) | Low | Very serious imprecision, few events and wide confidence intervals |
|
Siristatidis 2015 Long protocol: administration of GnRHa for 2 vs 3 weeks before stimulation for pituitary suppression |
585 per 1000 | 568 per 1000 (355 to 757) |
OR 0.93 (0.39 to 2.21) |
85 (1 study) | Low | Poor reporting of methods, serious imprecision with wide confidence intervals |
|
Siristatidis 2015 Short protocol compared with stop short protocol for pituitary suppression |
226 per 1000 | 147 per 1000 (81 to 255) | OR 0.59 (0.3 to 1.17) | 230 (1 study) | Low | Poor reporting of methods, serious imprecision with wide confidence intervals |
| 4. Ovarian stimulation | ||||||
| 4.1. Medication type | ||||||
|
Kamath 2017 Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population |
248 per 1000 | 248 per 1000 (213 to 288) | RR 1.00 (0.86 to 1.16) | 1998 (12 RCTs) | Moderate | In some included trials, method of allocation concealment not adequately described or not mentioned at all |
|
Kamath 2017 Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in poor responders |
128 per 1000 | 109 per 1000 (82 to 143) | RR 0.85 (0.64 to 1.12) | 1462 (8 RCTs) | Low | In some included trials, method of allocation concealment not adequately described or not mentioned at all; serious imprecision |
|
Mochtar 2017 Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) vs rFSH alone for controlled ovarian hyperstimulation |
274 per 1000 | 282 to 367 per 1000 | OR 1.18 (1.03 to 1.34 |
5071 (23 RCTs) |
Moderate | Some trials lacked sufficient methodological details |
|
van Wely 2011 rFSH vs urinary gonadotrophins |
282 per 1000 | 280 per 1000 (263 to 299) |
OR 0.99 (0.91 to 1.09) |
9482 (41 RCTs) |
Moderate | No evidence that blinding was conducted in most studies |
|
Martins 2013 FSH replaced by low‐dose hCG in the late follicular phase vs continued FSH for assisted reproductive techniques |
350 per 1000 | 410 per 1000 (320 to 540) |
RR 1.19 (0.92 to 1.55 | 351 (5 RCTs) |
Low | Serious imprecision and high risk of bias |
|
Farquhar 2017 Combined oral contraceptive plus agonist vs agonist |
333 per 1000 | 373 per 1000 (209 to 571) | OR 1.19 (0.53 to 2.66) | 102 (1 RCT) | Very low | Serious imprecision: single RCT with wide confidence intervals that crossed the line of no effect |
|
Farquhar 2017 Combined oral contraceptive plus antagonist vs antagonist |
255 per 1000 | 191 per 1000 (146 to 248) | OR 0.69 (0.5 to 0.96) | 847 (4 RCTs) | Low | Serious imprecision and serious risk of bias |
|
Farquhar 2017 Combined oral contraceptive plus antagonist vs agonist |
245 per 1000 | 210 per 1000 (147 to 290) | OR 0.82 (0.53 to 1.26) | 472 (3 RCTs) | Low | Serious imprecision; 1 study did not describe satisfactory method of sequence generation, 2 did not describe satisfactory method of allocation concealment, and 1 was at high risk of attrition bias |
|
Kalampokas 2017 Glucocorticoid supplementation vs placebo |
236 per 1000 | 343 per 1000 (233 to 473) | OR 1.69 (0.98 to 2.90) | 310 (2 RCTs) | Low | Very serious imprecision (few events, wide confidence interval) |
|
Lensen 2018 ORT‐based algorithm vs standard dose FSH |
321 per 1000 | 313 per 1000 (280 to 349) | OR 0.96 (0.82 to 1.13) | 2823 (4 RCTs) | Moderate | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting |
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated low responders 1. 300/450 IU vs 150 IU 2. 400/450 IU vs 300 IU 3. 600 IU vs 450 IU |
1. 184 per 1000 | 101 per 1000 (53 to 184) | OR 0.50 (0.25 to 1.00) | 286 (2 RCTs) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events |
| 2. 127 per 1000 | 109 per 1000 (37 to 282) | OR 0.84 (0.26 to 2.69) | 110 (2 RCTs) | |||
| 3. 159 per 1000 | 177 per 1000 (111 to 274) | OR 1.14 (0.66 to 1.99) | 356 (1 RCT) | |||
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated normal responders 1. 200 IU vs 100 IU 2. 225/200 IU vs 150 IU 3. 300 IU vs 225 IU |
1. 202 per 1000 | 179 per 1000 (113 to 274) | OR 0.86 (0.73 to 1.31) | 330 (1 RCT) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events |
| 2. 236 per 1000 | 232 per 1000 (184 to 288) | OR 0.98 (0.75 to 1.33) | 1037 (5 RCTs) | |||
| 3. 441 per 1000 | 418 per 1000 (266 to 587) | OR 0.91 (0.46 to 1.80) | 135 (1 RCT) | |||
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated high responders 150 IU vs 100 IU |
275 per 1000 | 301 per 1000 (228 to 386) | OR 1.14 (0.78 to 1.66) | 521 (1 RCT) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events |
| 4.2. Monitoring | ||||||
|
Kwan 2014 Ultrasound + oestradiol vs ultrasound only |
337 per 1000 | 361 per 1000 (287 to 439) |
OR 1.05 (0.79 to 1.54) |
617 (4 RCTs) |
Low | Methods of allocation concealment inadequately described in the 4 trials. None of these trials adequately described blinding. Serious imprecision with wide confidence intervals |
| 4.3. Interventions for poor responders | ||||||
|
Pandian 2010 Cessation of GnRHa on stop protocol vs conventional GnRHa long protocol |
176 per 1000 | 138 per 1000 (43 to 370) |
OR 0.75 (0.21 to 2.74) |
70 (1 RCT) | Low | Evidence based on a single trial with no blinding |
|
Pandian 2010 GnRH antagonist vs conventional GnRHa long protocol |
67 per 1000 | 167 per 1000 (34 to 529) |
OR 2.8 (0.5 to 15.73) |
60 (1 RCT) | Very low | Evidence based on a single trial with lack of methodological detail and serious imprecision |
|
Pandian 2010 GnRHa flare‐up vs GnRHa long protocol |
286 per 1000 | 77 per 1000 (16 to 304) |
OR 0.21 (0.04 to 1.09) |
54 (1 RCT) | Very low | Evidence based on a single trial with lack of methodological detail and serious imprecision |
|
Pandian 2010 GnRH antagonist vs GnRHa flare‐up protocol |
163 per 1000 | 163 per 1000 (62 to 363) |
OR 1 (0.34 to 2.92) |
98 (2 RCTs) |
Low | Lack of methodological details and serious imprecision |
|
Pandian 2010 Low‐dose GnRHa flare‐up protocol vs spontaneous natural cycle IVF |
119 per 1000 | 101 per 1000 (35 to 252) |
OR 0.83 (0.27 to 2.5) |
129 (1 RCT) |
Low | Evidence based on a single trial with lack of methodological detail and serious imprecision |
|
Pandian 2010 Multiple‐dose GnRH agonist vs mini‐dose long agonist protocol |
244 per 1000 | 227 per 1000 (99 to 439) |
OR 0.91 (0.34 to 2.42) |
89 (1 RCT) | Low | No allocation concealment or blinding, evidence based on a single trial with serious imprecision |
|
Pandian 2010 Flare‐up protocol vs modified long protocol |
381 per 1000 | 142 per 1000 (36 to 429) |
OR 0.27 (0.06 to 1.22) |
42 (1 RCT) | Low | Evidence based on a single trial with serious imprecision |
|
Pandian 2010 Long protocol vs modified long protocol |
381 per 1000 | 105 per 1000 (18 to 398) |
OR 0.19 (0.03 to 1.06) |
40 (1 RCT) | Low | Evidence based on a single trial with serious imprecision |
| 4.4. Natural cycle IVF | ||||||
|
Allersma 2013 Natural cycle vs standard IVF |
112 per 1000 | 86 per 1000 (36 to 194) |
OR 0.75 (0.3 to 1.91) |
219 (3 RCTs) |
Low | 1/3 studies did not report adequate allocation concealment, risk of performance bias; serious imprecision with wide confidence intervals |
| 5. Ovulation triggering | ||||||
|
Youssef 2014 GnRH agonist vs hCG Outcome = ongoing pregnancy rather than clinical pregnancy |
256 per 1000 | 194 per 1000 (157 to 238) |
OR 0.7 (0.54 to 0.91) | 1198 (11 RCTs) |
Low | Substantial heterogeneity: I2 = 59% to 66%. 5/11 studies at high risk of bias because of early termination and/or inadequate allocation concealment. No studies clearly reported blinded outcome assessment |
|
Youssef 2016a rhCG vs uhCG |
330 per 1000 | 343 per 1000 (300 to 388) | OR 1.06 (0.87 to 1.29) | 1806 (13 studies) | Moderate | Serious imprecision |
|
Youssef 2016a rhLH vs uhCG |
407 per 1000 | 392 per 1000 (270 to 530) | OR 0.94 (0.54 to 1.64) | 289 (2 studies) | Very low | Poor reporting of study methods, very serious imprecision |
| 6. Oocyte retrieval | ||||||
|
Reavey 2016 hCG priming vs no priming |
225 per 1000 | 131 per 1000 (70 to 230) | OR 0.52 (0.26 to 1.03) | 282 (2 RCTs | Low | Serious risk of bias, serious imprecision |
|
Kwan 2018 Conscious sedation and analgesia (CSA) vs CSA + electro‐acupuncture |
594 per 1000 | 243 per 1000 (95 to 491) |
OR 0.22 (0.07 to 0.66) |
61 (1 RCT) | Very low | Serious risk of bias and very serious imprecision with only 1 small RCT |
|
Kwan 2018 Conscious sedation and analgesia (CSA) vs CSA + acupuncture |
344 per 1000 | 242 per 1000 (95 to 493) |
OR 0.61 (0.20 to 1.86) |
61 (1 RCT) |
Very low | Serious risk of bias and very serious imprecision with only 1 small RCT |
|
Kwan 2018 Conscious sedation and analgesia vs general anaesthesia |
278 per 1000 | 278 per 1000 (142 to 475) |
OR 1.00 (0.43 to 2.35) |
108 (2 RCTs) | Very low | Serious risk of bias and very serious imprecision |
|
Kwan 2018 Conscious sedation and analgesia (CSA) + paracervical block vs general anaesthesia |
375 per 1000 | 296 per 1000 | OR 0.70 (0.22 to 1.26 | 50 (1 RCT) |
Very low | Serious risk of bias and very serious imprecision with only 1 small RCT |
|
Kwan 2018 Conscious sedation and analgesia + paracervical block vs spinal anaesthesia |
375 per 1000 | 358 per 1000 | OR 0.93 (0.24 to 3.65) | 38 (1 RCT) |
Very low | Serious risk of bias and very serious imprecision with only 1 small RCT |
|
Kwan 2018 Conscious sedation and analgesia (CSA) + paracervical block vs paracervical block only |
253 per 1000 | 240 per 1000 | OR 0.93 (0.44 to 1.96) | 150 (1 RCT) |
Very low | Very serious imprecision with only 1 RCT |
|
Kwan 2018 Conscious sedation and analgesia (CSA) + paracervical block vs electro‐acupuncture + paracervical block |
367 per 1000 | 358 per 1000 | OR 0.96 (0.72 to 1.29) | 783 (4 RCTs) |
Low | Serious risk of bias with serious inconsistency |
|
Kwan 2018 Conscious sedation and analgesia (CSA) + paracervical block vs paracervical block |
253 per 1000 | 240 per 1000 (130 to 399) |
OR 0.93 (0.44 to 1.96) |
150 (1 RCT) | Low | Very serious imprecision |
|
Kwan 2018 Conscious sedation and analgesia: patient‐controlled vs physician‐controlled |
182 per 1000 | 168 per 1000 | OR 0.91 (0.45 to 1.83) | 218 (2 RCTs) |
Moderate | Adequate methods, low heterogeneity, suboptimal sample size |
|
Georgiou 2018 Follicular flushing vs aspiration alone |
362 per 1000 | 378 per 1000 (307to 453) |
OR 1.07 (0.78 to 1.46) |
704 (5 RCTs) |
Moderate | Seroius risk of bias: includes at least 1 open‐label study |
| 7. Sperm retrieval | ||||||
|
Proctor 2008 Microsurgical epididymal sperm aspiration vs 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 RCT) |
Low | Evidence based on a single trial with insufficient methodological detail |
|
McDowell 2014 Conventional sperm selection vs hyaluronan sperm selection (HA‐ICSI) |
470 per 1000 | 480 per 1000 (390 to 570) |
RR 0.99 (0.82 to 1.20) |
482 (1 RCT) |
Low | Serious risk of bias with discrepancy in reporting of pregnancy losses. Serious imprecision as 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 RCT) |
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 vs no assisted hatching |
332 per 1000 | 360 per 1000 (334 to 387) |
OR 1.13 (1.01 to 1.27) |
5728 (31 RCTs) | Moderate | Methodological limitations or missing information in most trials |
|
Glujovsky 2014 Vitrification vs slow freezing for women undergoing oocyte cryopreservation |
116 per 1000 | 449 per 1000 | RR 3.86 (1.63 to 9.11) |
106 (2 RCTs) |
Moderate | Live birth not reported, wide CIs |
|
Van Rumste 2003 Intracytoplasmic sperm injection vs in vitro fertilisation |
252 per 1000 | 329 per 1000 (242 to 428) |
OR 1.45 (0.95 to 2.22) |
415 (1 RCT) |
Low | Details of blinding unclear, evidence based on a single trial |
|
Bontekoe 2012 Embryo culture with low oxygen concentrations vs atmospheric oxygen concentration |
369 per 1000 | 442 per 1000 (387 to 494) |
OR 1.35 (1.08 to 1.67 |
1382 (4 RCTs) |
Moderate | In 1 trial, no allocation concealment; in another trial, method of allocation concealment unclear |
|
Twisk 2006 Pre‐implantation genetic screening vs no screening in women with advanced age |
291 per 1000 | 187 per 1000 (144 to 235) |
OR 0.59 (0.44 to 0.81) |
1062 (5 RCTs) |
Moderate | Only 1 study described an adequate method of allocation concealment |
|
Twisk 2006 Pre‐implantation genetic screening vs no screening in women with repeated IVF failure |
Not calculated | OR 0.49 (0.24 to 1.02 |
139 (1 RCT) |
Very low | No allocation concealment and serious imprecision with few events | |
|
Huang 2013 Brief co‐incubation vs standard insemination |
177 per 1000 | 337 per 1000 (238 to 453) |
OR 2.36 (1.45 to 3.85) |
372 (3 RCTs) | Low | One trial lacked adequate explanation of methods of sequence generation. Allocation concealment was not mentioned in any trial |
|
Teixeira 2013 Regular (ICSI) vs ultra‐high magnification (IMSI) sperm selection for assisted reproduction |
330 per 1000 | 430 per 1000 (360 to 520) |
RR 1.29 (1.06 to 1.55) |
2014 (9 RCTs) |
Very low | High risk of bias (differences within studies between number of oocytes transferred), inconsistency across studies, publication bias strongly suspected |
|
Armstrong 2015 TLS with or without cell‐tracking algorithms vs conventional incubation for embryo incubation in assisted reproduction |
558 per 1000 | 609 per 1000 (548 to 668) |
OR 1.23 (0.96 to 1.59) |
994 (3 RCTs) |
Low | Overall high risk of selection, performance, attrition, and reporting bias. Largest study used donor and autologous oocytes, whereas the remaining 2 studies used autologous oocytes only. Donor oocytes were generally from young women, which may behave differently from the usual population of oocytes and embryos of couples undergoing ART |
|
Siristatidis 2018 Metabolomic vs non‐metabolomic assessment |
421 per 1000 | 446 per 1000 (446 to 586) | OR 1.11 (0.85 to 1.45) |
924 (4 RCTs) |
Low | Serious risk of bias and serious imprecision |
| 9. Embryo transfer | ||||||
| 9.1. Developmental stage | ||||||
|
Glujovsky 2016 Blastocyst stage transfer vs cleavage stage transfer |
362 per 1000 | 425 per 1000 (393 to 455) | OR 1.30 (1.14 to 1.47) | 4031 (27 RCTs) | Moderate | Several studies did not describe acceptable methods of sequence generation and/or allocation concealment, several were at unclear or high risk of attrition bias, and none clearly had blinded outcome assessment |
| 9.3. Transfer techniques and procedures | ||||||
|
Ata 2018 Seminal plasma to genital tract vs no seminal plasma |
220 per 1000 | 252 per 1000 (222 to 288) | RR 1.15 (1.01 to 1.31) | 2768 (10 RCTs) | Very low | Very serious risk of bias and serious imprecision. Post hoc sensitivity analysis excluding studies at overall high risk of bias negated the statistical significance of the finding (RR 1.06, 95% CI 0.81 to 1.39; participants = 547; studies = 3; I2 = 0%) |
|
Brown 2016 Day 2 vs day 3 embryo transfer |
386 per 1000 | 417 per 1000 (378 to 459) |
OR 1.08 (0.98 to 1.19) |
2461 (12 RCTs) |
Very low | Serious inconsistency, poor reporting of allocation concealment and blinding, high risk of selective reporting |
|
Bontekoe 2014 Transfer medium enriched with high level of hyaluronic acid vs medium with low level or no hyaluronic acid |
350 per 1000 | 428 per 1000 (394 to 462) |
OR 1.39 (1.21 to 1.6) |
3542 (14 RCTs) |
Moderate | All studies except 1 were at high risk of bias in at least 1 domain, moderate heterogeneity (I2 = 46%) |
|
Brown 2016a Ultrasound guidance vs clinical touch for embryo transfer |
267 per 1000 | 323 per 1000 (299 to 346) | OR 1.31 (1.17 to 1.45) | 6711 (20 RCTs) | Moderate | Poor reporting of study methods |
|
Kroon 2012 Antibiotics before embryo transfer vs no antibiotics |
355 per 1000 | 359 per 1000 (266 to 465) |
1.02 (0.66 to 1.58) | 350 (1 RCT) |
Moderate | Serious imprecision with single RCT |
|
Derks 2009 Cervical dilatation vs no intervention |
232 per 1000 | 124 per 1000 (78 to 189) |
OR 0.47 (0.28 to 0.77) |
288 (1 RCT) |
Moderate | Evidence based on a single RCT |
|
Derks 2009 Straightening the endocervical angle vs no intervention |
271 per 1000 | 267 per 1000 (175 to 384) |
OR 0.98 (0.57 to 1.68) |
273 (2 RCTs) |
Moderate | Serious imprecision |
|
Derks 2009 Removal of cervical mucus vs no intervention |
327 per 1000 | 320 per 1000 (169 to 522) |
OR 0.97 (0.42 to 2.25) |
97 (1 RCT) |
Low | Lack of methodological details, serious imprecision: evidence based on a single trial |
|
Derks 2009 Flushing the endocervical canal vs no intervention |
413 per 1000 | 445 per 1000 9360 to 533) |
OR 1.14 (0.8 to 1.62) |
537 (3 RCTs) |
Low | Lack of methodological details; heterogeneity (I2 > 50%) |
|
Derks 2009 Flushing the endometrial cavity vs no intervention |
519 per 1000 | 584 per 1000 (437 to 718) |
OR 1.3 (0.72 to 2.36) |
181 (1 RCT) |
Low | Lack of methodological details, serious imprecision with evidence based on a single trial |
|
Abou‐Setta 2014 Mechanical pressure vs no intervention |
478 per 1000 | 637 per 1000 (561 to 706) |
OR 1.92 (1.4 to 2.63) |
639 (1 RCT) |
Very low | Evidence based on a single trial; method of randomisation unclear and trial open‐label |
|
Abou‐Setta 2014 Fibrin sealant vs no intervention |
291 per 1000 | 287 per 1000 (181 to 422) |
OR 0.98 (0.54 to 1.78) |
211 (1 RCT) |
Low | Evidence based on a single trial with inadequate allocation concealment |
|
Abou‐Setta 2014 More bed rest vs less bed rest |
302 per 1000 | 276 per 1000 (206 to 362) |
OR 0.88 (0.6 to 1.31 |
542 (2 RCTs) |
Moderate | One trial was open‐label |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG; cleavage stage hCG < 500 IU |
579 per 1000 | 509 per 1000 (405 to 637) |
RR 0.88 (0.70 to 1.10) |
280 (1 RCT) | Very low | Very serious risk of bias, with poor reporting of methods and premature termination of study; serious imprecision |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG; cleavage stage hCG⋟ 500 IU |
321 per 1000 | 453 per 1000 (401 to 507) |
RR 1.41 (1.25 to 1.58) |
1414 (7 RCTs) |
Moderate | Serious risk of bias: poor reporting of methods, lack of blinding |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG; blastocyst stage hCG ⋟ 500 IU |
430 per 1000 | 408 per 1000 (370 to 455) |
RR 0.95 (0.86 to 1.06) |
1991 (3 RCTs) |
Moderate | Serious risk of bias: poor reporting of methods, lack of blinding |
| 10. Luteal phase support | ||||||
|
van der Linden 2015 hCG vs placebo/no treatment |
155 per 1000 | 192 per 1000 (141 to 256) | OR 1.3 (0.9 to 1.88) | 746 (5 RCTs) | Very low | Poor reporting of study methods, very serious imprecision |
|
van der Linden 2015 Progesterone vs placebo/no treatment |
100 per 1000 | 174 per 1000 (126 to 234) | OR 1.89 (1.3 to 2.75) | 841 (7 RCTs) | Low | Poor reporting of study methods, very serious imprecision |
|
van der Linden 2015 Progesterone vs hCG regimens |
284 per 1000 | 300 per 1000 (263 to 340) | OR 1.08 (0.9 to 1.3) | 2355 (16 RCTs) | Moderate | Poor reporting of study methods |
|
van der Linden 2015 Progesterone vs progesterone + oestrogen |
433 per 1000 | 391 per 1000 (355 to 443) | OR 0.86 (0.72 to 1.04) | 2169 (14 RCTs) | Low | Poor reporting of study methods, serious inconsistency |
|
van der Linden 2015 Progesterone vs progesterone + GnRH agonist |
405 per 1000 | 310 per 1000 (258 to 367) | OR 0.66 (0.51 to 0.85) | 2435 (8 RCTs) | Low | Poor reporting of study methods, serious inconsistency |
|
Boomsma 2012 Peri‐implantation glucocorticoids vs no glucocorticoids |
290 per 1000 | 320 per 1000 (275 to 369) |
OR 1.15 (0.93 to 1.43) |
1759 (13 RCTs) |
Moderate | Most studies lacked adequate blinding |
|
Akhtar 2013 Heparin vs placebo or no treatment |
250 per 1000 | 271 per 1000 (256 to 458) |
OR 1.61 (1.03 to 2.53) |
386 (3 RCTs) |
Low | Imprecise, sensitive to choice of statistical model: estimate using random‐effects model: OR 1.66, 95% CI 0.94 to 2.90 |
| 11. Prevention of ovarian hyperstimulation syndrome (OHSS) | ||||||
|
D'Angelo 2007 Cryopreservation vs fresh embryo transfer |
463 per 1000 | 482 per 1000 (318 to 654) |
OR 1.08 (0.54 to 2.19) |
125 (1 RCT) |
Low | Evidence based on a single open‐label RCT that provided insufficient methodological details. Serious imprecision |
|
D'Angelo 2007 Cryopreservation vs intravenous albumin |
385 per 1000 | 36 per 1000 (0 to 423) |
OR 0.06 (0 to 1.17) |
26 (1 RCT) |
Low | Evidence based on a single open‐label trial with serious imprecision |
|
Youssef 2016 Intravenous human albumin vs no treatment or placebo |
396 per 1000 | 321 per 1000 (265 to 381) | OR 0.72 (0.55 to 0.94) | 1069 (7 RCTs) | Moderate | Lack of blinding, inadequate reporting of allocation concealment, unclear risk of attrition bias |
|
Youssef 2016 Intravenous hydroxyethyl starch vs placebo |
120 per 1000 | 141 per 1000 (63 to 286) |
OR 1.2 (0.49 to 2.93) |
168 (1 RCT) |
Very low | Lack of blinding, inadequate reporting of allocation concealment, unclear risk of attrition bias, and serious imprecision, with low event rate |
|
Youssef 2016 Mannitol vs placebo |
276 per 1000 | 245 per 1000 (152 to 371) | OR 0.85 (0.47 to 1.55) | 226 (1 RCT) | Low | Inadequate reporting of allocation concealment, serious imprecision, with low event rate |
|
D'Angelo 2017 Coasting vs no coasting |
390 per 1000 | 344 per 1000 (228 to 480) | OR 0.82 (0.46 to 1.44) | 207 (2 RCTs) |
Low | Insufficient methodological details provided and serious imprecision |
|
D'Angelo 2017 Coasting vs early unilateral follicular aspiration |
317 per 1000 | 237 per 1000 (104 to 454) | OR 0.67 (0.25 to 1.79) | 83 (2 RCTs) |
Very low | One study did not clearly describe methods; lack of blinding, very serious imprecision |
|
D'Angelo 2017 Coasting vs gonadotrophin‐releasing hormone antagonist |
553 per 1000 | 478 per 1000 (342 to 619) | OR 0.74 (0.42 to 1.31) | 190 (1 RCT) | Low | Method of sequence generation not reported; lack of blinding and serious imprecision |
|
D'Angelo 2017 Coasting vs follicle‐stimulating hormone administration at time of hCG |
510 per 1000 | 489 per 1000 (309 to 676) | OR 0.92 (0.43 to 2.01) | 102 (1 RCT) | Very low | Method of sequence generation not reported; lack of blinding and serious imprecision |
|
D'Angelo 2017 Coasting vs cabergoline |
367 per 1000 | 180 per 1000 (85 to 338) | OR 0.38 (0.16 to 0.88) |
120 (2 RCTs) | Very low | One study did not clearly define methods; method of sequence generation not reported; lack of blinding, few events |
|
Tang 2016 Dopamine agonist vs placebo or no intervention |
401 per 1000 | 352 per 1000 (266 to 450) |
OR 0.81 (0.54 to 1.22) |
432 (4 RCTs) |
Moderate | Poor reporting of study methods |
| 12. Frozen embryo replacement cycles | ||||||
|
Ghobara 2017 Oestrogen + progesterone frozen thawed embryo transfer (FET) vs natural cycle FET |
205 per 1000 | 214 per 1000 (93 to 419) |
OR 1.06 (0.4 to 2.8) |
100 (1 RCT) |
Very low | Evidence based on a single trial, insufficient methodological details provided, open‐label, and serious imprecision |
|
Ghobara 2017 Oestrogen + progesterone frozen thawed embryo transfer (FET) vs 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 RCTs) |
Low | Heterogeneity > 50%, included open‐label trials; some trials failed to provide adequate methodological details |
|
Ghobara 201 Oestrogen + progesterone frozen thawed embryo transfer (FET) vs FSH ovulation induction FET |
128 per 1000 | 109 per 1000 949 to 228) |
OR 0.84 (0.35 to 2.02) |
194 (1 RCT) |
Very low | Evidence based on a single trial with insufficient methodological details provided; trial was open‐label. Also serious imprecision |
|
Ghobara 2017 Clomiphene frozen thawed embryo transfer (FET) vs oestrogen and progesterone FET |
96 per 1000 | 75 per 1000 (22 to 228) |
OR 0.76 (0.21 to 2.77) |
119 (1 RCT) |
Very low | Evidence based on a single trial with insufficient methodological details provided. Also serious imprecision |
|
Ghobara 2017 Clomiphene frozen thawed embryo transfer (FET) vs GnRHa + oestrogen and progesterone FET |
162 per 1000 | 75 per 1000 (23 to 221) |
OR 0.42 (0.12 to 1.47) |
104 (1 RCT) |
Very low | Evidence based on a single trial with insufficient methodological details provided. Also serious imprecision |
|
Ghobara 2017 Clomiphene + hMG frozen thawed embryo transfer (FET) vs hMG FET |
275 per 1000 | 148 per 1000 | OR 0.46 (0.23 to 0.92) |
209 (1 RCT) |
Low | Evidence based on a single trial with insufficient methodological details provided |
|
Glujovsky 2010 GnRH agonists vs 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 RCTs) |
Moderate | All trials were open‐label; insufficient reporting of methodological details in many studies |
|
Glujovsky 2010 Intramuscular progesterone vs vaginal progesterone for endometrial preparation for embryo transfer with frozen embryos or donor oocytes |
282 per 1000 | 361 per 1000 (278 to 452) |
OR 1.44 (0.98 to 2.1) |
655 (4 RCTs) |
Moderate | All trials were open‐label; insufficient reporting of methodological details in many studies. Wide confidence interval crosses the line of no effect |
|
Glujovsky 2010 Starting progesterone on the day of oocyte pickup (OPU) or the day after OPU vs starting progesterone the day before OPU |
381 per 1000 | 533 per 1000 (400 to 712) |
OR 1.8 (1.13 to 3.08) | 282 (1 RCT) |
Moderate | Serious risk of bias with no intention‐to‐treat analysis |
ART: assisted reproduction techniques.
CI: confidence interval.
COH: controlled ovarian hyperstimulation.
CSA: conscious sedation and analgesia.
DHEA: dehydroepiandrosterone.
E2: oestrogen.
ET: embryo transfer.
FET: frozen embryo transfer.
FSH: follicle‐stimulating hormone.
GnRH: gonadotrophin‐releasing hormone.
GnRHa: gonadotrophin‐releasing hormone agonist.
HA: hyaluronic acid.
HA‐ICSI: conventional sperm selection vs hyaluronan sperm selection.
hCG: human chorionic gonadotrophin.
hLH: human luteinising hormone.
hMG: human menopausal gonadotrophin.
HT: hormone therapy.
ICSI: intracytoplasmic sperm injection.
IU: international units.
IV: intravenous.
IVF: in vitro fertilisation.
N/A: not applicable.
OHSS: ovarian hyperstimulation syndrome.
OPU: oocyte pickup.
OR: odds ratio.
ORT: ovarian reserve test.
PCB: paracervical block.
PICSI: physiological intracytoplasmic sperm injection.
RCT: randomised controlled trial.
rFSH: recombinant follicle‐stimulating hormone.
rhCG: recombinant human chorionic gonadotrophin.
rhLH: recombinant human luteinising hormone.
RR: risk ratio.
TLS: time‐lapse imaging.
uhCG: urinary human chorionic gonadotrophin.
VAS: visual analogue scale.
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 2015 IVF vs intrauterine insemination + ovarian stimulation for unexplained subfertility (treatment naïve women ) |
58 per 1000 | 66 per 1000 (26 to 158) | OR 1.15 (0.43 to 3.06) | 324 (2 RCTs) | Low | Serious risk of bias and serious imprecision |
| 2. Pre‐ART and adjuvant strategies | ||||||
| For selected populations | ||||||
|
Tso 2014 Metformin vs placebo or no treatment |
270 per 1000 | 97 per 1000 (62 to 153) |
OR 0.29 (0.18 to 0.49) |
798 (8 RCTs |
Moderate | Serious imprecision, as total events were fewer than 300 |
| 3. Down‐regulation with agonists or antagonists | ||||||
|
Albuquerque 2013 GnRHa depot vs daily injection |
3 per 100 | 2 per 100 (1 to 6) |
OR 0.84 (0.29 to 2.42) |
570 (5 RCTs) | Low | Most studies classified as at unclear risk of bias for all domains. Serious imprecision as total events were fewer than 300 |
|
Al‐Inany 2016 GnRH antagonist vs long course GnRH agonist |
114 per 1000 | 73 per 1000 (62 to 85) | OR 0.61 (0.51 to 0.72) | 7944 (36 studies) | Moderate | Serious risk of bias |
| 4. Ovarian stimulation | ||||||
| 4.1. Medication type | ||||||
|
Kamath 2017 Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population |
63 per 1000 | 14 per 1000 (7 to 27) | Peto OR 0.21 (0.11 to 0.41) | 1067 (5 RCTs) | Low | Serious risk of bias associated with unclear reporting of methods of allocation concealment. Imprecision as there were few participants and few events |
|
Pouwer 2015 Long‐acting FSH (low dose) vs daily FSH |
47 per 1000 | 57 per 1000 (26 to 125) |
RR 1.22 (0.56 to 2.66) |
645 (3 RCTs) |
Moderate | Serious imprecision with few events |
|
Pouwer 2015 Long‐acting FSH (medium dose) vs daily FSH |
63 per 1000 | 60 per 1000 (45 to 85) |
RR 0.96 (0.68 to 1.35) |
3075 (5 RCTs) |
Low | Serious imprecision as wide confidence intervals compatible with clinically meaningful benefit in either arm or with no effect. High risk of attrition bias in 2 studies |
|
Pouwer 2015 Long‐acting FSH (high dose) vs daily FSH |
0 per 1000 | 0 per 1000 (0 to 0) |
RR 1.73 (0.09 to 32.75) |
33 (1 RCT) |
Very low | Very serious imprecision as very wide confidence intervals compatible with clinically meaningful benefit in either arm or with no effect. High risk of attrition bias |
|
Mochtar 2017 Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) vs rFSH alone for controlled ovarian hyperstimulation |
13 per 1000 | 5 per 1000 (2 to 13) |
OR 0.38 (0.14 to 1.01) |
2178 (6 RCTs) |
Low | Very serious imprecision with wide confidence intervals and low event rates |
|
Martins 2013 FSH replaced by low‐dose hCG in the late follicular phase vs continued FSH for assisted reproductive techniques |
3 per 100 | 1 per 100 (0 to 4) |
OR 0.30 (0.06 to1.59) |
351 (5 RCTs) |
Very low | Very serious imprecision, inconsistency, and high risk of bias |
|
Farquhar 2017 Combined oral contraceptive pill plus antagonist vs antagonist |
17 per 1000 | 25 per 1000 (5 to 133) | OR 1.5 (0.26 to 8.8) | 234 (1 RCT) | Very low | Serious imprecision as wide confidence intervals compatible with clinically meaningful benefit in either arm or with no effect. High risk of attrition bias |
|
Farquhar 2017 Combined oral contraceptive pill plus antagonist vs agonist |
55 per 1000 | 35 per 1000 (12 to 100) | OR 0.63 (0.21 to 1.92) | 290 (2 RCTs) | Very low | Serious imprecision with wide confidence intervals that cross the line of no effect. One RCT has high risk of attrition bias |
|
Lensen 2018 ORT‐based algorithm vs standard dose FSH Moderate or severe OHSS |
8 per 1000 | 14 per 1000 (8 to 25) | OR 0.58 (0.34 to 1.00) | 2823 (4 RCTs) | Low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Serious imprecision associated with small number of events |
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated low responders Moderate or severe OHSS 1. 300/450 IU vs 150 IU 2. 400/450 IU vs 300 IU 3. 600 IU vs 450 IU |
1. 0 per 1000 | 0 per 1000 (0 to 0) | Not estimable | 286 (2 RCTs) | Very low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Very serious imprecision associated with very small number of events |
| 2. 0 per 1000 | 0 per 1000 (0 to 0) | Not estimable | 62 (1 RCT) | |||
| 3. 0 per 1000 | 0 per 1000 (0 to 0) | OR 7.23 (0.14 to 364) | 356 (1 study) | |||
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated normal responders Moderate or severe OHSS 1. 200 IU vs 100 IU 2. 225/200 IU vs 150 IU 3. 300 IU vs 225 IU |
1. 31 per 1000 | 19 per 1000 (7 to 56) | OR 0.62 (0.21 to 1.87) | 522 (2 RCTs) | Very low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Very serious imprecision associated with very small number of events |
| 2. 27 per 1000 | 32 per 1000 (14 to 73) | OR 1.21 (0.51 to 2.85) | 740 (4 RCTs) | |||
| 3. 44 per 1000 | 30 per 1000 (5 to 156) | OR 0.67 (0.11 to 3.99) | 135 (1 study) | |||
|
Lensen 2018 Higher‐dose FSH vs lower‐dose FSH in anticipated high responders Moderate or severe OHSS 150 IU vs 100 IU |
16 per 1000 | 36 per 1000 (13 to 96) | OR 2.31 (0.80 to 6.67) | 521 (1 RCT) |
Very low | Serious risk of bias associated mainly with performance bias due to lack of blinding and/or selective reporting. Very serious imprecision associated with very small number of events |
| 4.2. Monitoring | ||||||
|
Kwan 2014 Ultrasound + oestradiol vs ultrasound only |
36 per 1000 | 36 per 1000 (18 to 75) |
OR 1.03 (0.48 to 2.20) |
781 (6 RCTs) |
Low | Methods of randomisation inadequately described in 3 of the 6 trials, allocation concealment inadequately described in all 6 trials, and blinding inadequately described in 5 of the 6 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 Natural cycle vs standard IVF |
67 per 1000 | 13 per 1000 (1 to 393) |
OR 0.10 (0.01 to 4.06) |
60 (1 RCT) |
Very low | Allocation concealment method not reported, very serious imprecision |
| 5. Ovulation triggering | ||||||
|
Youssef 2014 GnRH agonist vs hCG |
5 per 1000 | 1 per 1000 (0 to 2) |
OR 0.15 (0.05 to 0.47) |
989 (8 RCTs) |
Moderate | All studies at high risk of bias in 1 or more domains. None clearly reported blinded outcome assessment |
|
Georgiou 2018 rFSH vs urinary gonadotrophins |
19 per 1000 | 22 per 1000 (16 to 30) |
OR 1.18 (0.86 to 1.61) |
7740 (32 RCTs) |
High | Lack of blinding |
|
Youssef 2016a rhCG vs uhCG |
10 per 1000 | 17 per 1000 (11 to 84) | OR 1.76 (0.37 to 8.45) | 417 (3 RCTs) | Low | Very serious imprecision |
|
Youssef 2016a rhLH vs uhCG |
126 per 1000 | 107 per 1000 (55 to 197) |
OR 0.83 (0.40 to 1.70) |
289 (2 RCTs) |
Very low | One trial lacked adequate methodological details; serious imprecision |
| 10. Luteal phase support | ||||||
|
van der Linden 2015 hCG vs placebo/no treatment |
41 per 1000 | 155 per 1000 (76 to 292) |
OR 4.28 (1.91 to 9.6) | 387 (1 RCT) |
Low | Poor reporting of study methods, serious imprecision with low event rate |
|
van der Linden 2015 Progesterone vs hCG regimens |
118 per 1000 | 58 per 1000 (39 to 87) |
OR 0.46 (0.30 to 0.71) |
1293 (5 studies) |
Low | Poor reporting of study methods with serious imprecision |
|
van der Linden 2015 Progesterone compared with progesterone + oestrogen |
51 per 1000 | 30 per 1000 (11 to 82) | OR 0.58 (0.2 to 1.68) | 461 (2 RCTs) | Low | Poor reporting of study methods with serious imprecision |
|
van der Linden 2015 Progesterone compared with progesterone + GnRH agonist |
50 per 1000 | 50 per 1000 (17 to 137) |
OR 1.00 (0.33 to 3.01) |
300 (1 RCT) |
Very low | Poor reporting of study methods with very serious imprecision |
|
Akhtar 2013 Heparin vs placebo or no treatment |
250 per 1000 | 349 per 1000 (256 to 458) |
OR 1.61 (1.03 to 2.53) |
386 (3 RCTs) |
Very low | Selection bias found in 1 study. High heterogeneity. Results sensitive to choice of statistical model |
|
Boomsma 2012 Peri‐implantation glucocorticoids vs no glucocorticoids |
194 per 1000 | 159 per 1000 (64 to 392) |
OR 0.82 (0.33 to 2.02) |
151 (2 RCTs) |
Low | Methodological limitations and serious imprecision |
| 11. Prevention of ovarian hyperstimulation syndrome (OHSS) | ||||||
|
Tang 2016 Dopamine agonist vs placebo/no treatment |
286 per 1000 | 97 per 1000 (71 to 135) |
OR 0.27 (0.19 to 0.39) |
1022 (8 RCTs) |
Moderate | Poor reporting of study methods |
|
D'Angelo 2007 Cryopreservation vs fresh embryo transfer |
60 per 1000 | 8 per 1000 (1 to 128) |
OR 1.12 (0.01 to 2.29) |
125 (1 RCT) |
Low | Evidence based on a single open‐label study with insufficient methodological details provided. Serious imprecision |
|
D'Angelo 2007 Cryopreservation vs intravenous albumin |
77 per 1000 | 308 per 1000 (41 to 824) |
OR 5.33 (0.51 to 56.24) |
26 (1 RCT) |
Very low | Evidence based on a single open‐label trial with serious imprecision |
|
Youssef 2016 Intravenous human albumin vs no treatment or placebo |
122 per 1000 | 85 per 1000 (61 to 117) | OR 0.67 (0.47 to 0.95) | 1452 (7 RCTs) | Very low | Lack of blinding, inadequate reporting of allocation concealment, unclear risk of attrition bias, serious imprecision with low event rate, and serious inconsistency (I2 = 69%) |
|
Youssef 2016 Intravenous hydroxyethyl starch vs placebo |
164 per 1000 | 50 per 1000 (23 to 104) | OR 0.27 (0.12 to 0.59) | 272 (2 RCTs) | Very low | Inadequate reporting of allocation concealment and blinding with unclear risk of attrition bias |
|
Youssef 2016 Mannitol vs placebo or no treatment |
517 per 1000 | 289 per 1000 (191 to 407) | OR 0.38 (0.22 to 0.64) | 226 (1 RCT) | Low | Inadequate reporting of allocation concealment and serious imprecision with low event rate |
|
D'Angelo 2017 Coasting vs no coasting |
457 per 1000 | 85 per 1000 (40 to 168) | OR 0.11 (0.05 to 0.24) | 207 (2 RCTs) | Low | Serious risk of bias as 1 study did not clearly describe the methods used and studies were not blinded. Serious imprecision |
|
D'Angelo 2017 Coasting vs early unilateral follicular aspiration |
244 per 1000 | 240 per 1000 (99 to 479) | OR 0.98 (0.34 to 2.85) | 83 (2 RCTs) | Very low | One study did not clearly describe methods; lack of blinding and serious imprecision |
|
D'Angelo 2017 Coasting vs gonadotrophin‐releasing hormone antagonist |
No events occurred | No events occurred | Not estimable | 190 (1 RCT) |
Very low | Method of sequence generation not reported; lack of blinding and very serious imprecision |
|
D'Angelo 2017 Coasting vs follicle‐stimulating hormone administration at time of hCG |
No events occurred | 15 events all in the coasting arm | OR 43.74 (2.54 to 754.58) | 102 (1 RCT) | Very low | Method of sequence generation not reported; lack of blinding and very serious imprecision |
|
D'Angelo 2017 Coasting vs cabergoline |
100 per 1000 | 180 per 1000 (71 to 387) | OR 1.98 (0.69 to 5.68) | 120 (2 RCTs) | Very low | One study did not clearly define methods; method of sequence generation not reported, lack of blinding, very serious imprecision |
| 12. Frozen embryo replacement cycles | ||||||
|
Wong 2017 Frozen vs fresh and frozen embryo transfer Per cycle with ovarian stimulation |
70 per 1000 | 18 per 1000 (11 to 28) | OR 0.24 (0.15 to 0.38) | 1633 (2 RCTs) | Low | Serious risk of bias and serious imprecision with low event rate |
ART: assisted reproduction techniques.
CI: confidence interval.
FET: frozen embryo transfer.
FSH: follicle‐stimulating hormone.
GnRH: gonadotrophin‐releasing hormone.
GnRHa: gonadotrophin‐releasing hormone agonist.
HA: hyaluronic acid.
hCG: human chorionic gonadotrophin.
hLH: human luteinising hormone.
hMG: human menopausal gonadotrophin.
ICSI: intracytoplasmic sperm injection.
IU: international units.
IVF: in vitro fertilisation.
OHSS: ovarian hyperstimulation syndrome.
OR: odds ratio.
ORT: ovarian reserve test.
RCT: randomised controlled trial.
rFSH: recombinant follicle‐stimulating hormone.
rhCG: recombinant human chorionic gonadotrophin.
rhLH: recombinant human luteinising hormone.
RR: risk ratio.
uhCG: urinary human chorionic gonadotrophin.
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 (RCTs) |
Quality of the evidence (GRADE) |
Comments |
| 1. Indication for ART | ||||||
|
Pandian 2015 IVF vs unstimulated intrauterine insemination for unexplained subfertility |
30 per 1000 | 31 per 1000 (1 to 460) | OR 1.03 (0.04 to 27.29) | 43 (1 RCT) | Very low | Very serious imprecision |
|
Pandian 2015 IVF vs intrauterine insemination + ovarian stimulation for unexplained subfertility (treatment naïve women ) |
58 per 1000 | 47 per 1000 (28 to 78) | OR 0.81 (0.47 to 1.39) | 848 (4 RCTs) | Moderate | Serious imprecision with wide confidence interval |
| 2. Pre‐ART and adjuvant strategies | ||||||
|
Siristatidis 2016 Aspirin vs placebo or no treatment |
84 per 1000 | 56 per 1000 (31 to 105) | RR 0.67 (0.37 to 1.25) |
656 (2 RCTs) | Low | Very serious imprecision with very low event rate and wide confidence interval |
|
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 RCTs) |
Moderate | Serious imprecision |
|
Cheong 2013 Acupuncture vs 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 RCTs) |
Low | Only 1/2 studies described adequate allocation concealment; wide confidence intervals crossed the line of no effect |
|
Nastri 2015 Endometrial injury before ovulation induction (pipelle induced) vs no endometrial injury |
278 per 1000 | 251 per 1000 (81 to 559) |
OR 0.87 (0.23 to 3.3) |
46 (1 RCT) |
Very low | Evidence based on a single trial with serious 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 RCTs) |
Moderate | Studies had low or unclear risk of bias but serious imprecision |
|
Nagels 2015 DHEA vs placebo or no treatment |
Not calculable | Not calculable | OR 3.23 (0.13 to 81.01) | 267 (5 RCTs) | Very low | Very serious imprecision |
|
Nagels 2015 Testosterone vs placebo or no treatment |
Not calculable | Not calculable | OR 3.09 (0.48 to 19.98) | 292 (3 RCTs) | Very low | Very serious imprecision |
| 3. Down‐regulation with agonists or antagonists | ||||||
|
Albuquerque 2013 GnRHa depot vs daily injection |
24 per 100 | 25 per 100 (13 to 43) |
OR 1.1 (0.49 to 2.46) |
132 (4 RCTs) | Low | Most studies classified as at unclear risk of bias for all domains. Serious imprecision as total events were fewer than 300 |
|
Boomsma 2012 Peri‐implantation glucocorticoids vs no glucocorticoids |
38 per 1000 | 74 per 1000 (31 to 168) |
OR 2.02 (0.8 to 5.11) |
372 (4 RCTs) |
Moderate | Poor reporting of methodological details |
| 4. Ovarian stimulation | ||||||
| 4.1. Medication type | ||||||
|
Kamath 2017 Clomiphene citrate (± urinary or recombinant gonadotrophin) vs 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 RCTs) |
Moderate | Poor reporting of methodological details |
|
Farquhar 2017 Combined oral contraceptive pill plus antagonist vs antagonist |
47 per 1000 | 98 per 1000 (25 to 313) | OR 2.21 (0.53 to 9.26) | 125 (2 RCTs) | Low | Very serious imprecision with wide confidence intervals |
|
Farquhar 2017 Combined oral contraceptive pill plus antagonist vs agonist |
147 per 1000 | 189 per 1000 (127 to 273) | OR 1.36 (0.85 to 2.19) | 546 (4 RCTs) | Moderate | Serious imprecision with wide confidence intervals |
|
Farquhar 2017 Progesterone plus antagonist vs antagonist |
42 per 1000 | 44 per 1000 (3 to 438) | OR 1.05 (0.06 to 17.76) | 47 (1 RCT) | Low | Very serious imprecision with wide confidence intervals |
|
Farquhar 2017 Oestrogen plus antagonist vs agonist |
No events in this group | Only two events (both in this group) | OR 2.24 (0.09 to 53.59) | 22 (1 RCT) | Very low | Poor reporting of methods and very serious imprecision |
|
Kalampokas 2017 Glucocorticoid supplementation vs placebo |
Not calculable | Not calculable | OR 3.32 (0.12 to 91.60) | 20 (1 study) | Very low | Risk of bias and very serious imprecision with only 1 event (in glucocorticoid group) |
| 4.4. Natural cycle IVF | ||||||
|
Allersma 2013 Natural cycle vs standard IVF |
29 per 1000 | 6 per 1000 (0 to 117) |
OR 0.21 (0.01 to 4.38) |
132 (1 RCT) |
Very low | Methods of sequence generation and allocation concealment not stated, high risk of attrition bias, very serious imprecision |
| 5. Ovulation triggering | ||||||
|
Youssef 2014 GnRH agonist vs hCG |
82 per 1000 | 134 per 1000 (71 to 238) |
OR 1.74 (0.86 to 3.5) |
342 (3 RCTs) |
Moderate | No evidence of blinding in many trials |
|
van Wely 2011 rFSH vs urinary gonadotrophins |
85 per 1000 | 78 per 1000 (66 to 92) |
OR 0.91 (0.76 to 1.09) |
6329 (25 RCTs) |
Moderate | No evidence of blinding in many trials |
| 8. Laboratory phase | ||||||
|
Twisk 2006 Pre‐implantation genetic screening vs 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 RCTs) |
Low | Poor reporting of methods and serious imprecision |
|
Carney 2012 Assisted hatching vs no assisted hatching |
102 per 1000 | 136 per 1000 (112 to 162) |
OR 1.38 (1.11 to 1.7) |
3447 (14 RCTs) | Low | Methodological limitations or missing information in most trials. Inconsistency between trials (I2 = 57%) |
|
Bontekoe 2012 Embryo culture with low oxygen concentration vs atmospheric oxygen concentration |
88 per 1000 | 113 per 1000 (80 to 158) |
OR 1.33 (0.91 to 1.95) |
1382 (4 RCTs) |
Low | Poor reporting of methods and serious imprecision |
|
Siristatidis 2018 Metabolomic vs non‐metabolomic assessment |
189 per 1000 | 255 per 1000 (139 to 421) |
OR 1.52 (0.71 to 3.23) |
181 (2 RCTs) | Low | Serious risk of bias and serious imprecision |
| 9. Embryo transfer | ||||||
| 9.1. Developmental stage | ||||||
|
Glujovsky 2016 Cleavage stage transfer vs blastocyst stage transfer |
122 per 1000 | 127 per 1000 (103 to 156) | OR 1.05 (0.83 to 1.33) | 3019 (19 RCTs) | Low | Several studies did not describe acceptable methods of sequence generation and/or allocation concealment, several were at unclear or high risk of attrition bias, and none clearly had blinded outcome assessment. |
| 9.2. Number of embryos | ||||||
|
Pandian 2013 Single‐ vs double‐embryo transfer (one cycle only) |
144 per 1000 | 20 per 1000 (12 to 32) |
OR 0.12 (0.07 to 0.20) |
1612 (10 RCTs) |
High | Moderate heterogeneity attributable to 36% of women non‐compliant with treatment allocation in 1 study (I2 = 45%) |
|
Pandian 2013 Repeated single‐embryo transfer vs double‐embryo transfer |
133 per 1000 | 5 per 1000 (2 to 19) |
OR 0.03 (0.01 to 0.13) |
811 (3 RCTs) |
Moderate | Methods poorly described |
|
Pandian 2013 Double‐embryo transfer vs three embryo transfers |
91 per 1000 | 17 per 1000 (1 to 278) |
OR 0.17 (0.01 to 3.85) |
45 (1 RCT) |
Very low | Randomisation and blinding unclear; evidence based on a single trial with very serious imprecision |
|
Pandian 2013 Double‐embryo transfer vs four embryo transfers |
214 per 1000 | 107 per 1000 (27 to 349) |
OR 0.44 (0.1 to 1.97) |
56 (1 RCT) |
Very low | Randomisation, allocation concealment, and blinding unclear; evidence based on a single trial with very serious imprecision |
| 9.3. Transfer techniques | ||||||
|
Ata 2018 Seminal plasma to genital tract vs no seminal plasma |
70 per 1000 | 77 per 1000 (53 to 114) | RR 1.11 (0.76 to 1.64) | 1642 (5 RCTs) | Low | Serious imprecision, serious risk of bias: allocation concealment poorly reported or not utliised |
|
Brown 2016 Day 3 vs day 2 embryo transfer |
106 per 1000 | 118 per 1000 (91 to 152) |
OR 1.12 (0.86 to 1.44) |
1837 (8 RCTs) |
Moderate | Poor reporting of allocation concealment and blinding |
|
Bontekoe 2014 Transfer medium enriched with high level of hyaluronic acid vs medium with low level or no hyaluronic acid |
20 per 1000 | 37 per 1000 (240 to 328) |
OR 1.86 (1.49 to 2.31) |
1951 (5 RCTs) |
Moderate | All studies except 1 at high risk of bias in 1 or more domains |
|
Brown 2016a Ultrasound guidance vs clinical touch for embryo transfer |
60 per 1000 | 67 per 1000 (53 to 85) | OR 1.13 (0.87 to 1.45) | 3379 (8 RCTs) | Moderate | Poor reporting of study methods |
|
Abou‐Setta 2014 Less bed rest vs more bed rest |
73 per 1000 | 113 per 1000 (25 to 383) |
OR 1.62 (0.33 to 7.9) |
542 (2 RCTs) |
Very low | Heterogeneity (I2 > 70%) and serious imprecision with wide confidence intervals; 1 trial open |
|
Abou‐Setta 2014 Mechanical pressure on cervix vs no intervention |
121 per 1000 | 243 per 1000 (174 to 329) |
OR 2.33 (1.53 to 3.56) |
639 (1 RCT) |
Very low | Evidence based on a single trial; open‐label trial with unclear method of randomisation |
| 11. Prevention of OHSS | ||||||
|
D'Angelo 2017 Coasting vs no coasting |
268 per 1000 | 102 per 1000 (42 to 228) | OR 0.31 (0.12 to 0.81) | 139 (1 RCT) | Low | Poor reporting of methods |
|
D'Angelo 2017 Coasting vs gonadotrophin‐releasing hormone antagonist |
181 per 1000 | 156 per 1000 (79 to 284) | OR 0.84 (0.39 to 1.80) | 98 (1 RCT) | Very low | Method of sequence generation not reported, lack of blinding, serious imprecision |
|
Tang 2016 Dopamine agonist vs placebo/no intervention |
50 per 1000 | 17 per 1000 (1 to 303) |
OR 0.32 (0.01 to 8.26) |
40 (1 RCT) | Very low | Poor reporting of study methods and very serious imprecision |
| 12. Frozen embryo replacement cycles | ||||||
|
Wong 2017 Frozen vs fresh and frozen embryo transfer |
161 per 1000 | 176 per 1000 (141 to 217) |
OR 1.11 (0.85 to 1.44) |
1630 (2 RCTs) |
Low | Serious risk of bias and serious imprecision |
|
Ghobara 2017 Natural cycle FET vs hormone therapy FET |
Not estimable | Not estimable | OR 2.48 (0.09 to 68.14) | 21 (1 RCT) | Very low | Unclear risk of bias, very serious imprecision: no events in control group |
|
Ghobara 2017 Natural cycle FET vs hormone therapy plus GnRHa suppression FET |
63 per 1000 | 38 per 1000 (9 to 144) | OR 0.58 (0.13 to 2.50) | 159 (1 RCT) | Low | Very serious imprecision: single study, few events, wide confidence intervals |
|
Ghobara 2017 hMG FET vs clomiphene + hMG FET |
28 per 1000 | 39 per 1000 (9 to 157) | OR 1.41 (0.31 to 6.48) | 209 (1 RCT) | Very low | Unclear risk of bias in all domains, very serious imprecision with very few events and wide confidence intervals |
ART: assisted reproduction techniques.
CI: confidence interval.
DHEA: dehydroepiandrosterone.
FET: frozen embryo transfer.
GnRH: gonadotrophin‐releasing hormone.
GnRHa: gonadotrophin‐releasing hormone agonist.
hCG: human chorionic gonadotrophin.
hMG: human menopausal gonadotrophin.
IVF: in vitro fertilisation.
OHSS: ovarian hyperstimulation syndrome.
OR: odds ratio.
RCT: randomised controlled trial.
rFSH: recombinant follicle‐stimulating hormone.
rhCG: recombinant human chorionic gonadotrophin.
RR: risk ratio.
uhCG: urinary human chorionic gonadotrophin.
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 vs 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 RCTs) |
Low | Only 2/6 studies described adequate allocation concealment, serious imprecision |
|
Cheong 2013 Acupuncture vs 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 RCTs) |
Low | Only 1/4 studies described adequate allocation concealment, serious imprecision |
|
Siristatidis 2016 Aspirin vs placebo or no treatment |
43 per 1000 | 47 per 1000 (29 to 76) | RR 1.10 (0.68 to 1.77) |
1497 (5 RCTs) |
Low | Serious imprecision with low event rate |
|
Tso 2014 Metformin vs placebo or no treatment |
139 per 1000 | 110 per 1000 (65 to 182) |
OR 0.76 (0.43 to 1.37) |
521 (6 RCTs) |
Moderate | Serious imprecision with low event rate |
|
Nastri 2015 Endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle vs no control |
158 per 1000 | 147 per 1000 (100 to 242) |
RR 0.99 (0.63 to 1.53) |
500 (8 RCTs) |
Low | Serious imprecision and high risk of bias in included studies |
|
Benschop 2010 Aspiration of endometrioma vs expectant management |
100 per 1000 | 97 per 1000 (25 to 316) |
Peto OR 0.97 (0.23 to 4.15) |
81 (1 RCT) |
Very low | Very serious imprecision as evidence based on a single trial with wide confidence intervals that crossed the line of no effect |
|
Benschop 2010 GnRH antagonist vs GnRH agonist |
30 per 1000 | 29 per 1000 (2 to 331) |
Peto OR 0.97 (0.06 to 15.85) |
67 (1 RCT) |
Very low | Very serious imprecision as evidence based on a single trial with wide confidence intervals that crossed the line of no effect |
|
Johnson 2010 Salpingectomy vs no surgical treatment |
53 per 1000 | 46 per 1000 (17 to 117) |
OR 0.86 (0.31 to 2.38) |
329 (3 RCTs) |
Moderate | Randomisation methods not fully described. Serioius imprecision with wide confidence intervals that crossed the line of no effect |
|
Johnson 2010 Tubal occlusion vs no surgical treatment |
67 per 1000 | 60 per 1000 (6 to 399) |
OR 0.89 (0.09 to 9.28) |
65 (1 RCT) | Very low | Evidence based on a single trial. Evidence of imprecision: wide confidence intervals that crossed the line of no effect |
|
Johnson 2010 Aspiration of hydrosalpingeal fluid vs no surgical treatment |
31 per 1000 | 63 per 1000 (6 to 436) |
OR 2.07 (0.18 to 24.01) |
64 (1 RCT) | Very low | Evidence based on a single trial. Serious imprecision: wide confidence intervals that crossed the 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 (3 RCTs) |
Moderate | Studies had low or unclear risk of bias but serious imprecision |
|
Nagels 2015 DHEA vs placebo |
64 per 1000 | 38 per 1000 (19 to 74) | OR 0.58 (0.29 to 1.17) | 950 (8 RCTs) | Moderate | Serious imprecision |
|
Nagels 2015 Testosterone vs placebo |
25 per 1000 | 50 per 1000 (15 to 155) | OR 2.04 (0.58 to 7.13) | 345 (4 RCTs) | Low | Very serious imprecision |
| 3. Down‐regulation with agonists or antagonists | ||||||
|
Albuquerque 2013 GnRHa depot vs daily injection |
13 per 100 | 14 per 100 (9 to 22) |
OR 1.16 (0.7 to 1.94) |
512 (9 RCTs) | Low | Most studies classified as at unclear risk of bias for all domains. Serious imprecision as total events were fewer than 300 |
|
Al‐Inany 2016 GnRH antagonist vs long course GnRH agonist |
48 per 1000 | 49 per 1000 (40 to 61) | OR 1.03 (0.82 to 1.29) | 7082 (34 RCTs) | Moderate | Serious risk of bias |
|
Boomsma 2012 Peri‐implantation glucocorticoids vs no glucocorticoids |
57 per 1000 | 80 per 1000 (47 to 132) |
OR 1.44 (0.82 to 2.51) |
832 (7 RCTs) |
Low | Methodological limitations including lack of blinding and serious imprecision |
| 4. Ovarian stimulation | ||||||
| 4.1. Type of medication | ||||||
|
Pandian 2010 Multiple‐dose GnRH agonist vs mini‐dose long agonist protocol |
22 per 1000 | 46 per 1000 (4 to 353) |
OR 2.1 (0.18 to 23.98) |
89 (1 RCT) |
Very low | Single trial with no allocation concealment or blinding and very serious imprecision |
|
Kamath 2017 Clomiphene citrate (+/‐ urinary or recombinant gonadotrophin) vs 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 RCTs) |
Moderate | Poor reporting of methods in most trials |
|
Kamath 2017 Clomiphene citrate (+/‐ urinary or recombinant gonadotrophin) and mid cycle antagonists vs 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 RCTs) |
Moderate | Poor reporting of methods in most trials |
|
Mochtar 2017 Recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH) vs rFSH alone for controlled ovarian hyperstimulation |
70 per 1000 | 65 per 1000 (45 to 93) |
OR 0.93 (0.63 to 1.36) |
1711 (13 RCTs) |
Moderate | Serious imprecision with wide confidence intervals |
|
Martins 2013 FSH replaced by low‐dose hCG in the late follicular phase vs continued FSH for assisted reproductive techniques |
160 per 1000 | 170 per 1000 (80 to 360) |
RR 1.08 (0.50 to 2.31) |
127 (4 RCTs) |
Very low | Very serious imprecision and high risk of bias |
|
Farquhar 2017 Combined oral contraceptive pill plus antagonist vs antagonist |
270 per 1000 | 215 per 1000 (177 to 260) | OR 0.74 (0.58 to 0.95) | 1335 (6 RCTs) | Moderate | Serious risk of bias due to poor reporting of sequence generation and allocation concealment |
|
Farquhar 2017 Combined oral contraceptive pill plus antagonist vs agonist |
296 per 1000 | 273 per 1000 (212 to 345) | OR 0.89 (0.64 to 1.25) | 724 (4 RCTs) | Moderate | Serious imprecision with wide confidence intervals |
|
Farquhar 2017 Progestagen plus agonist vs agonist |
36 per 1000 | 78 per 1000 (24 to 220) | OR 2.26 (0.67 to 7.55) | 222 (2 RCTs) | Low | Very serious imprecision with wide confidence intervals |
|
Farquhar 2017 Progestagen plus antagonist vs antagonist |
208 per 1000 | 86 per 1000 (16 to 354) | OR 0.36 (0.06 to 2.09) | 47 (1 RCT) | Low | Very serious imprecision with wide confidence intervals |
|
Farquhar 2017 Oestrogen plus antagonist vs antagonist |
208 per 1000 | 40 per 1000 (5 to 279) | OR 0.16 (0.02 to 1.47) | 49 (1 RCT) | Very low | Serious risk of bias due to poor reporting; very serious imprecision with wide confidence intervals |
|
Farquhar 2017 Oestrogen plus antagonist vs agonist |
72 per 1000 | 110 per 1000 (46 to 240) | OR 1.59 (0.62 to 4.06) | 220 (1 RCT) | Very low | Serious risk of bias due to poor reporting; very serious imprecision with wide confidence intervals |
|
Kalampokas 2017 Glucocorticoid supplementation vs placebo |
Not calculable | Not calculable | OR 1.00 (0.05 to 18.57) | 20 (1 RCT) | Very low | Serious risk of bias and very serious imprecision |
| 5. Ovulation triggering | ||||||
|
Youssef 2014 GnRH agonist vs hCG |
67 per 1000 | 111 per 1000 (73 to 165) |
OR 1.74 (1.10 to 2.75) |
1198 (11 RCTs) |
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 vs urinary gonadotrophins |
50 per 1000 | 57 per 1000 (46 to 70) |
OR 1.16 (0.93 to 1.44) |
6663 (30 RCTs) |
Moderate | No evidence of blinding in many trials |
|
Youssef 2016a rhCG vs uhCG |
51 per 1000 | 37 per 1000 (21 to 63) | OR 0.72 (0.41 to 1.25) | 1347 (9 RCTs) | Low | Very serious imprecision |
|
Youssef 2016a rhLH vs uhCG |
66 per 1000 | 62 per 1000 (25 to 144) |
OR 0.94 (0.37 to 2.38) |
280 (2 RCTs) |
Low | One trial lacked adequate methodological details and had serious imprecision |
| 6. Oocyte retrieval | ||||||
|
Reavey 2016 hCG priming vs no priming |
70 per 1000 | 43 per 1000 (16 to 115) | OR 0.60 (0.21 to 1.72) | 282 (2 RCTs) | Low | Serious risk of bias and serious 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 RCT) |
Low | Serious risk of bias as study methods not reported in adequate detail. Serious imprecision as 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 vs atmospheric oxygen concentration |
75 per 1000 | 94 per 1000 (65 to 133) |
OR 1.28 (0.86 to 1.9) |
1291 (3 RCTs) |
Low | Methodological limitations and serious imprecision |
|
Carney 2012 Assisted hatching vs no assisted hatching |
45 per 1000 | 46 per 1000 (32 to 68) |
OR 1.03 (0.69 to 1.54) |
2131 (14 RCTs) | Moderate | Methodological limitations or missing information in most trials |
|
Twisk 2006 Pre‐implantation genetic screening vs 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 RCTs) |
Moderate | Most included trials lacked adequate methodological details |
|
Twisk 2006 Pre‐implantation genetic screening vs 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 RCTs) |
Very low | Open‐label studies with evidence of imprecision; heterogeneity > 60% |
|
Huang 2013 Brief co‐incubation vs standard insemination |
24 per 1000 | 47 per 1000 (9 to 217) |
OR 1.98 (0.35 to 11.09) |
167 (1 RCT) | Low | One trial only; method of randomisation or allocation concealment not stated |
|
Teixeira 2013 Regular (ICSI) vs ultra‐high magnification (IMSI) sperm selection for assisted reproduction |
220 per 1000 | 180 per 1000 (130 to 250) |
RR 0.82 (0.59 to 1.14) |
552 (6 RCTs) |
Very low | High risk of bias and very serious imprecision |
|
Armstrong 2015 TLS with or without cell‐tracking algorithms vs conventional incubation |
143 per 1000 | 105 per 1000 (73 to 143) |
OR 0.7 (0.47 to 1.04) |
994 (3 RCTs) |
Low | Overall high risk of selection, performance, attrition, and reporting bias. Largest study used donor and autologous oocytes, whereas the remaining 2 studies used autologous oocytes only. Donor oocytes were generally from young women, which may behave differently from the usual population of oocytes and embryos from couples undergoing ART |
|
Siristatidis 2018 Metabolomic vs non‐metabolomic assessment |
114 per 1000 | 109 per 1000 (61 to 184) | OR 0.96 (0.52 to 1.78) | 434 (2 RCTs) | Low | Serious risk of bias and serious imprecision |
| 9. Embryo transfer | ||||||
|
Ata 2018 Seminal plasma to genital tract vs no seminal plasma |
38 per 1000 | 38 per 1000 (21 to 67) | RR 1.01 (0.57 to 1.79) | 1209 (4 RCTs) | Low | Serious risk of bias associated with poor reporting; serious imprecision |
|
Glujovsky 2016 Cleavage stage transfer vs blastocyst stage transfer |
68 per 1000 | 78 per 1000 (68 to 119) | OR 1.15 (0.88 to 1.50) | 2917 (18 RCTs) | Low | Several studies did not describe acceptable methods of sequence generation and/or allocation concealment, several were at unclear or high risk of attrition bias, and none clearly reported blinded outcome assessment. Serious imprecision as findings were compatible with benefit in either group or with no effect |
|
Brown 2016 Day 3 vs day 2 embryo transfer |
59 per 1000 | 69 per 1000 (50 to 95) |
OR 1.16 (0.84 to 1.60) |
2153 (9 RCTs) |
Moderate | Poor reporting of allocation concealment and blinding |
|
Brown 2016a Ultrasound guidance vs clinical touch for embryo transfer |
44 per 1000 | 44 per 1000 (33 to 57) | OR 0.99 (0.74 to 1.31) | 4053 (11 RCTs) | Low | Poor reporting of study methods |
|
Derks 2009 Cervical dilatation vs no intervention |
35 per 1000 | 23 per 1000 | OR 0.64 (0.21 to 1.93) |
288 (1 RCT) |
Moderate | Serious imprecision and evidence based on a single trial |
|
Abou‐Setta 2014 Less bed rest vs more bed rest |
47 per 1000 | 75 per 1000 (38 to 143) |
OR 1.63 (0.79 to 3.35) |
542 (2 RCTs) |
Moderate | Open‐label trial |
|
Craciunas 2016 Intrauterine hCG vs no intrauterine hCG |
48 per 1000 | 52 per 1000 (40 to 68) |
RR 1.09 (0.83 to 1.43) |
3395 (7 RCTs) |
Very low | Serious risk of bias and very serious imprecision |
| 11. Prevention of ovarian hyperstimulation syndrome (OHSS) | ||||||
|
Tang 2016 Dopamine agonists vs placebo or no treatment |
72 per 1000 | 49 per 1000 (15 to 151) |
OR 0.66 (0.19 to 2.28) |
168 (2 RCTs) |
Low | Poor reporting of study methods and serious imprecision |
|
D'Angelo 2017 Coasting vs no coasting |
57 per 1000 | 49 per 1000 (15 to 148) |
OR 0.85 (0.25 to 2.86) |
207 (2 RCTs) | Very low | One study did not clearly describe the methods used; studies not blinded; serious imprecision |
| 12. Frozen embryo transfer cycles | ||||||
|
Wong 2017 Fresh vs fresh and frozen embryo transfer |
184 per 1000 | 131 per 1000 (105 to 162) |
OR 0.67 (0.52 to 0.86) |
1892 (4 RCTs) | Low | Serious risk of bias and serious imprecision |
|
Ghobara 2017 Natural cycle FET vs modified natural cycle FET (hCG trigger) |
24 per 1000 | 5 per 1000 (0 to 92) | OR 0.20 (0.01 to 4.13) | 168 (1 RCT) | Very low | Serious risk of bias as there was no allocation concealment. Very serious imprecision associated with single study, few events, and wide confidence intervals |
|
Ghobara 2017 Modified natural cycle FET (hCG trigger) vs hormone therapy + GnRHa FET |
68 per 1000 | 51 per 1000 (18 to 138) | OR 0.74 (0.25 to 2.19) | 236 (1 RCT) | Low | Unclear risk of bias in most domains, serious imprecision with wide confidence intervals |
|
Ghobara 2017 Hormone therapy FET vs hormone therapy + GnRHa FET |
48 per 1000 | 31 per 1000 (18 to 53) | OR 0.64 (0.37 to 1.12) | 991 (6 RCTs) | Low | Unclear reporting of methods, serious imprecision with wide confidence intervals |
|
Ghobara 2017 hMG FET vs clomiphene + hMG FET |
37 per 1000 | 49 per 1000 (13 to 164) | OR 1.33 (0.35 to 5.09) | 209 (1 RCT) | Very low | Unclear risk of bias in all domains, very serious imprecision with very few events and wide confidence intervals |
ART: assisted reproduction techniques.
CI: confidence interval.
DHEA: dehydroepiandrosterone.
ET: embryo transfer.
FET: frozen embryo transfer.
FSH: follicle‐stimulating hormone.
GnRH: gonadotrophin‐releasing hormone.
GnRHa: gonadotrophin‐releasing hormone agonist.
HA: hyaluronic acid.
hCG: human chorionic gonadotrophin.
hMG: human menopausal gonadotrophin.
IMSI: ultra‐high magnification sperm selection.
IVF: in vitro fertilisation.
OHSS: ovarian hyperstimulation syndrome.
OR: odds ratio.
PICSI: physiological intracytoplasmic sperm injection.
RCT: randomised controlled trial.
rFSH: recombinant follicle‐stimulating hormone.
rhCG: recombinant human chorionic gonadotrophin.
RR: risk ratio.
TLS: time‐lapse imaging.
uhCG: urinary human chorionic gonadotrophin.
Effect of interventions
For statistical evidence from the reviews for each outcome, which will indicate the extent of any benefit or harm, please see the following additional tables. These tables present odds or risk ratios and also absolute event rates per thousand in each group.
Table 4: live birth or live birth/ongoing pregnancy (composite outcome) per woman (data from 52 reviews).
Table 5: clinical pregnancy per woman (data from 63 reviews).
Table 6: ovarian hyperstimulation syndrome per woman (data from 23 reviews).
Table 7: multiple pregnancy per woman (data from 32 reviews).
Table 8: miscarriage per woman (data from 41 reviews).
Summary of review findings for each stage of the ART pathway
1. Indication for ART
We identified three reviews.
Pandian 2015: "In vitro fertilisation for unexplained subfertility" (ZP672).
Yossry 2006: "In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation" (AMY731).
Siristatidis 2009: "In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction" (CS1400).
Pandian 2015 reported that IVF may be associated with higher rates of live birth and clinical pregnancy than expectant management (very low‐quality evidence), but evidence is insufficient to permit firm conclusions. IVF may also be associated with higher live birth rates than unstimulated intrauterine insemination (IUI) (low‐quality evidence). In women pre‐treated with clomiphene + IUI, IVF appears to be associated with higher live birth rates than IUI + gonadotropins (moderate‐quality evidence). However in women who were treatment‐naive, evidence was insufficient to show whether there is a difference in rates of live birth or clinical pregnancy between IVF and IUI + gonadotropins, or between IVF and IUI + clomiphene (moderate‐quality evidence). We could not adequately assess adverse events associated with these interventions owing to lack of evidence.
Neither Yossry 2006 nor Siristatidis 2009 identified any randomised controlled trial evidence to address their review questions.
2. Pre‐ART and adjuvant strategies
2.1. Strategies for unselected populations
We identified nine reviews.
Anderson 2010: "Preconception lifestyle advice for people with subfertility" (KA992).
Nastri 2015: "Endometrial injury in women undergoing assisted reproductive techniques" (WM1504).
Showell 2014: "Antioxidants for male subfertility" (MGS1510).
Showell 2017: "Antioxidants for female subfertility" (MGS1630).
Duffy 2010: "Growth hormone for in vitro fertilisation" (KH291).
Siristatidis 2016: "Aspirin for in vitro fertilisation" (VJP951).
Cheong 2013: "Acupuncture and assisted reproductive technology" (IRS911).
Gutarra‐Vilchez 2014: "Vasodilators for women undergoing fertility treatment" (RBG1760).
Nagels 2015: "Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction" (HEN1730).
2.1.1. Lifestyle advice
Anderson 2010 identified a single trial that compared smoking cessation advice versus standard clinical advice for women attending an infertility clinic. Live birth was not reported as an outcome. Review authors identified no evidence regarding the effect of pre‐conception advice on the chance of a live birth outcome.
2.1.2. Surgical therapy
Endometrial injury
Nastri 2015 reported moderate‐quality evidence showing that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle was associated with improvement in live birth or ongoing pregnancy rates and in clinical pregnancy rates among women with more than two previous embryo transfers. Evidence was insufficient to show whether there was a difference in rates of multiple pregnancy (very low‐quality evidence), miscarriage (low‐quality evidence), or bleeding. Evidence suggested that endometrial injury on the day of oocyte retrieval was associated with lower clinical and ongoing pregnancy rates (low‐quality evidence).
2.1.3. Medical therapy
Antioxidants
Showell 2014 included three randomised controlled trials (RCTs) with 111 male partners of women undergoing ART, two of which reported live birth and pregnancy rates in this subgroup. The evidence suggested that antioxidant supplementation in subfertile males may improve live birth rates (low‐quality evidence), but there was no clear evidence of a difference in clinical pregnancy rates (low‐quality evidence).
Showell 2017 included 27 RCTs of over 3000 women undergoing ART. Evidence was insufficient to show whether antioxidant supplementation was of benefit with regard to birth rate (very low‐quality evidence), and review authors found no clear evidence of a difference with regard to clinical pregnancy rates (very low‐quality evidence).
Growth hormone
Duffy 2010 reported no evidence of overall benefit in fertility outcomes for growth hormone compared with placebo during an IVF protocol (moderate‐quality evidence). A subgroup of women who were considered to be 'poor responders' showed an increase in rates of live birth (moderate‐quality evidence) and clinical pregnancy (high‐quality evidence) in favour of adjuvant growth hormone compared with placebo. Results were based on a small number of trials with relatively small sample sizes, and the review authors recommend that the evidence should be interpreted with caution.
Androgens
Nagels 2015 concluded that in women identified as poor responders undergoing ART, pre‐treatment with dehydroepiandrosterone (DHEA) or testosterone may be associated with improved rates of live birth or ongoing pregnancy (moderate‐quality evidence). Evidence was insufficient to permit conclusions about the safety of either androgen.
Aspirin
Siristatidis 2016 found no evidence in favour of routine use of aspirin to improve clinical pregnancy rates for a general IVF population (moderate‐quality evidence).
Vasodilators
Gutarra‐Vilchez 2014 found insufficient evidence to show whether vasodilators influenced the live birth rate in women undergoing fertility treatment (moderate‐quality evidence). However, low‐quality evidence suggests that vasodilators may increase clinical pregnancy rates in comparison with placebo or no treatment. Data were insufficient to support any conclusions regarding adverse effects.
2.1.4. Alternative therapy
Acupuncture
Cheong 2013 reported that evidence was insufficient to show the effect of acupuncture on live birth rate, regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer (low‐quality evidence). No evidence suggested that acupuncture had any effect on rates of pregnancy (low‐ to very low‐quality evidence) or miscarriage (low‐quality evidence), nor that acupuncture led to significant side effects.
2.2. Strategies for selected populations
We identified four reviews.
Johnson 2010: "Surgical treatment for tubal disease in women due to undergo in vitro fertilisation" (NJ472).
Benschop 2010: "Interventions for women with endometrioma prior to assisted reproductive technology" (SG1241).
Tso 2014: "Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome" (LDT1201).
McDonnell 2014: "Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility" (SH1141).
2.2.1. Tubal pathology
Johnson 2010 found that both laparoscopic salpingectomy and tubal occlusion before IVF increased the chances of clinical pregnancy (moderate‐quality evidence). Review authors concluded that surgical treatment should be considered for all women with hydrosalpinges before IVF treatment. Previous evidence supported only unilateral salpingectomy for a unilateral hydrosalpinx (bilateral salpingectomy for bilateral hydrosalpinges). Johnson 2010 suggested laparoscopic tubal occlusion as an alternative to laparoscopic salpingectomy for improving pregnancy rates among women with hydrosalpinges undergoing IVF. Evidence was insufficient to allow assessment of the value of aspiration of hydrosalpinges before or during IVF procedures (very low‐quality evidence) or the value of tubal restorative surgery as an alternative (or as a preliminary) to IVF.
2.2.2. Endometriosis
Benschop 2010 reported that evidence was insufficient to show whether there was a difference in clinical pregnancy rates among those given gonadotropin‐releasing hormone (GnRH) agonists and antagonists for endometrioma before ART (low‐quality evidence), or whether there was a difference in clinical pregnancy outcomes between surgery (cystectomy or aspiration) before ART and expectant management (low‐quality evidence), or between pre‐ART ablation and cystectomy in women with endometrioma (very low‐quality evidence).
2.2.3. Polycystic ovary syndrome (PCOS)
Tso 2014 found no clear evidence that metformin treatment before or during ART cycles improved live birth rates among women with PCOS (low‐quality evidence). However, use of this insulin‐sensitising agent increased clinical pregnancy rates (moderate‐quality evidence) and decreased the risk of ovarian hyperstimulation syndrome (OHSS) (moderate‐quality evidence).
2.2.4. Ovarian cysts
McDonnell 2014 found insufficient evidence to determine whether drainage of functional ovarian cysts before controlled ovarian hyperstimulation (COH) influenced clinical pregnancy rates (very low‐quality evidence). None of the studies reported live birth. The review authors concluded that there was no supportive evidence for cyst drainage, in view of the requirement for anaesthesia, extra costs, psychological stress, and risk of surgical complications.
3. Down‐regulation with agonists or antagonists
We identified four reviews for inclusion.
Sallam 2006: "Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis" (HNS881).
Albuquerque 2013: "Depot versus daily administration of gonadotrophin‐releasing hormone agonist protocols for pituitary down regulation in assisted reproduction cycles" (LA541).
Al‐Inany 2016: "Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology" (HA412).
Siristatidis 2015: "Gonadotrophin‐releasing hormone agonist protocols for pituitary suppression in assisted reproductive treatment" (SD265).
Sallam 2006 reported that the live birth rate per woman was higher among women receiving the GnRH agonist (GnRHa) than among those given the control intervention. Administration of GnRHa for a period of three to six months before IVF or ICSI in women with endometriosis increased the odds of clinical pregnancy (very low‐quality evidence). This evidence was of very low quality, and the review is being updated.
Albuquerque 2013 found insufficient evidence to determine whether there was a difference in rates of live birth (low‐quality evidence) or clinical pregnancy (moderate‐quality evidence) or OHSS (low‐quality evidence) between depot and daily GnRHa use for pituitary down‐regulation in IVF cycles using the long protocol, but substantial differences could not be ruled out. Given that depot GnRHa requires more gonadotrophins and a longer duration of use, this approach may increase the overall costs of IVF treatment.
Al‐Inany 2016 reported that use of GnRH antagonist compared with long‐course GnRHa protocols was associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth (moderate‐quality evidence).
Siristatidis 2015 compared long GnRHa protocols and short GnRHa protocols and found no clear evidence of a difference in live birth and ongoing pregnancy rates (low‐quality evidence) but provided moderate‐quality evidence showing higher clinical pregnancy rates in the long protocol group. Evidence was insufficient to show whether there was a difference in birth or pregnancy outcomes between any of the other compared protocols (low‐ or very low‐quality evidence).
4. Ovarian stimulation
We identified 11 reviews.
Kamath 2017: "Clomiphene citrate for controlled ovarian stimulation in women undergoing IVF" (AM1335).
Pouwer 2015: "Long‐acting FSH versus daily FSH for women undergoing assisted reproduction" (AWP1710).
Mochtar 2017: "Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles" (MHM931).
van Wely 2011: "Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles" (IOK973).
Martins 2013: "FSH replaced by low‐dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques" (WPM1780).
Farquhar 2017: "Oral contraceptive pill, progestogen or oestrogen pre‐treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques" (DHH752).
Kwan 2014: "Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI)" (IOK972).
Pandian 2010: "Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in‐vitro fertilisation (IVF)" (RSS791).
Allersma 2013: "Natural cycle IVF for subfertile couples" (TA1860).
Kalampokas 2017: "Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI" (BKT841).
Lensen 2018: "Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)" (SL1977).
4.1. Medication type
Kamath 2017 found insufficient evidence to determine whether clomiphene citrate or letrozole with or without gonadotrophins differed from gonadotrophins in GnRH agonist or antagonist protocols with respect to their effects on live birth (low‐quality evidence) or pregnancy rates (low‐ to moderate‐quality evidence), either in the general population of women undergoing IVF treatment or among women who were poor responders. Use of clomiphene or letrozole led to a reduction in the quantity of gonadotrophins required and the incidence of OHSS (low‐quality evidence). However, use of clomiphene citrate or letrozole appeared to be associated with an increase in the incidence of cycle cancellations, as well as with reductions in the mean number of oocytes retrieved in both the general IVF population and among poor responders.
Pouwer 2015 compared long‐acting versus daily follicle‐stimulating hormone (FSH) and reported no clear evidence of a difference between groups in live birth rates or OHSS (moderate‐quality evidence). A subgroup analysis of doses of long‐acting FSH yielded evidence of reduced live birth rate among women who received lower doses (60 to 120 μg) of long‐acting FSH compared with daily FSH (moderate‐ quality evidence). Evidence was insufficient to show whether there was a difference in live birth rates in medium‐dose (moderate‐quality evidence) or high‐dose (very low‐quality evidence) subgroups, or an effect on any of the other fertility outcomes examined. A medium dose of long‐acting FSH appeared to be a safe treatment option and seemed as effective as daily FSH. The review authors indicated that further research is needed to determine whether long‐acting FSH is safe and effective for use in hyper‐responders or poor responders and in women with all causes of subfertility.
Mochtar 2017 found no clear evidence of a difference between recombinant luteinising hormone (rLH) combined with recombinant follicle‐stimulating hormone (rFSH) and rFSH alone in rates of live birth (very low‐quality evidence) or OHSS (low‐quality evidence), but evidence suggested that use of rLH combined with rFSH may lead to more clinical pregnancies than use of rFSH alone (moderate‐quality evidence). Results show little or no difference between groups in rates of miscarriage (moderate‐quality evidence). The review authors concluded that the evidence was insufficient to encourage or discourage stimulation regimens that include rLH combined with rFSH in IVF/ICSI cycles.
van Wely 2011 reported insufficient evidence to show whether there was a difference in live birth rates (high‐quality evidence) or in clinical pregnancy rates (moderate‐quality evidence) when rFSH was compared with any of the other gonadotrophins, irrespective of the down‐regulation protocol used. The gonadotrophins compared appeared to be equally effective. The review authors concluded that the clinical choice of gonadotrophin should depend on availability, convenience, and cost, and that turther research on these comparisons was unlikely to identify substantive differences in effectiveness or safety.
Martins 2013 concluded that the effect on live birth of using low‐dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART compared with conventional COH was very uncertain (very low‐quality evidence). Evidence suggested that this intervention did not influence the chance of clinical pregnancy (low‐quality evidence), and that it was likely to result in an equivalent number of oocytes retrieved, with less FSH expended. The review authors suggested that more studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.
Farquhar 2017 found that among women undergoing ovarian stimulation in antagonist protocols, pre‐treatment with the combined oral contraceptive pill (COCP) was associated with a lower rate of live birth or ongoing pregnancy than no pre‐treatment (moderate‐quality evidence). Evidence was insufficient to show whether rates of live birth or ongoing pregnancy were influenced by pre‐treatment with progestogens or oestrogens (low‐ to moderate‐quality evidence), or by COCP pre‐treatment using other stimulation protocols (low‐quality evidence). Findings on adverse events were inconclusive, except that progesterone pre‐treatment may reduce the risk of ovarian cysts in agonist cycles, and COCP in antagonist cycles may reduce the risk of pregnancy loss compared with no pre‐treatment in agonist cycles.
Kalampokas 2017 concluded that the safety and effectiveness of glucocorticoid administration in women undergoing controlled ovarian hyperstimulation for IVF/ICSI cycle glucocorticoids were unclear owing to lack of data. Glucocorticoids may increase clinical pregnancy rates but may have little or no impact on live birth rates (low‐quality evidence).
Lensen 2018 found no conclusive evidence to show that tailoring the FSH dose in any particular ovarian reserve test (ORT) population influenced rates of live birth/ongoing pregnancy (low‐quality evidence). In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS (very low‐quality evidence). ORT‐based individualisation was associated with live birth/ongoing pregnancy rates similar to a policy of giving all women 150 IU (moderate‐quality evidence). ORT algorithms reduced the incidence of OHSS compared with standard dosing of 150 IU, but the size of the effect was unclear (low‐quality evidence).
4.2. Monitoring
Kwan 2014 found no evidence to suggest that combined monitoring of ovarian stimulation by ultrasound plus serum oestradiol was more efficacious than ultrasound alone, with regard to clinical pregnancy rates and incidence of OHSS (low‐quality evidence).
4.3. Interventions for poor responders
Pandian 2010 summarised the evidence from 10 RCTs and suggested that evidence is insufficient to support the routine use of any one particular intervention for the treatment of women who are 'poor responders'. Only one of the trials reported on live birth (low‐ to very low‐quality evidence).
4.4. Natural cycle IVF
Allersma 2013 found no clear evidence of a difference between natural cycle and standard IVF in subfertile couples with regard to rates of live birth (very low‐quality evidence), OHSS (very low‐quality evidence), clinical pregnancy (low‐quality evidence), multiple pregnancy (very low‐quality evidence), or other outcomes (ongoing pregnancy, number of oocytes retrieved, number of cycles needed to conceive, cumulative pregnancy, cycle cancellation, gestational abnormalities, cancellation of treatment due to patient motivation, or adverse effects).
5. Ovulation triggering
We identified two reviews that reported on ovulation triggering.
Youssef 2014: "Gonadotropin‐releasing hormone agonist versus hCG for oocyte triggering in antagonist assisted reproductive technology" (MM1690).
Youssef 2016a: "Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles" (HA413).
Youssef 2014 reported evidence of lower live birth rate (moderate‐quality evidence), reduced ongoing pregnancy rate (low‐quality evidence), and higher miscarriage rate (moderate‐quality evidence) in women who received a GnRH agonist for final oocyte maturation triggering compared with women given hCG in fresh autologous cycles (women's own eggs). However, the incidence of OHSS was lower in the GnRH agonist group (moderate‐quality evidence).
Youssef 2016a found no clear evidence of a difference between recombinant human chorionic gonadotrophin (rhCG) and urinary human chorionic gonadotrophin (uhCG), or between recombinant human luteinising hormone (rhLH) and uhCG, with respect to rates of live birth or ongoing pregnancy (moderate‐quality evidence), clinical pregnancy (moderate‐quality evidence), OHSS (low‐quality evidence), or miscarriage (low‐quality evidence).
6. Oocyte retrieval
We identified three reviews.
Reavey 2016: "Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation" (IG1250).
Kwan 2018: "Pain relief for women undergoing oocyte retrieval for assisted reproduction" (IOK971).
Georgiou 2018: "Follicular flushing during oocyte retrieval in assisted reproductive techniques" (SW811).
Reavey 2016 found insufficient evidence to determine whether hCG priming had an effect on rates of live birth (low‐quality evidence) or miscarriage (low‐quality evidence) in oocyte maturation in vivo (IVM). Evidence suggested that hCG priming might reduce clinical pregnancy rates (low‐quality evidence), but these findings were limited by the small quantity of data included.
Kwan 2018 compared a variety of head‐to‐head and placebo‐controlled interventions for conscious sedation. The study reporting live birth described a higher birth rate following conscious sedation plus electroacupuncture plus paracervical block compared with conscious sedation plus paracervical block (low‐quality evidence). There was no evidence of a difference in clinical pregnancy rate for the same comparison. Simultaneous use of sedation combined with analgesia such as the opiates, further enhanced by paracervical block or acupuncture techniques, resulted in better pain relief than occurred with one modality alone. The review did not support one particular method or technique over another for providing effective conscious sedation and analgesia for pain relief during and after oocyte recovery (low‐ or very low‐quality evidence for most comparisons).
Georgiou 2018 reported that follicular flushing probably has little or no effect on live birth rates or clinical pregnancy rates compared with aspiration alone. Evidence was insufficient to permit any firm conclusions with regard to adverse events or safety.
7. Sperm retrieval
We identified two reviews.
Proctor 2008: "Techniques for surgical retrieval of sperm prior to intra‐cytoplasmic sperm injection (ICSI) for azoospermia" (AMVP611).
McDowell 2014: "Advanced sperm selection techniques for assisted reproduction" (SMD1810).
Proctor 2008 reported evidence based on a single trial. The review authors concluded that the evidence was insufficient to allow recommendations on any specific sperm retrieval technique for azo‐ospermic men undergoing ICSI. The single trial provided some evidence that microsurgical epididymal sperm aspiration (MESA) was associated with a lower pregnancy rate than the micropuncture with perivascular nerve stimulation technique (low‐quality evidence).
McDowell 2014 reported that evidence was insufficient to show whether sperm selected by hyaluronic acid binding improves rates of live birth or clinical pregnancy (low‐quality evidence), or whether there is a difference in efficacy between the hyaluronic acid binding methods SpermSlow and PICSI (physiological intracytoplasmic sperm injection). Review authors found no randomised evidence evaluating sperm selection by sperm apoptosis, sperm birefringence, or surface charge.
8. Laboratory phase
We identified 10 reviews.
Carney 2012: "Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI))" (MWS391).
Glujovsky 2014: "Vitrification versus slow freezing for women undergoing oocyte cryopreservation" (DG1352).
Van Rumste 2003: "Intra‐cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in couples with non‐male subfertility" (MVR461).
Bontekoe 2012: "Low oxygen concentrations for embryo culture in assisted reproductive technologies" (SB1283).
Twisk 2006; "Preimplanation genetic screening for abnormal numbers of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection" (SMA991).
Huang 2013: "Brief co‐incubation of sperm and oocytes for in vitro fertilization techniques" (ZH1093).
Teixeira 2013: "Regular (ICSI) versus ultra‐high magnification (IMSI) sperm selection for assisted reproduction" (WPM1800).
Armstrong 2015: "Time‐lapse systems for embryo incubation and assessment in assisted reproduction" (SCA1950).
Youssef 2015: "Culture media for human pre‐implantation embryos in assisted reproductive technology cycles" (MM1610).
Siristatidis 2018: "Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies" (CS1968).
Carney 2012 found no evidence of an influence on live birth rates from assisted hatching compared with no assisted hatching (moderate‐quality evidence). Although assisted hatching (AH) appeared to offer an increased chance of achieving a clinical pregnancy, the finding only just reached statistical significance (moderate‐quality evidence). The included trials provided insufficient data to show the impact of AH on several important outcomes, and most trials failed to report live birth rates. Miscarriage rates per woman were similar in both groups (moderate‐quality evidence), but multiple pregnancy rates were increased in the AH groups (low‐quality evidence).
Glujovsky 2014 found that vitrification probably increased clinical pregnancy rates compared with slow freezing (moderate‐quality evidence). However the total number of women and of pregnancies was low. No data were available on live birth or adverse events.
Van Rumste 2003 reported that neither live birth nor miscarriage rates or other adverse events were reported in the single trial in their review. Evidence was insufficient to show whether there was a difference in clinical pregnancy rates between ICSI and IVF (low‐quality evidence).
Bontekoe 2012 reported an increase in live birth rates associated with embryo culture using low oxygen concentrations (˜5%) compared with atmospheric oxygen concentrations (˜20%) (moderate‐quality evidence). This equated to an increase from a 30% success rate to 32% to 42% success with low oxygen concentrations. Similar results were reported for ongoing and clinical pregnancy rates. Review authors found no clear evidence of an increase in adverse events (multiple pregnancy or miscarriage (low‐quality evidence)) associated with embryo culture with low oxygen concentrations.
Twisk 2006 reported that live birth rates were lower following IVF or ICSI with pre‐implantation genetic screening with fluorescent in situ hybridisation compared with no pre‐implantation genetic screening, both in women with advanced age (moderate‐quality evidence) and in those with repeated IVF failure (very low‐quality evidence). For women with a good prognosis, no clear evidence suggested a difference between intervention and control groups (very low‐quality evidence). Until further research findings are available for newer techniques in pre‐implantation genetic screening, the review authors do not recommend the routine offer of screening to couples undergoing IVF or ICSI.
Huang 2013 reported that brief co‐incubation of sperm and oocytes may improve ongoing pregnancy and clinical pregnancy rates for infertile women undergoing IVF cycles, although more RCTs are required (low‐quality evidence).
Teixeira 2013 reported that evidence was insufficient to show whether there was a difference between regular (ICSI) and ultra‐high magnification sperm selection (IMSI) with respect to rates of live birth (low‐quality evidence) and miscarriage (very low‐quality evidence), and evidence suggesting that IMSI improved clinical pregnancy was of very low quality. There was no indication that IMSI increased congenital abnormalities.
Armstrong 2015 reported that evidence of any difference in rates of live birth (moderate‐quality evidence), miscarriage (low‐quality evidence), or stillbirth or clinical pregnancy (low‐quality evidence) is insufficient to guide selection of time‐lapse systems and conventional incubation.
Youssef 2015 concluded that evidence was insufficient to support or refute the use of any specific culture medium (very low‐quality evidence). Properly designed and executed randomised trials are necessary.
Siristatidis 2018 concluded that evidence was insufficient to show whether metabolomic assessment of embryos before implantation had any meaningful effect on rates of live birth, ongoing pregnancy, or miscarriage. All evidence was of low quality.
9. Embryo transfer
We identified 10 reviews that looked at embryo transfer.
Glujovsky 2016: "Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology" (DB551).
Brown 2016: "Day three versus day two embryo transfer following in vitro fertilisation or intracytoplasmic sperm injection" (CO226).
Pandian 2013: "Number of embryos for transfer following in vitro fertilisation or intra cytoplasmic sperm injection" (ZP661).
Ata 2018: "Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer)" (BA1920).
Bontekoe 2014: "Adherence compounds in embryo transfer media for assisted reproductive technologies" (DB552).
Derks 2009: "Techniques for preparation prior to embryo transfer" (SV602).
Kroon 2012: "Antibiotics prior to embryo transfer in ART" (EN1382).
Brown 2016a: "Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women" (JB604).
Abou‐Setta 2014: "Post‐embryo transfer interventions for assisted reproduction technology cycles" (AAS605).
Craciunas 2016: "Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction" (LC1966).
9.1. Developmental stage
Glujovsky 2016 reported that fresh blastocyst stage transfer was associated with higher rates of live birth (low‐quality evidence) and clinical pregnancy (moderate‐quality evidence) than were seen with fresh cleavage stage transfer, but blastocyst transfer was also associated with a reduction in the number of embryos transferred and in the number for embryo freezing. Evidence was insufficient to show whether there was a difference between groups in cumulative pregnancy rates derived from fresh and frozen‐thawed cycles following a single oocyte retrieval, but the evidence for this outcome was of very low quality. Thus, although benefit favours blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts cumulative live birth and pregnancy rates.
9.2. Number of embryos
Pandian 2013 found that in a single assisted reproduction cycle, the live birth rate was lower following single embryo transfer than after double embryo transfer (high‐quality evidence). Elective single embryo transfer resulted in fewer multiple pregnancies than double embryo transfer (high‐quality evidence). Although pregnancy and live birth rates per fresh IVF cycle were lower, the cumulative live birth rate associated with single embryo transfer followed by a single frozen and thawed embryo transfer was comparable with that after one cycle of double embryo transfer (low‐quality evidence).
9.3. Transfer techniques and procedures
Ata 2018 found insufficient evidence to show whether there was a difference between seminal plasma and standard ART groups in rates of live birth (low‐quality evidence) or miscarriage (low‐quality evidence). Low‐quality evidence suggested that seminal plasma application may be associated with more clinical pregnancies than standard ART, and low‐quality evidence suggested little or no difference between groups in rates of multiple pregnancy. Evidence was insufficient to permit any conclusions about the risk of ectopic pregnancy, and no data were available on infectious complications or other adverse events. The review authors concluded that seminal plasma application is worth further investigation, with focus on live birth and miscarriage rates.
Bontekoe 2014 reported on the use of adherence compounds in embryo transfer media. They found evidence of improved rates of live birth (moderate‐quality evidence) and pregnancy with use of functional concentrations of hyaluronic acid, along with an increase in multiple pregnancy rates (moderate‐quality evidence). The review authors suggested that the increased multiple pregnancy rate might be the result of use of an adherence compound together with a policy of transferring more than one embryo.
Derks 2009 reported on a variety of techniques that could be used at the time of embryo transfer. Few studies reported live birth, but moderate‐quality evidence showed that cervical dilatation was associated with a lower live birth rate than no intervention. Evidence was insufficient to show whether straightening the endocervical angle, having a full bladder, removing cervical mucus, or flushing the endometrial or endocervical cavity at the time of embryo transfer had an effect on fertility outcomes (low‐ to moderate‐quality evidence). Review authors identified no trials for dummy transfer, change of position during transfer, use of a tenaculum, or embryo afterloading.
Kroon 2012 noted that although upper genital tract microbial contamination may have been reduced by the use of antibiotics, no clear evidence indicated that the use of amoxicillin plus clavulanic acid influenced the clinical pregnancy rate compared with use of no antibiotics (moderate‐quality evidence). Live births were not reported.
Brown 2016 reported very low‐quality evidence suggesting no difference between day three and day two embryo transfer for live birth, ongoing pregnancy, or clinical pregnancy. Moreover, review authors found no clear evidence of a difference for other outcomes, including multiple pregnancy (moderate‐quality evidence) and miscarriage (moderate‐quality evidence).
Brown 2016a reported that the evidence suggests that ultrasound guidance improves rates of live birth (low‐quality evidence) and clinical pregnancy (moderate‐quality evidence) compared with clinical touch, without increasing the chance of multiple pregnancy (moderate‐quality evidence), ectopic pregnancy, or miscarriage (low‐quality evidence).
Abou‐Setta 2014 concluded that evidence was insufficient to support a certain amount of time for women to remain recumbent following ET (moderate‐quality evidence), or to support the use of fibrin sealants (low‐quality evidence). Review authors found limited evidence to support the use of mechanical closure of the cervical canal following embryo transfer (very low‐quality evidence).
Craciunas 2016 concluded that live birth and pregnancy outcomes for cleavage‐stage embryo transfer with an intra‐cavity human chorionic gonadotropin (IC‐hCG) dose of 500 international units or greater were promising (moderate‐quality evidence). However this finding was derived from a subgroup analysis. The review authors found no evidence that miscarriage was influenced by intrauterine hCG administration, irrespective of embryo stage at transfer or dose of IC‐hCG (very low‐quality evidence), and events were too few to allow any conclusions with regard to other complications.
9.4 Interventions for recurrent implantation failure
No reviews have yet been published on this topic. One (Nastri 2013) is at protocol stage.
10. Luteal phase support
We identified three reviews.
van der Linden 2015: "Luteal phase support in ART cycles" (MV263).
Boomsma 2012: "Peri‐implantation glucocorticoid administration for assisted reproductive technology cycles" (CMB126).
Akhtar 2013: "Heparin for assisted reproduction" (MA1441).
van der Linden 2015 reported that progesterone appeared to be the best method of providing luteal phase support, as it was associated with higher rates of live birth or ongoing pregnancy and of clinical pregnancy than placebo (low‐quality evidence) and lower rates of OHSS than hCG. Moreover, addition of one or more doses of GnRH agonists to progesterone was associated with higher live birth and ongoing pregnancy rates than progesterone alone (low‐quality evidence). Overall, addition of other substances such as oestrogen or hCG did not seem to improve outcomes. The route of progesterone administration did not seem to matter (low‐quality evidence for most comparisons).
Boomsma 2012 reported no overall differences between peri‐implantation glucocorticoids and no glucocorticoids for rates of live birth (low‐quality evidence) or clinical pregnancy (moderate‐quality evidence). However, a subgroup analysis indicated that for couples undergoing IVF, evidence suggested a higher clinical pregnancy rate for peri‐implantation glucocorticoids than for no glucocorticoids. This difference was not observed in couples undergoing ICSI. The review authors urged caution in extrapolating conclusions from this subgroup analysis.
Akhtar 2013 reported that peri‐implantation low molecular weight heparin in ART cycles may improve rates of live birth (very low‐quality evidence) and clinical pregnancy (low‐quality evidence). Side effects were reported with the use of heparin, and no reliable data on long‐term effects were available. The review authors concluded that their results do not justify use of heparin outside of well‐conducted research trials.
11. Prevention of ovarian hyperstimulation syndrome (OHSS)
We identified four reviews that examined prevention of OHSS.
[See also Al‐Inany 2016: "Gonadotrophin‐releasing hormone (GnRH) antagonists for ART" in Section 3; and Youssef 2014: "GnRHa versus hCG for oocyte triggering in antagonist ART cycles" in Section 5.]
Tang 2016: "Dopamine agonists for preventing ovarian hyperstimulation syndrome" (TH1338).
D'Angelo 2007: "Embryo freezing for preventing ovarian hyperstimulation syndrome" (ADA561).
D'Angelo 2017: "Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome" (ADA563).
Youssef 2016: "Volume expanders for the prevention of ovarian hyperstimulation syndrome" (PMA481).
Tang 2016 reported that dopamine agonists seemed effective for prevention of moderate or severe OHSS in women at high risk of OHSS (low‐quality evidence). Review authors found no clear evidence of a difference in rates of live birth (low‐quality evidence), clinical pregnancy (moderate‐quality evidence), multiple pregnancy (very low‐quality evidence), or miscarriage (low‐quality evidence). However, dopamine agonists might increase the risk of adverse events, such as gastrointestinal symptoms.
D'Angelo 2007 identified only two randomised trials. The review authors concluded that the evidence was insufficient to support routine cryopreservation and the relative merits of intravenous albumin versus cryopreservation in the reduction of OHSS (very low‐quality evidence). Evidence was insufficient to show whether there was a difference in rates of live birth or clinical pregnancy (low‐quality evidence).
D'Angelo 2017 found very low‐quality evidence to suggest that coasting reduced rates of moderate or severe OHSS more than no coasting. Review authors found no evidence to suggest that coasting was more beneficial than other interventions (early unilateral follicular aspiration, GnRH antagonist, FSH co‐trigger, cabergoline), except that very low‐quality evidence from a single small study suggested that using FSH co‐trigger at the time of hCG administration may be better for reducing the risk of OHSS than coasting. Data were too few to show clearly whether there was a difference between groups for any other outcomes (low‐quality evidence).
Youssef 2016 reported that the plasma expanders assessed (human albumin, hydroxyethyl starch (HES), and mannitol) reduced rates of moderate and severe OHSS for women at high risk. Review authors provided no data on live birth but reported evidence that human albumin reduces clinical pregnancy rates (moderate‐quality evidence). Although there was no evidence that HES or mannitol had any influence on pregnancy rates, information on effectiveness was based on low‐ or very low‐quality evidence from very few trials, which needs to be confirmed in additional, larger RCTs.
12. Frozen embryo replacement cycles
We identified three reviews that examined frozen cycles.
Wong 2017: "Fresh versus frozen embryo transfers in assisted reproduction" (KMW1790).
Ghobara 2017: "Cycle regimens for frozen‐thawed embryo transfer (FET)" (TG691).
Glujovsky 2010: "Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes" (DG1351).
Wong 2017 compared a freeze‐all strategy for embryo transfer versus a conventional strategy with transfer of fresh and subsequent frozen‐thawed embryos, and found that neither strategy was superior to the other in terms of cumulative live birth rates (moderate‐quality evidence). Evidence suggested that not performing a fresh transfer lowers risk for women at risk of OHSS.
Ghobara 2017 did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for frozen‐thawed embryo transfer (FET) in women with regular ovulatory cycles (low‐ or very low‐quality evidence for live birth).
Glujovsky 2010 reported insufficient evidence to show whether one particular intervention for endometrial preparation clearly improves the treatment outcome for women receiving embryo transfers with either frozen embryos or embryos derived from donated oocytes. However, the review authors found evidence of a lower pregnancy rate and a higher cycle cancellation rate when progesterone supplementation was commenced before oocyte retrieval in oocyte donation cycles (moderate‐quality evidence). Adequately powered studies are needed to evaluate each treatment more accurately.
Discussion
Summary of main results
We have summarised the main results of the included reviews by categorising their findings in the following framework.
Effective interventions: indicating that the review found evidence of effectiveness (or improved safety) for an intervention.
Promising interventions (more evidence needed): indicating that the review found some evidence of effectiveness (or improved safety) for an intervention, but more evidence is needed.
Ineffective interventions: indicating that the review found evidence of lack of effectiveness (or reduced safety) for an intervention.
Possibly ineffective interventions (more evidence needed): indicating that the review found evidence suggesting lack of effectiveness (or reduced safety) for an intervention, but more evidence is needed.
No conclusions possible due to lack of evidence: indicating that the review found insufficient evidence to comment on the effectiveness or safety of an intervention.
The choice of category reflected the conclusions of the authors of the individual reviews, in the judgement of the overview authors. There were no disagreements between the overview authors.
1. Indication for assisted reproductive technology (ART)
Promising interventions (more evidence needed)
In women with unexplained subfertility, evidence suggests that in vitro fertilisation (IVF) may be associated with higher live birth rates than unstimulated intrauterine insemination (IUI) (low‐quality evidence), and in women pre‐treated with clomiphene + IUI, IVF appeared to be associated with higher birth rates than IUI + gonadotropins (moderate‐quality evidence) (Pandian 2015)
No conclusions possible due to lack of evidence
In women with unexplained subfertility, there was no conclusive evidence of a difference in live birth rates between IVF and expectant management (very low‐quality evidence), and in those who were treatment‐naive, there was insufficient evidence to determine whether there was a difference in live birth rates between IVF and IUI + gonadotropins or between IVF and IUI + clomiphene (moderate‐quality evidence) (Pandian 2015)
IVF versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation: no randomised controlled trials (RCTs) found (Yossry 2006)
In vitro maturation in subfertile women with polycystic ovarian syndrome (PCOS) undergoing assisted reproduction: no RCTs found (Siristatidis 2009)
2. Pre‐ART and adjuvant strategies
Effective interventions
Endometrial injury in women undergoing ART procedures: endometrial injury performed in the month before ovulation induction for ART appeared to increase both the live birth or ongoing pregnancy rate and the clinical pregnancy rate (moderate‐quality evidence). Evidence was insufficient to show whether there was a difference between groups in miscarriage, multiple pregnancy, or bleeding rates (low‐ to very low‐quality evidence). Evidence suggests that endometrial injury on the day of oocyte retrieval was associated with a lower live birth or ongoing pregnancy rate (low‐quality evidence) (Nastri 2015)
Growth hormone for IVF: use of growth hormone in poor responders was associated with significant improvement in live birth rates (moderate‐quality evidence) (Duffy 2010)
Metformin treatment before and during IVF or intracytoplasmic sperm injection (ICSI) in women with PCOS: there was no clear evidence that metformin treatment before or during ART cycles improved live birth rates (low‐quality evidence). However, use of this insulin‐sensitising agent increased clinical pregnancy rates and decreased the risk of OHSS (moderate‐quality evidence) (Tso 2014)
Surgical treatment for tubal disease in women due to undergo IVF: laparoscopic tubal occlusion was suggested as an alternative to laparoscopic salpingectomy in improving IVF pregnancy rates among women with hydrosalpinges (moderate‐quality evidence) (Johnson 2010)
Promising interventions (more evidence needed)
Antioxidants for male subfertility: oral antioxidants given to men in couples with male factor or unexplained subfertility may improve live birth rates (low‐quality evidence), but more evidence is needed (low‐quality evidence) (Showell 2014)
Vasodilators for women undergoing fertility treatment: vasodilators may increase clinical pregnancy rates in women undergoing ART (low‐quality evidence). Evidence was insufficient to show whether an effect on live birth rates was found, but few studies reported this outcome (moderate‐quality evidence) (Gutarra‐Vilchez 2014)
In women undergoing ART who are identified as poor responders, pre‐treatment with dehydroepiandrosterone (DHEA) or testosterone may be associated with improved live birth rates (moderate‐quality evidence). Evidence is insufficient to permit conclusions about the safety of either androgen (Nagels 2015)
In women undergoing ART who are identified as poor responders, use of growth hormone appears to increase live birth and clinical pregnancy rates (moderate‐ to high‐quality evidence) (Duffy 2010)
Possibly ineffective interventions (more evidence needed)
Acupuncture and ART: evidence was insufficient to show whether acupuncture improves live birth or pregnancy rates in assisted conception (low‐quality evidence) (Cheong 2013)
Interventions for women with endometrioma before ART: evidence was insufficient to show whether there was an effect on reproductive outcomes in any of the four included trials. Therapies considered included surgery, medicines, and expectant management (low‐ to very low‐quality evidence) (Benschop 2010)
Antioxidants for female subfertility: evidence was insufficient to show whether antioxidants were associated with an effect on live birth rates (very low‐quality evidence), nor was there a clear difference between groups in clinical pregnancy rates (very low‐quality evidence), although more evidence is needed (Showell 2017)
Ovarian cyst aspiration before in vitro fertilisation treatment for subfertility: evidence is insufficient to show whether cyst aspiration was associated with an effect on clinical pregnancy rates (very low‐quality evidence). None of the studies reported live birth (McDonnell 2014)
No conclusions possible due to lack of evidence
Pre‐conception lifestyle advice for people with subfertility: evidence was insufficient to permit a conclusion, with only one RCT (Anderson 2010)
Aspirin for IVF: evidence from adequately powered RCTs was insufficient to permit a conclusion (Siristatidis 2016)
3. Down‐regulation with agonists or antagonists
Effective interventions
Gonadotrophin‐releasing hormone agonist (GnRHa) protocols for pituitary suppression in assisted reproductive technology cycles: the pregnancy rate was higher when GnRHa was used in a long protocol as compared to a short protocol (moderate‐quality evidence) (Siristatidis 2015)
Gonadotrophin‐releasing hormone (GnRH) antagonists for ART: use of GnRH antagonists compared with long‐course GnRH agonist protocols was associated with a substantial reduction in ovarian hyperstimulation syndrome (OHSS) without reducing the likelihood of achieving live birth (moderate‐quality evidence) (Al‐Inany 2016)
Long‐term pituitary down‐regulation before IVF for women with endometriosis: administration of GnRHa for a period of three to six months before IVF or ICSI in women with endometriosis increased the odds of clinical pregnancy (very low‐quality evidence) (Sallam 2006)
Possibly ineffective interventions (more evidence needed)
Depot versus daily administration of GnRHa protocols for pituitary desensitisation in assisted reproduction cycles: evidence was insufficient to show whether there was a difference in live birth or pregnancy outcomes between depot and daily GnRHa use for pituitary down‐regulation in IVF cycles using the long protocol, but substantial differences could not be ruled out (low‐ to moderate‐quality evidence) (Albuquerque 2013)
4. Ovarian stimulation
Effective interventions
Recombinant versus urinary gonadotrophin for ovarian stimulation in ART cycles: it appears that all available gonadotrophins were equally effective and safe. Review authors stated that the choice of one or the other product would depend upon the availability of the product, the convenience of its use, and the associated costs, and that any specific differences were likely to be too small to justify further research (moderate‐ to high‐quality evidence) (van Wely 2011)
Long‐acting follicle‐stimulating hormone (FSH) versus daily FSH for women undergoing assisted reproduction: use of a medium dose (150 to 180 μg) of long‐acting follicle‐stimulating hormone (FSH) appeared to be a safe treatment option and as effective as daily FSH in women with unexplained subfertility. There was evidence of a reduced live birth rate in women receiving a low dose (60 to 120 μg) of long‐acting FSH compared to daily FSH (moderate‐quality evidence) (Pouwer 2015)
Individualised gonadotrophin dose selection using markers of ovarian reserve for women undergoing IVF/ICSI: a decreased dose of FSH in predicted high responders appeared to reduce the likelihood of moderate or severe OHSS (low‐quality evidence). Furthermore, ovarian reserve test (ORT) algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions among women with a predicted high response (moderate‐quality evidence) (Lensen 2018)
Promising interventions (more evidence needed)
Recombinant luteinising hormone (rLH) for controlled ovarian hyperstimulation (COH) in assisted reproductive cycles: there is no clear evidence that co‐administration of rLH to recombinant follicle‐stimulating hormone (rFSH) in GnRHa down‐regulated women resulted in more live births or fewer cases of OHSS than COH with rFSH alone (very low‐ or low‐quality evidence). Nevertheless, pooled clinical and ongoing pregnancy estimates suggested a beneficial effect of co‐treatment with rLH (moderate‐quality evidence) (Mochtar 2017)
Use of clomiphene or letrozole for COH (with or without gonadotrophins) reduced the quantity of gonadotrophins required and the incidence of OHSS. Evidence was insufficient to determine whether there was any effect on live birth or pregnancy rates (low‐ to moderate‐quality evidence). However, use of clomiphene citrate or letrozole was possibly associated with an increase in the incidence of cycle cancellations, as well as reductions in the mean number of oocytes retrieved, in both the general IVF population and among poor responders, so the review authors suggested that further evidence is needed before they are adopted into routine clinical practice (low‐ to moderate‐quality evidence) (Kamath 2017)
FSH replaced by low‐dose human chorionic gonadotropin (hCG) in the late follicular phase versus FSH alone for ARTs: the review authors were very uncertain about the effect on live birth, OHSS, and miscarriage, but evidence suggests that this intervention did not reduce the chance of ongoing and clinical pregnancy, and that it was likely to result in an equivalent number of oocytes retrieved while expending less FSH (very low‐quality evidence) (Martins 2013)
Natural cycle IVF for subfertile couples: there was no clear evidence of a difference between natural cycle and standard IVF for outcomes including live birth, OHSS, clinical pregnancy, and multiple pregnancy (very low‐quality evidence) (Allersma 2013)
Possibly ineffective interventions (more evidence needed)
Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI): RCTs provided no evidence to support cycle monitoring by ultrasound plus serum oestradiol was more efficacious than cycle monitoring by ultrasound only on the outcomes of clinical pregnancy and OHSS. A large well‐designed RCT is needed (low‐quality evidence) (Kwan 2014)
Combined oral contraceptive pill (COCP), progestogen or oestrogen pre‐treatment for ovarian stimulation protocols for women undergoing ARTs: COCP pre‐treatment was associated with a lower rate of live birth or ongoing pregnancy than no pre‐treatment (moderate‐quality evidence). Evidence was insufficient to show whether rates of live birth or ongoing pregnancy were influenced by pre‐treatment with progestogens or oestrogens, or by COCP pre‐treatment using other stimulation protocols (low‐ to moderate‐quality evidence) (Farquhar 2017)
The safety and effectiveness of glucocorticoid administration in women undergoing COH for IVF/ICSI cycles were unclear because data were lacking. Glucocorticoids may increase the clinical pregnancy rates but may have little or no impact on live birth rates (low‐quality evidence) (Kalampokas 2017)
Individualised gonadotrophin dose selection using markers of ovarian reserve for women undergoing IVF/ICSI: current evidence did not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders (low‐quality evidence) (Lensen 2018)
No conclusions possible due to lack of evidence
Interventions for 'poor responders' to COH in IVF: evidence was insufficient to support the routine use of any particular intervention for pituitary down‐regulation, ovarian stimulation, or adjuvant therapy in the treatment of poor responders to COH in IVF (low‐ to very low‐quality evidence) (Pandian 2010)
5. Ovulation triggering
Effective interventions
Recombinant hCG and rLH as the final oocyte maturation triggers did not seem to be better than uhCG for reproductive outcomes of the IVF or ICSI cycle, as there was no clear evidence of a difference between rhCG and uhCG (moderate‐quality evidence), or between rhLH and uhCG (very low‐quality evidence), with respect to rates of live birth or ongoing pregnancy (Youssef 2016a)
GnRHa versus hCG for oocyte triggering in antagonist ART cycles: there was evidence of a lower live birth rate (moderate‐quality evidence), a reduced ongoing pregnancy rate (low‐quality evidence), and a higher miscarriage rate (moderate‐quality evidence) among women who received GnRHa. However, OHSS rates were reduced with GnRHa triggering (moderate‐quality evidence); therefore there was a trade off between benefits and harms (Youssef 2014)
6. Oocyte retrieval
Effective interventions
Pain relief for women undergoing oocyte retrieval for assisted reproduction: the various approaches and techniques reviewed (five different categories of conscious sedation and analgesia) appeared to be acceptable and were associated with a high degree of satisfaction in women. Simultaneous use of sedation combined with analgesia such as the opiates, further enhanced by paracervical block or acupuncture techniques, resulted in better pain relief than occurred with one modality alone. The review authors proposed that women’s preferences and resource availability for choice of pain relief merit consideration in practice.(low‐ or very low‐quality evidence for most comparisons) (Kwan 2018)
Possibly ineffective interventions (more evidence needed)
hCG priming in in vitro maturation: evidence was insufficient to show whether hCG priming had an effect on live birth or miscarriage rates in oocyte maturation in vivo (IVM) (low‐quality evidence). Some evidence suggests that hCG priming may reduce clinical pregnancy rates, but these findings were limited by the small quantity of data included (low‐quality evidence) (Reavey 2016)
Ineffective interventions
Follicular flushing during oocyte retrieval may have little or no effect on live birth rates or clinical pregnancy rates compared with aspiration alone (moderate‐quality evidence). Evidence was insufficient to permit any firm conclusions with regard to adverse events or safety (Georgiou 2018)
7. Sperm retrieval
No conclusions possible due to lack of evidence
Techniques for surgical retrieval of sperm before ICSI for azo‐ospermia: evidence was insufficient to support recommendations for any specific sperm retrieval technique for azo‐ospermic men undergoing ICSI (only one RCT) (low‐quality evidence) (Proctor 2008)
Advanced sperm selection techniques for assisted reproduction: evidence was insufficient to show whether sperm selected by hyaluronic acid binding improves live birth or pregnancy outcomes in ART, or whether there was a difference in efficacy between the hyaluronic acid binding methods SpermSlow and PICSI. Review authors found no randomised evidence evaluating sperm selection by sperm apoptosis, sperm birefringence, or surface charge (low‐quality evidence) (McDowell 2014)
8. Laboratory phase
Effective interventions
Low oxygen concentrations for embryo culture in ART: review authors found evidence of an increase in live birth rates associated with embryo culture with low oxygen concentrations (moderate‐quality evidence) (Bontekoe 2012)
Promising interventions (more evidence needed)
Assisted hatching on assisted conception (IVF and ICSI): although assisted hatching (AH) appears to offer an increased chance of achieving a clinical pregnancy (moderate‐quality evidence), the extent to which it might do so only just reached statistical significance. Review authors found no evidence of an effect on live birth rates (moderate‐quality evidence), and multiple pregnancy rates were increased in AH groups (low‐quality evidence) (Carney 2012)
Brief co‐incubation of sperm and oocytes for IVF techniques: brief co‐incubation of sperm and oocytes may improve ongoing pregnancy and clinical pregnancy rates for women undergoing IVF cycles compared to the standard overnight insemination protocol. More RCTs are required (low‐quality evidence) (Huang 2013)
Vitrification probably increases clinical pregnancy rates compared to slow freezing (moderate‐quality evidence). However, the total number of women and of pregnancies was low, and no data on live birth or adverse events.were available (moderate‐quality evidence) (Glujovsky 2014)
Possibly ineffective interventions (more evidence needed)
Regular (ICSI) versus ultra‐high magnification sperm selection (IMSI) for assisted reproduction: evidence was insufficient to show whether there was a difference between ICSI and IMSI with respect to rates of live birth (low‐quality evidence) or miscarriage (very low‐quality evidence), and evidence suggesting that IMSI improved clinical pregnancy was of very low quality (Teixeira 2013)
Evidence is insufficient to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, or miscarriage (low‐quality evidence) (Siristatidis 2018)
Ineffective interventions
Pre‐implantation genetic screening (PGS) for abnormal numbers of chromosomes (aneuploidies) in IVF or ICSI: pre‐implantation genetic screening using fluorescent in situ hybridisation decreased live birth rates among women of advanced maternal age and those with repeated IVF failure. RCTs provided no clear evidence of a difference between groups when PGS was offered to women with a good prognosis (moderate‐quality evidence) (Twisk 2006)
No conclusions possible due to lack of evidence
ICSI versus conventional techniques for oocyte insemination during IVF in patients with non‐male subfertility: evidence was insufficient to permit a conclusion, with only one RCT (low‐quality evidence) (Van Rumste 2003)
Time‐lapse systems versus conventional embryo incubation and assessment: evidence of differences in live birth, miscarriage, stillbirth, or clinical pregnancy was insufficient to permit a conclusion (low‐ to moderate‐quality evidence) (Armstrong 2015)
Evidence is insufficient to support or refute the use of any specific culture medium (very low‐quality evidence). Properly designed and executed randomised trials are necessary (Youssef 2015)
9. Embryo transfer
Effective interventions
Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women: evidence suggests that ultrasound guidance improves the chance of live birth (low‐quality evidence) and clinical pregnancy (moderate‐quality evidence) compared with clinical touch, without increasing the chance of multiple pregnancy, ectopic pregnancy, or miscarriage (low‐ to moderate‐quality evidence) (Brown 2016a)
.Adherence compounds in embryo transfer media for ART: evidence suggested improved live birth and clinical pregnancy rates with the use of hyaluronic acid. Multiple pregnancy rates were also increased in the intervention group, which the review authors suggested might relate to use of an adherence compound together with a policy of transferring more than one embryo (moderate‐quality evidence) (Bontekoe 2014)
Number of embryos for transfer following IVF or ICSI: although in a single ART cycle the live birth rate was lower following single‐embryo transfer compared with double‐embryo transfer, elective single embryo transfer resulted in fewer multiple pregnancies than double embryo transfer (high‐quality evidence). The cumulative live birth rate associated with single‐embryo transfer followed by a single frozen and thawed embryo transfer was comparable with that after one cycle of double‐embryo transfer (low‐quality evidence) (Pandian 2013)
Evidence suggests that day three and day two embryo transfers following IVF or ICSI are equally effective (very low‐ to moderate‐quality evidence) (Brown 2016)
Promising interventions (more evidence needed)
Pregnancy outcomes for cleavage‐stage embryo transfer using an intra‐cavity human chorionic gonadotropin (IC‐hCG) dose of 500 international units or greater are promising. However evidence quality was variable, and this finding was derived from a subgroup analysis. No evidence suggests that miscarriage was influenced by intrauterine hCG administration, irrespective of embryo stage at transfer or dose of IC‐hCG, and events were too few to allow any conclusions to be drawn with regard to other complications. More research is needed (Craciunas 2016)
Evidence was insufficient to show whether application of seminal plasma to the genital tract influenced rates of live birth or miscarriage (low‐quality evidence). However, low‐quality evidence suggests that seminal plasma application may be associated with more clinical pregnancies than standard ART. The review authors concluded that the intervention is worth further investigation, with focus on live birth and miscarriage rates
Possibly ineffective interventions (more evidence needed)
Techniques for preparation before embryo transfer: evidence was insufficient to show whether benefit was associated with any of the following interventions at the time of embryo transfer: full bladder, removal of cervical mucus, or flushing the endocervical canal or the endometrial cavity (low‐ to moderate‐quality evidence). More and larger studies on embryo transfer preparation techniques are needed (Derks 2009)
Antibiotics before embryo transfer in ART: administration of amoxicillin and clavulanic acid before embryo transfer reduced upper genital tract microbial contamination but had no clear effect on clinical pregnancy rates (moderate‐quality evidence). No data were available from RCTs to support or refute other antibiotic regimens in this setting. Future research is warranted (Kroon 2012)
No conclusions possible due to lack of evidence
Cleavage‐stage versus blastocyst‐stage embryo transfer in ART: the margin of benefit between cleavage stage and blastocyst transfer is unclear. Although live birth rates were increased with fresh blastocyst transfer, it was also associated with a reduction in the number of embryos transferred and in embryo freezing (low‐quality evidence). Researchers provided insufficient evidence to show whether there was a difference between groups in cumulative pregnancy rates derived from fresh and frozen‐thawed cycles following a single oocyte retrieval (very low‐quality evidence). Future RCTs should report miscarriage and live birth and cumulative live birth rates to facilitate well‐informed decisions on the best treatment option available (Glujovsky 2016)
Post‐embryo transfer interventions for patients with IVF and ICSI: evidence was insufficient to support a certain amount of time for women to remain recumbent following embryo transfer, or to support the use of fibrin sealants. Limited evidence was available to support the use of mechanical closure of the cervical canal following embryo transfer. Further well‐designed studies are required (Abou‐Setta 2014)
10. Luteal phase support
Effective interventions
Luteal phase support in ART cycles: this review concluded that progesterone appeared to be the best method of providing luteal phase support, as it was associated with higher rates of live birth or ongoing pregnancy than placebo (very low‐quality evidence) and lower rates of OHSS than hCG (low‐quality evidence). Addition of one or more doses of GnRH agonists to progesterone was associated with higher live birth and ongoing pregnancy rates than progesterone alone. Overall, addition of other substances such as oestrogen or hCG did not seem to improve outcomes. The route of progesterone administration did not seem to matter (quality of evidence was low for most comparisons) (van der Linden 2015)
Promising interventions (more evidence needed)
Heparin for assisted reproduction: Akhtar 2013 reported that peri‐implantation low molecular weight heparin in ART cycles may improve the live birth rate among women undergoing assisted reproduction. However, these results did not justify the use of heparin outside well‐conducted research trials, as evidence quality was poor (low‐ to very low‐quality evidence)
Possibly ineffective interventions (more evidence needed)
Peri‐implantation glucocorticoid administration for ART cycles: overall, no clear evidence suggests that administration of peri‐implantation glucocorticoids in ART cycles significantly improved clinical outcomes (moderate‐quality evidence) (Boomsma 2012)
11. Prevention of ovarian hyperstimulation syndrome (OHSS)
Effective interventions
Dopamine agonists for preventing OHSS: dopamine agonists seemed effective for prevention of moderate or severe OHSS in women at high risk of OHSS (low‐quality evidence). Review authors found no clear evidence of a difference in rates of live birth, clinical pregnancy, multiple pregnancy, or miscarriage. However, dopamine agonists might increase the risk of adverse events, such as gastrointestinal symptoms (very low‐ to moderate‐quality evidence) (Tang 2016)
Gonadotrophin‐releasing hormone (GnRH) antagonists for ART: as noted in Section 3 above, the use of antagonists compared with long GnRHa protocols was associated with a large reduction in OHSS, and no evidence suggested a difference in live birth rates (moderate‐quality evidence) (Al‐Inany 2016)
GnRHa versus hCG for oocyte triggering in antagonist ART cycles: as noted in Section 3 above, researchers provided evidence of a lower live birth rate, a reduced ongoing pregnancy rate, and a higher miscarriage rate among women who received a GnRHa. However, OHSS rates were reduced with GnRHa triggering; therefore there was a tradeoff between benefits and harms (moderate‐quality evidence) (Youssef 2014)
Promising interventions (more evidence needed)
The plasma expanders human albumin, hydroxyethyl starch (HES), and mannitol reduced rates of moderate and severe OHSS in women at high risk. Trials provided no data on live birth but reported evidence that human albumin reduced clinical pregnancy rates. Although no evidence suggests that HES, or mannitol, had any influence on pregnancy rates, evidence of effectiveness was based on very few trials, and this needs to be confirmed in additional, larger RCTs before these plasma expanders should be considered for routine use in clinical practice (low‐ or very low‐quality evidence) (Youssef 2016)
Possibly ineffective interventions (more evidence needed)
Embryo freezing for preventing OHSS: evidence was insufficient to support routine cryopreservation and the relative merits of intravenous albumin versus cryopreservation (low‐quality evidence) (D'Angelo 2007)
Coasting (withholding gonadotrophins) for preventing OHSS: evidence suggests benefit derived from coasting rather than no coasting to reduce rates of moderate or severe OHSS (low‐quality evidence), but evidence does not suggest that coasting was more beneficial than other interventions, such as early unilateral follicular aspiration, gonadotrophin‐releasing hormone antagonist, or cabergoline (very low‐quality evidence). A single small study suggested that using an FSH co‐trigger at the time of hCG administration may be better than coasting for reducing risk of OHSS (very low‐quality evidence) (D'Angelo 2017)
12. Frozen embryo replacement cycles
Effective interventions
A freeze‐all strategy for embryo transfer versus a conventional strategy with transfer of fresh and subsequently frozen‐thawed embryos: one strategy was not superior to the other in terms of cumulative live birth rates (moderate‐quality evidence). Evidence suggests that not performing a fresh transfer lowers risk of OHSS for women at risk of OHSS (low‐quality evidence) (Wong 2017)
No conclusions possible due to lack of evidence
Cycle regimens for frozen‐thawed embryo transfer: at the present time, evidence is insufficient to support the use of one intervention in preference to another (Ghobara 2017)
Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes: evidence was insufficient to support recommendations for any one particular protocol for endometrial preparation over another with regard to pregnancy rates after embryo transfers (Glujovsky 2010)
Overall completeness and applicability of evidence
This overview summarises published Cochrane systematic reviews of all randomised controlled trials on the different stages of an ART cycle and the different populations undergoing ART. We consider it to be complete, although we acknowledge that not all systematic reviews in this overview are up‐to‐date. We consider that the information in this study can be applied to couples undergoing an ART cycle in most parts of the world, including use of low‐cost strategies such as modified natural cycle IVF.
Quality of the evidence
We have assessed each of the reviews by using the AMSTAR tool for assessing systematic reviews. We have presented these results in the 'AMSTAR assessment' table (Table 2). Overall, the quality of the reviews was high and almost all criteria were met. The only exception was assessment of publication bias, which we considered inadequate in two of the 67 reviews. The main limitation of the reviews was that only 44% had been updated with a search within the past three years (to May 2018) or had been deemed "stable, with no updating planned".
Potential biases in the overview process
We identified no specific biases in the overview process. However it is acknowledged that decisions about effectiveness, possible ineffectiveness, and insufficient evidence could be considered subjective. Ideally, these decisions should be made by a larger group of clinical and methodological experts.
Agreements and disagreements with other studies or reviews
No reviews are comparable with this overview.
Several of the reviews included in this overview have been used to help develop World Health Organization fertility guidelines. The National Institute for Health and Care Excellence (NICE) clinical guidelines on assessment and treatment of people with fertility problems also were based on information provided in many of our reviews (NICE 2013).
Authors' conclusions
Implications for practice.
This overview provides the most up‐to‐date evidence on ART cycles from systematic reviews of randomised controlled trials. Fertility treatments are costly and the stakes are high. Best practice requires using the best available evidence to optimise outcomes. Evidence from this overview could be used to develop clinical practice guidelines and protocols for use in daily clinical practice, to improve live birth rates, and to reduce rates of multiple pregnancy, cycle cancellation, and ovarian hyperstimulation syndrome.
Implications for research.
This overview highlights areas for which evidence is insufficient because of lack of primary research or lack of reporting of important outcomes, and it can be used to generate research questions. The most important outcomes are live birth, cumulative live birth, multiple pregnancy, cycle cancellation, and ovarian hyperstimulation syndrome.
What's new
| Date | Event | Description |
|---|---|---|
| 19 June 2018 | New citation required and conclusions have changed | The addition of 9 new reviews has led to a change in the conclusions of this overview |
| 19 June 2018 | New search has been performed | In the 2018 update, we added 9 new reviews (Ata 2018; Craciunas 2016; Kalampokas 2017; Lensen 2018; Nagels 2015; Reavey 2016; Siristatidis 2018; Wong 2017; Youssef 2015) and updated the findings of 18 reviews (Al‐Inany 2016; Brown 2016; Brown 2016a; D'Angelo 2017; Farquhar 2017; Georgiou 2018; Ghobara 2017; Glujovsky 2016; Kamath 2017; Kwan 2018; Mochtar 2017; Pandian 2015; Showell 2017; Siristatidis 2015; Siristatidis 2016; Tang 2016; Youssef 2016; Youssef 2016a) |
History
Protocol first published: Issue 5, 2013 Review first published: Issue 8, 2013
| Date | Event | Description |
|---|---|---|
| 19 April 2016 | Amended | Updated declaration of interest |
| 23 September 2015 | Amended | Corrected minor typos in text |
| 11 September 2015 | Amended | Made minor corrections to text and data tables |
| 13 August 2015 | Amended | Made minor correction to data in additional tables |
| 8 July 2015 | New citation required but conclusions have not changed | Additional information has not led to a change in the conclusions of this review |
| 1 July 2015 | New search has been performed | Added one new review: SCA1950 (Armstrong 2015) Updated three reviews: MV263 (van der Linden 2015), AWP1710 (Pouwer 2015), and WM 1504 (Nastri 2015) |
| 22 December 2014 | New citation required but conclusions have not changed | Added evidence from four new and six updated reviews |
| 31 October 2014 | New search has been performed | Updated six reviews: AAS605 (Abou‐Setta 2014); DB552 (Bontekoe 2014); IOK972 (Kwan 2014); MGS1510 (Showell 2014); MM1690 (Youssef 2014); LDT 1201(Tso 2014) Added four new reviews: DG1352 (Glujovsky 2014); RBG1760 (Gutarra‐Vilchez 2014); SMD1810 (McDowell 2014); SH1141 (McDonnell 2014) |
| 13 November 2013 | Amended | Made minor correction to data in one included review ‐ no effect on findings of this overview |
| 14 October 2013 | Amended | Made minor amendment to abstract and results |
Acknowledgements
Dr. Julie Brown, Josephine Rishworth and Dr Willianne Nelen were co‐authors of the original version of this overview and the 2015 update and helped with all aspects of the review.
We would like to acknowledge the support of the editorial base of the Cochrane Gynaecology and Fertility Group (formerly the Menstrual Disorders and Subfertility Group)
Appendices
Appendix 1. ART protocols and titles
Protocols
The following 11 protocols (published and in authoring phase for full review) were identified. They will be added to the overview when they are published as full reviews and the overview is updated.
Pre‐ART or adjuvant strategies
Benschop 2012: "Immune therapies for women with history of failed implantation undergoing IVF treatment"‐ KH1670
Nyachieo 2009: "Nonsteroidal anti‐inflammatory drugs for assisted reproductive technology" ‐ LMW1121
Zhu 2013: "Acupuncture for female subfertility" ‐ XZ1550
Kamath 2017a:"Screening hysteroscopy in subfertile women undergoing assisted reproduction" ‐ JK1940
Siristatidis 2018: "Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction" ‐ CS1985
Embryo transfer
Baak 2016: "Temperature of embryo culture for assisted reproduction" ‐ NAB1977
Craciunas 2016a: "Oxytocin antagonists for assisted reproduction" ‐ LC1971
Nastri 2013:"Interventions for improving reproductive outcomes in women with recurrent implantation failure undergoing assisted reproductive techniques" ‐ WPM1850
Frozen cycles
Chua 2012: "Slow freeze versus vitrification for embryo cryopreservation" ‐ CB994
Luteal phase support
Abou‐Setta 2006: "Soft versus firm embryo transfer catheters for assisted reproductive technology" ‐ GG603
Checa 2016: "Luteal phase support for women trying to conceive by intrauterine insemination or sexual intercourse" ‐ MAC1967
Titles
Three active titles were identified.
AYW1983 ‐ "Day 3 versus day 5 embryo biopsy for preimplantation genetic diagnosis"
JML1979 ‐ "GM‐CSF (granulocyte macrophage colony stimulating factor) supplementation in culture media for subfertile women undergoing ART"
SHJ881 ‐ "Long‐term GnRH agonist therapy before in vitro fertilization (IVF) for improving fertility outcomes in women with endometriosis"
Contributions of authors
For the 2018 update, JM and CF extracted and checked the data, drafted the text and interpreted the evidence.
Sources of support
Internal sources
University of Auckland research grant, New Zealand.
External sources
None, Other.
Declarations of interest
Professor Farquhar, and Jane Marjoribanks are authors on some of the included reviews. They have no conflicts of interest related to commercial funding.
Professor Farquhar is a director/shareholder of a fertility/gynaecology clinic and undertakes private practice within those premises.
New search for studies and content updated (conclusions changed)
References
References to included reviews
Abou‐Setta 2014
- Abou‐Setta AM, Peters LR, D'Angelo A, Sallam HN, Hart RJ, Al‐Inany HG. Post‐embryo transfer interventions for assisted reproduction technology cycles. Cochrane Database of Systematic Reviews 2014, Issue 8. [DOI: 10.1002/14651858.CD006567.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Akhtar 2013
- Akhtar M, Sur S, Raine‐Fenning N, Jayaprakasan K, Thornton JG, Quenby S. Heparin for assisted reproduction. Cochrane Database of Systematic Reviews 2013, Issue 8. [DOI: 10.1002/14651858.CD009452.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Al‐Inany 2016
- Al‐Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD001750.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Albuquerque 2013
- Albuquerque LET, Tso LO, Saconato H, Albuquerque MCRM, Macedo CR. Depot versus daily administration of gonadotrophin‐releasing hormone agonist protocols for pituitary down regulation in assisted reproduction cycles. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD002808.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Allersma 2013
- Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. [DOI: 10.1002/14651858.CD010550.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Anderson 2010
- Anderson K, Norman RJ, Middleton P. Preconception lifestyle advice for people with subfertility. Cochrane Database of Systematic Reviews 2010, Issue 4. [DOI: 10.1002/14651858.CD008189.pub2] [DOI] [PubMed] [Google Scholar]
Armstrong 2015
- Armstrong S, Arroll N, Cree LM, Jordan V, Farquhar C. Time‐lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database of Systematic Reviews 2015, Issue 2. [DOI: 10.1002/14651858.CD011320.pub2] [DOI] [PubMed] [Google Scholar]
Ata 2018
- Ata B, Abou‐Setta AM, Seyhan A, Buckett W. Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer). Cochrane Database of Systematic Reviews 2018, Issue 2. [DOI: 10.1002/14651858.CD011809.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Benschop 2010
- Benschop L, Farquhar C, Poel N, Heineman MJ. Interventions for women with endometrioma prior to assisted reproductive technology. Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/14651858.CD008571.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Bontekoe 2012
- Bontekoe S, Mantikou E, Wely M, Seshadri S, Repping S, Mastenbroek S. Low oxygen concentrations for embryo culture in assisted reproductive technologies. Cochrane Database of Systematic Reviews 2012, Issue 7. [DOI: 10.1002/14651858.CD008950.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Bontekoe 2014
- Bontekoe S, Heineman MJ, Johnson N, Blake D. Adherence compounds in embryo transfer media for assisted reproductive technologies. Cochrane Database of Systematic Reviews 2014, Issue 2. [DOI: 10.1002/14651858.CD007421.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Boomsma 2012
- Boomsma CM, Keay SD, Macklon NS. Peri‐implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database of Systematic Reviews 2012, Issue 6. [DOI: 10.1002/14651858.CD005996.pub3] [DOI] [PubMed] [Google Scholar]
Brown 2016
- Brown J, Daya S, Matson P. Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2016, Issue 12. [DOI: 10.1002/14651858.CD004378.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Brown 2016a
- Brown J, Buckingham K, Buckett W, Abou‐Setta AM. Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women. Cochrane Database of Systematic Reviews 2016, Issue 3. [DOI: 10.1002/14651858.CD006107.pub4] [DOI] [PubMed] [Google Scholar]
Carney 2012
- Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L. Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)). Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.CD001894.pub5] [DOI] [PMC free article] [PubMed] [Google Scholar]
Cheong 2013
- Cheong YC, Dix S, Hung Yu Ng E, Ledger WL, Farquhar C. Acupuncture and assisted reproductive technology. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD006920.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Craciunas 2016
- Craciunas L, Tsampras N, Coomarasamy A, Raine‐Fenning N. Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction. Cochrane Database of Systematic Reviews 2016, Issue 5. [DOI: 10.1002/14651858.CD011537.pub2] [DOI] [PubMed] [Google Scholar]
D'Angelo 2007
- D'Angelo A, Amso NN. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD002806.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
D'Angelo 2017
- D'Angelo A, Amso NN, Hassan R. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2017, Issue 5. [DOI: 10.1002/14651858.CD002811.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Derks 2009
- Derks RS, Farquhar C, Mol BWJ, Buckingham K, Heineman MJ. Techniques for preparation prior to embryo transfer. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD007682.pub2] [DOI] [PubMed] [Google Scholar]
Duffy 2010
- Duffy JMN, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD000099.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Farquhar 2017
- Farquhar C, Rombauts L, Kremer JAM, Lethaby A, Ayeleke RO. Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database of Systematic Reviews 2017, Issue 5. [DOI: 10.1002/14651858.CD006109.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Georgiou 2018
- Georgiou EX, Melo P, Bronw J, Granne IE. Follicular flushing during oocyte retrieval in assisted reproductive techniques. Cochrane Database of Systematic Reviews 2018, Issue 4. [DOI: 10.1002/14651858.CD004634.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Ghobara 2017
- Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen‐thawed embryo transfer. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD003414.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Glujovsky 2010
- Glujovsky D, Pesce R, Fiszbajn G, Sueldo C, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD006359.pub2] [DOI] [PubMed] [Google Scholar]
Glujovsky 2014
- Glujovsky D, Riestra B, Sueldo C, Fiszbajn G, Repping S, Nodar F, et al. Vitrification versus slow freezing for women undergoing oocyte cryopreservation. Cochrane Database of Systematic Reviews 2014, Issue 9. [DOI: 10.1002/14651858.CD010047.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Glujovsky 2016
- Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 6. [DOI: 10.1002/14651858.CD002118.pub5] [DOI] [PubMed] [Google Scholar]
Gutarra‐Vilchez 2014
- Gutarra‐Vilchez RB, Urrútia G, Glujovsky D, Coscia A, Bonfill Cosp X. Vasodilators for women undergoing fertility treatment. Cochrane Database of Systematic Reviews 2014, Issue 10. [DOI: 10.1002/14651858.CD010001.pub2] [DOI] [PubMed] [Google Scholar]
Huang 2013
- Huang Z, Li J, Wang L, Yan J, Shi Y, Li S. Brief co‐incubation of sperm and oocytes for in vitro fertilization techniques. Cochrane Database of Systematic Reviews 2013, Issue 4. [DOI: 10.1002/14651858.CD009391.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Johnson 2010
- Johnson N, Voorst S, Sowter MC, Strandell A, Mol BWJ. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD002125.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kalampokas 2017
- Kalampokas T, Pandian Z, Keay SD, Bhattacharya S. Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI. Cochrane Database of Systematic Reviews 2017, Issue 3. [DOI: 10.1002/14651858.CD004752.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kamath 2017
- Kamath MS, Maheshwari A, Bhattacharya S, Lor KY, Gibreel A. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database of Systematic Reviews 2017, Issue 11. [DOI: 10.1002/14651858.CD008528.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kroon 2012
- Kroon B, Hart RJ, Wong BMS, Ford E, Yazdani A. Antibiotics prior to embryo transfer in ART. Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI: 10.1002/14651858.CD008995.pub2] [DOI] [PubMed] [Google Scholar]
Kwan 2014
- Kwan I, Bhattacharya S, Kang A, Woolner A. Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI). Cochrane Database of Systematic Reviews 2014, Issue 8. [DOI: 10.1002/14651858.CD005289.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kwan 2018
- Kwan I, Wang R, Pearce E, Bhattacharya S. Pain relief for women undergoing oocyte retrieval for assisted reproduction. Cochrane Database of Systematic Reviews 2018, Issue 5. [DOI: 10.1002/14651858.CD004829.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Lensen 2018
- Lensen SF, Wilkinson J, Leijdekkers JA, Marca A, Mol BWJ, Marjoribanks J, et al. Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). Cochrane Database of Systematic Reviews 2018, Issue 2. [DOI: 10.1002/14651858.CD012693.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Martins 2013
- Martins WP, Vieira ADD, Figueiredo JBP, Nastri CO. FSH replaced by low‐dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques. Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/14651858.CD010042.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
McDonnell 2014
- McDonnell R, Marjoribanks J, Hart RJ. Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility. Cochrane Database of Systematic Reviews 2014, Issue 12. [DOI: 10.1002/14651858.CD005999.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
McDowell 2014
- McDowell S, Kroon B, Ford E, Hook Y, Glujovsky D, Yazdani A. Advanced sperm selection techniques for assisted reproduction. Cochrane Database of Systematic Reviews 2014, Issue 10. [DOI: 10.1002/14651858.CD010461.pub2] [DOI] [PubMed] [Google Scholar]
Mochtar 2017
- Mochtar MH, Danhof NA, Ayeleke RO, Veen F, Wely M. Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles. Cochrane Database of Systematic Reviews 2017, Issue 5. [DOI: 10.1002/14651858.CD005070.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Nagels 2015
- Nagels HE, Rishworth JR, Siristatidis CS, Kroon B. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/14651858.CD009749.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Nastri 2015
- Nastri CO, Lensen SF, Gibreel A, Raine‐Fenning N, Ferriani RA, Bhattacharya S, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database of Systematic Reviews 2015, Issue 3. [DOI: 10.1002/14651858.CD009517] [DOI] [PubMed] [Google Scholar]
Pandian 2010
- Pandian Z, McTavish AR, Aucott L, Hamilton MPR, Bhattacharya S. Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in‐vitro fertilisation (IVF). Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD004379.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Pandian 2013
- Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra‐cytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD003416.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Pandian 2015
- Pandian Z, Gibreel A, Bhattacharya S. In vitro fertilisation for unexplained subfertility. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/14651858.CD003357.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Pouwer 2015
- Pouwer AW, Farquhar C, Kremer JAM. Long‐acting FSH versus daily FSH for women undergoing assisted reproduction. Cochrane Database of Systematic Reviews 2015, Issue 7. [DOI: 10.1002/14651858.CD009577.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Proctor 2008
- Proctor M, Johnson N, Peperstraten AM, Phillipson G. Techniques for surgical retrieval of sperm prior to intra‐cytoplasmic sperm injection (ICSI) for azoospermia. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD002807.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Reavey 2016
- Reavey J, Vincent K, Child T, Granne IE. Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation. Cochrane Database of Systematic Reviews 2016, Issue 11. [DOI: 10.1002/14651858.CD008720.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Sallam 2006
- Sallam HN, Garcia‐Velasco JA, Dias S, Arici A, Abou‐Setta AM. Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD004635.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Showell 2014
- Showell MG, Mackenzie‐Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2014, Issue 12. [DOI: 10.1002/14651858.CD007411.pub3] [DOI] [PubMed] [Google Scholar]
Showell 2017
- Showell MG, Mackenzie‐Proctor R, Jordan V, Hart RJ. Antioxidants for female subfertility. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD007807.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Siristatidis 2009
- Siristatidis CS, Maheshwari A, Bhattacharya S. In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD006606.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Siristatidis 2015
- Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S. Gonadotrophin‐releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/14651858.CD006919.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Siristatidis 2016
- Siristatidis CS, Basios G, Pergialiotis V, Vogiatzi P. Aspirin for in vitro fertilisation. Cochrane Database of Systematic Reviews 2016, Issue 11. [DOI: 10.1002/14651858.CD004832.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Siristatidis 2018
- Siristatidis CS, Sertedaki E, Vaidakis D, Varounis C, Trivella M. Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies. Cochrane Database of Systematic Reviews 2018, Issue 3. [DOI: 10.1002/14651858.CD011872.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Tang 2016
- Tang H, Mourad S, Zhai S‐D, Hart RJ. Dopamine agonists for preventing ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2016, Issue 11. [DOI: 10.1002/14651858.CD008605.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Teixeira 2013
- Teixeira DM, Barbosa MAP, Ferriani RA, Navarro PA, Raine‐Fenning N, Nastri CO, et al. Regular (ICSI) versus ultra‐high magnification (IMSI) sperm selection for assisted reproduction. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD010167.pub2] [DOI] [PubMed] [Google Scholar]
Tso 2014
- Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2014, Issue 11. [DOI: 10.1002/14651858.CD006105.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Twisk 2006
- Twisk M, Mastenbroek S, Wely M, Heineman MJ, Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD005291.pub2] [DOI] [PubMed] [Google Scholar]
van der Linden 2015
- Linden M, Buckingham K, Farquhar C, Kremer JAM, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database of Systematic Reviews 2015, Issue 7. [DOI: 10.1002/14651858.CD009154.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Van Rumste 2003
- Rumste MME, Evers JLH, Farquhar C. Intra‐cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in couples with non‐male subfertility. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD001301] [DOI] [PubMed] [Google Scholar]
van Wely 2011
- Wely M, Kwan I, Burt AL, Thomas J, Vail A, Veen F, Al‐Inany HG. Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. Cochrane Database of Systematic Reviews 2011, Issue 2. [DOI: 10.1002/14651858.CD005354.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Wong 2017
- Wong KM, Wely M, Mol F, Repping S, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database of Systematic Reviews 2017, Issue 3. [DOI: 10.1002/14651858.CD011184.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Yossry 2006
- Yossry M, Aboulghar M, D'Angelo A, Gillett W. In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD004144.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Youssef 2014
- Youssef MAFM, Veen F, Al‐Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, et al. Gonadotropin‐releasing hormone agonist versus HCG for oocyte triggering in antagonist‐assisted reproductive technology. Cochrane Database of Systematic Reviews 2014, Issue 10. [DOI: 10.1002/14651858.CD008046.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Youssef 2015
- Youssef MMA, Mantikou E, Wely M, Veen F, Al‐Inany HG, Repping S, et al. Culture media for human pre‐implantation embryos in assisted reproductive technology cycles. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/14651858.CD007876.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Youssef 2016
- Youssef M, Mourad S. Volume expanders for the prevention of ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2016, Issue 8. [DOI: 10.1002/14651858.CD001302.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Youssef 2016a
- Youssef MA, Abou‐Setta AM, Lam WS. Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD003719.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
Additional references
Abou‐Setta 2006
- Abou‐Setta AM, Al‐Inany HG, Hornstein MD, Richard‐Davis G, Veen F, Poel N. Soft versus firm embryo transfer catheters for assisted reproductive technology. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD005636] [DOI] [Google Scholar]
Baak 2016
- Baak NA, Cantineau AEP, Farquhar C, Brison D. Temperature of embryo culture for assisted reproduction. Cochrane Database of Systematic Reviews 2016, Issue 5. [DOI: 10.1002/14651858.CD012192] [DOI] [PMC free article] [PubMed] [Google Scholar]
Benschop 2012
- Benschop L, Seshadri S, Toulis KA, Vincent K, Child T, Granne IE, Goulis DG. Immune therapies for women with history of failed implantation undergoing IVF treatment. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/14651858.CD009602] [DOI] [Google Scholar]
Boivin 2007
- Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment‐seeking: potential need and demand for infertility medical care. Human Reproduction 2007;22(6):1506‐12. [DOI] [PubMed] [Google Scholar]
Checa 2016
- Checa MA, Teixeira DM, González‐Comadran M, Nastri CO, Martins WP. Luteal phase support for women trying to conceive by intrauterine insemination or sexual intercourse. Cochrane Database of Systematic Reviews 2016, Issue 11. [DOI: 10.1002/14651858.CD012396] [DOI] [PMC free article] [PubMed] [Google Scholar]
Chua 2012
- Chua W, Boothroyd C, Walls M, Hart RJ. Slow freeze versus vitrification for embryo cryopreservation. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/14651858.CD009589] [DOI] [Google Scholar]
Craciunas 2016a
- Craciunas L, Kollmann M, Tsampras N, Raine‐Fenning N, Choudhary M. Oxytocin antagonists for assisted reproduction. Cochrane Database of Systematic Reviews 2016, Issue 10. [DOI: 10.1002/14651858.CD012375] [DOI] [PMC free article] [PubMed] [Google Scholar]
ElDaly 2006
- ElDaly AA, Al‐Fozan HM, Al‐Inany HG, Bedaiwy MA, Saleh WF. Aromatase inhibitors for ovulation induction. Cochrane Database of Systematic Reviews 2015, Issue 3. [DOI: 10.1002/14651858.CD005635.pub2] [DOI] [Google Scholar]
Higgins 2011
- Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). Available from www.cochrane‐handbook.org., 2011. [Google Scholar]
Jones 2012
- Jones L, Othman M, Dowswell T, Alfirevic Z, Gates S, Newburn M, et al. Pain management for women in labour: an overview of systematic reviews. Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI: 10.1002/14651858.CD009234.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kamath 2017a
- Kamath MS, Bosteels J, D'Hooghe TM, Seshadri S, Weyers S, Mol BWJ, et al. Screening hysteroscopy in subfertile women and women undergoing assisted reproduction. Cochrane Database of Systematic Reviews 2017, Issue 11. [DOI: 10.1002/14651858.CD012856] [DOI] [PMC free article] [PubMed] [Google Scholar]
Nastri 2013
- Nastri CO, Teixeira DM, Moroni RM, Navarro PA, Ferriani RA, Martins WP. Interventions for improving reproductive outcomes in women with recurrent implantation failure undergoing assisted reproductive techniques. Cochrane Database of Systematic Reviews 2013, Issue 10. [DOI: 10.1002/14651858.CD010795] [DOI] [Google Scholar]
NICE 2013
- National Institute for Health and Clinical Excellence. Fertility: assessment and treatment for people with fertility problems. London: National Institute for Health and Care Excellence, 2013. [Google Scholar]
Nyachieo 2009
- Nyachieo A, Clarke J, Moridi I, Mahdian M. Nonsteroidal anti‐inflammatory drugs for assisted reproductive technology. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD007618] [DOI] [PMC free article] [PubMed] [Google Scholar]
Shea 2007
- Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007;7:10. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zegers‐Hochschild 2009
- Zegers‐Hochschild F, Adamson GD, Mouzon J, Ishihara O, Mansour R, Nygren K, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology. Human Reproduction 2009;24:2683‐7. [DOI] [PubMed] [Google Scholar]
Zhu 2013
- Zhu X, Lim CED, Nagels HE. Acupuncture for female subfertility. Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/14651858.CD010462] [DOI] [Google Scholar]
