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 will summarise the evidence for the different steps in ART.
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 for the objective of establishing a pregnancy (Zegers-Hochschild 2009).
Once couples have been prepared for treatment, these are the steps that make up an ART cycle:
- Drugs are initiated to stimulate multiple growth of ovarian follicles, while at the same time other medications are given to suppress the natural menstrual cycle and down-regulate the pituitary gland.
- After initiation of ovarian stimulatory drugs, scans are taken at intervals to follow the growth of the 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 oocyte triggering).
- The next step involves egg collection (usually with a vaginal probe to guide the pickup) and in some cases of male infertility, sperm retrieval.
- Next is the fertilisation process, which is usually completed by in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).
- Laboratory procedures follow for embryo culture: adhesion molecules, culture media.
- After fertilisation, the embryos are replaced into the uterus. Issues of importance here include the best timing for embryo transfer, how many to transfer, and what type of catheter to use.
- Then there is luteal phase support, for which several options are available, including progesterone, estrogen (E
2), and human chorionic gonadotropin (hCG).
Finally, adverse effects, such as ovarian hyperstimulation syndrome, are associated with the assisted reproduction process.
How the intervention might work
Assisted reproductive technology (ART) treats a variety of causes of infertility by collecting gametes, creating embryos from these in the laboratory, and replacing 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 provides 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.
To summarise the evidence from Cochrane systematic reviews on procedures and treatment options available to couples with subfertility undergoing ART.
Criteria for considering reviews for inclusion
Only published Cochrane systematic reviews will be considered in this overview.
Participants will be couples with subfertility seeking a pregnancy and undergoing ART. Specifically, participants will include women with endometriosis, women with a previous poor response or recurrent pregnancy losses, and couples undergoing frozen embryo replacement cycles and/or oocyte donation cycles.
The interventions of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) will be considered. Intrauterine insemination and ovulation induction will be excluded from the overview.
The primary outcome will be live birth.
Secondary outcomes will be clinical pregnancy, multiple pregnancy, miscarriage, and ovarian hyperstimulation syndrome.
Search methods for identification of reviews
The Cochrane Database of Systematic Reviews and the Menstrual Disorders and Subfertility Group specialist registry will be searched using the term Assisted Reproductive Technology. The search term will be limited to title, abstract, or keywords. No other databases will be searched.
Data collection and analysis
Selection of reviews
Reviews addressing the stages/steps of ART interventions will be selected. These reviews will be identified by one review author and confirmed by a second review author. Disagreements will be resolved by consensus or by discussion with a third party.
The reviews will be separated into the following topics:
1. Indication for ART.
2. Pre-ART strategies:
a. In general (e.g. life style, supplements).
b. For specific populations (e.g. endometriosis, polycystic ovary syndrome, male infertility, tubal pathology).
3. Down-regulation with agonists or antagonists.
4. Ovarian stimulation.
a. Medication type.
c. In case of poor response.
5. Ovulation triggering.
6. Oocyte retrieval.
7. Sperm retrieval.
8. Laboratory phase.
9. Embryo transfer:
a. Developmental stage.
b. Number of embryos.
c. Transfer techniques and procedures.
10. Luteal phase support.
11. Prevention of ovarian hyperstimulation syndrome (OHSS).
12. Frozen embryo replacement cycles.
Data extraction and management
Data on the above outcomes will be extracted independently by two review authors (from JR, JB, CF, WN) using an Excel spreadsheet. Disagreements will be resolved by consensus. In cases where significant data are missing, the original review authors will be contacted for assistance. Information will be extracted on the following:
- Population demographics: we will summarise participant characteristics.
- Review characteristics: the number of included trials; the number of participants in each review; the date that the review was assessed as up to date; interventions and comparisons; all outcomes; and limitations of the review.
- Statistical summary: the summary effects from relevant comparisons and outcomes.
Assessment of methodological quality of included reviews
Quality of included reviews
The quality of the included reviews will be described in a narrative manner. The risk of systematic errors or bias in the systematic reviews is subject to the risk of bias in the original trials included in the systematic review.
Quality of evidence from primary studies in included reviews
The quality of the data within the original reviews will be described and GRADEPro summary of findings tables will be produced for each review to indicate the quality of the included studies. The following criteria will be taken into account: study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness, and publication bias.
A narrative description of the included trials will be undertaken. A network meta-analysis will not be undertaken at this point.
We would like to acknowledge the support of the Menstrual Disorders and Subfertility Group editorial base.
Contributions of authors
Professor Farquhar, Drs Brown and Nelen, and Josephine Rishworh have all contributed to the development of this protocol.
Declarations of interest
Professor Farquhar and Dr Brown are authors on some of the included reviews. There are no conflicts of interest that relate to industry.
Sources of support
- University of Auckland research grant, New Zealand.
- No sources of support supplied