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Cochrane Special Collections

In vitro fertilisation – effectiveness of add-ons

15 July 2021
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Special Collection

First published on 16 October 2020, updated on 15 July 2021 (changes detailed below) 

As many as one in seven couples experience difficulty becoming pregnant [1], and many of them turn to fertility treatments for help. In vitro fertilisation (IVF) is generally considered the most advanced treatment option, and is recommended in many cases, regardless of the cause of subfertility. IVF is now widely available as a treatment option, with over 1 million IVF cycles taking place across the globe each year. However, despite numerous advances in IVF technology over the years, the success rate remains modest, at approximately 30% per IVF cycle [2]; although success rates vary depending on many patient and treatment factors, such as female age and cause of infertility. Even though the probability of getting pregnant and having a baby increases with additional IVF cycles, unfortunately many people finish their IVF treatment without success.

To attempt to improve pregnancy outcomes, many treatments have been added to standard IVF over the past two decades. These adjunctive treatments are called IVF ‘add-ons’. Although there is no agreed definition for IVF add-ons, the term has gained popularity and describes any extra (non-essential) procedures, techniques or medicines, which can be added to standard IVF protocols. Examples include endometrial scratching, assisted hatching of embryos, steroid treatments, and pre-implantation genetic testing of embryos. Add-ons often claim to increase the chance of a successful outcome, while posing an additional cost to standard IVF, but the evidence available for many of them is limited.

This Special Collection summarizes evidence for specific IVF add-ons from systematic reviews published by the Cochrane Gynaecology and Fertility Group. It aims to provide recent evidence to support health professionals and people undergoing IVF, to help decision making about offering or using IVF add-ons.  The reviews cover treatment options which are often considered to be IVF add-ons, but may not be viewed as add-ons in all settings as no formal definition for IVF add-ons exists.

To accompany this Special Collection Evidently Cochrane has published a blog discussing the evidence and its implications.

Updated 15 July 2021: added new Review 'Endometrial injury in women undergoing in vitro fertilisation (IVF)'

Laboratory add-ons

Hyaluronic acid in embryo transfer media for assisted reproductive technologies

In an IVF cycle, the embryo is transferred into the womb in a solution containing compounds to help the embryo adhere successfully to the inside of the womb (implantation). Hyaluronic acid is a natural compound found in the body that acts as a binding and protective agent, and is often added to embryo transfer media to help implant the embryo. This review aims to determine whether adding adherence compounds to embryo transfer media improves pregnancy outcomes, including improving live birth and decreasing miscarriage, in women undergoing assisted reproduction. Associated Cochrane Clinical AnswerFor women undergoing assisted reproductive technology (ART) procedures, how does high compare with low or no hyaluronic acid when used as an adherence compound during embryo transfer?

Time‐lapse systems for embryo incubation and assessment in assisted reproduction

In recent years, new machines for incubating embryos have been developed, called time-lapse systems (TLS), which have an inbuilt camera to take digital images of the embryos at frequent time intervals, instead of having to remove the embryos from the incubator for assessment. The potential advantage of using time-lapse systems is that they maintain stable environments for the growing embryos and the images can be used to help staff select which embryo to transfer. This review summarises the evidence for TLS compared to standard embryo incubation to assess any impact on the chance of getting pregnant and having a baby in couples undergoing IVF. Associated Cochrane Clinical Answer: What are the effects of time‐lapse systems for embryo incubation and assessment in couples undergoing assisted reproduction therapy (ART)? 

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

In ICSI (intracytoplasmic sperm injection) a single sperm is selected and injected directly into the egg, and useful for treating couples with lower sperm quality or quantity. An alternative method of sperm selection has been described where the sperm are selected under high magnification (over 6000x) and used for ICSI. This technique, named intracytoplasmic morphologically selected sperm injection (IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing IVF because it may allow the best quality sperm to be selected. This review aims to identify, appraise, and summarise the available evidence regarding efficacy and safety of IMSI compared to ICSI in couples undergoing assisted reproduction therapy (ART). Associated Cochrane Clinical Answer: For couples undergoing assisted reproductive technology (ART), how does ultra‐high magnification intracytoplasmic morphologically selected sperm injection (IMSI) compare with intracytoplasmic sperm injection (ICSI)?

Advanced sperm selection techniques for assisted reproduction

When compared with standard ICSI, advanced sperm selection techniques use more complex methods to select healthy, mature, and structurally sound sperm for fertilisation. This review summarises the evidence for advanced sperm selection techniques used in IVF, to evaluate the effectiveness and safety of advanced sperm selection techniques on ART outcomes. Associated Cochrane Clinical Answer: How does hyaluronic acid–selected sperm intracytoplasmic sperm injection (HA‐ICSI) compare with standard ICSI for assisted reproduction?

Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation

In IVF, the selection of the best embryo(s) for transfer is mainly based on an assessment of the appearance of the embryos. However, many women do not achieve a pregnancy even after 'good quality' embryo transfer. One of the suggested causes is that the embryos may have an abnormal number of chromosomes (aneuploidy). Preimplantation genetic testing for aneuploidies (PGT-A), also known as preimplantation genetic screening, was developed as a method to check the number of chromosomes present in embryos, and therefore select embryos with the correct number of chromosomes for transfer. This review summarises the evidence for PGT-A compared to regular IVF and whether it influences the chance of having a baby or a miscarriage.

GM‐CSF (granulocyte macrophage colony‐stimulating factor) supplementation in culture media for women undergoing assisted reproduction

GM-CSF (granulocyte macrophage colony-stimulating factor) is a growth factor that can be added to the embryo culture media to aid the development of the growing embryo, to lead to an increased probability of successful pregnancy. This review assesses the evidence on the effectiveness and safety of GM-CSF-supplemented human embryo culture media compared to standard culture media, and whether it influences live birth, pregnancy, and miscarriage rate in women or couples undergoing IVF.

Clinical add-ons

Granulocyte‐colony stimulating factor administration for subfertile women undergoing assisted reproduction

Granulocyte‐colony stimulating factor (G‐CSF) is a naturally occurring growth factor, and has been suggested to play an important role in the process of embryo implantation. It is proposed that giving women G‐CSF near the time of embryo transfer may increase the probability of the embryo implanting. This review summarises the available evidence on the effectiveness and safety of G-CSF in women undergoing IVF. Associated Cochrane Clinical Answer: How does granulocyte‐colony stimulating factor administration compare with placebo/no treatment for subfertile women undergoing assisted reproduction?

Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer)

The female genital tract is not exposed to seminal plasma during standard assisted reproductive ART cycles. However, it is thought that the inflammatory reaction triggered by seminal plasma may be beneficial by inducing maternal tolerance to paternal antigens expressed by the products of conception, and may increase the chance of successful implantation and live birth. This review assesses whether application of seminal plasma to the female genital tract around the time of embryo transfer improves live birth rates in IVF cycles. Associated Cochrane Clinical Answer: Can adding seminal plasma to the female genital tract before embryo transfer improve outcomes for couples undergoing assisted reproductive technology (ART)?

Aspirin for in vitro fertilisation

Aspirin is a medication commonly used to treat pain, fever or inflammation. It has been suggested that aspirin may also have a beneficial effect on some aspects required for a successful pregnancy. This Cochrane review assesses the evidence about the effectiveness and safety of aspirin used with the aim of increasing the chance of live birth in women undergoing IVF. Associated Cochrane Clinical Answer: What are the benefits and harms of aspirin for women undergoing in vitro fertilization?

Add-ons for the endometrium

Endometrial injury in women undergoing in vitro fertilisation (IVF)

Implantation of an embryo within the endometrial cavity is a critical step in the process of in vitro fertilisation (IVF). Previous research has suggested that endometrial injury (also known as endometrial scratching), defined as intentional damage to the endometrium, can increase the chance of pregnancy in women undergoing IVF. This review assesses the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing IVF including intracytoplasmic sperm injection and frozen embryo transfer.

Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction

Human chorionic gonadotropin (hCG) has an important role in embryo implantation and the early stages of pregnancy. It has been suggested that injection of hCG into the womb near the time of embryo transfer, might increase the chance of pregnancy. This review investigates whether intrauterine administration of hCG around the time of embryo transfer improves clinical outcomes in subfertile women undergoing IVF. Associated Cochrane Clinical AnswerWhat are the benefits and harms of intrauterine administration of human chorionic gonadotropin (hCG) around the time of embryo transfer for subfertile women undergoing assisted reproduction?

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction

Despite substantial improvements in the success of assisted reproduction techniques (ART), live birth rates may remain consistently low, and practitioners may look for innovative treatments to improve the outcomes. It has been suggested that injection of the embryo culture media (supernatant) into the endometrial cavity prior to embryo transfer stimulates the endometrium and provides better conditions for implantation to take place. An increased implantation rate would subsequently increase rates of clinical pregnancy and live birth, but current robust evidence on the efficacy of injected embryo culture supernatant is lacking. This review evaluates the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing ART. Associated Cochrane Clinical AnswerFor subfertile women undergoing assisted reproductive technology (ART), what are the effects of endometrial injection of embryo culture supernatant?

About this Special Collection

References

1. Infertility. NHS. 2020; Available at: https://www.nhs.uk/conditions/infertility/. (Last accessed 15 October 2020).
2. Adamson GD, de Mouzon J, Chambers GM, Zegers-Hochschild F, Mansour R, Ishihara O, et al. International Committee for Monitoring Assisted Reproductive Technology: world report on assisted reproductive technology, 2011. Fertil Steril 2018 Nov;110(6):1067-1080.

Acknowledgements

This Special Collection was developed by Sarah Lensen (Editor) and Elena Kostova (Managing Editor) with invaluable input and support from Madelon van Wely (Co-ordinating editor), Cindy Farquhar (Co-ordinating editor), Helen Nagels (Managing Editor), Melissa Vercoe (Managing editor), Marian Showell (Information Specialist), Vanessa Jordan (Cochrane Fellow) of the Cochrane Gynaecology and Fertility Group, working with Monaz Mehta (Editor, Cochrane Editorial and Methods Department). We thank all Cochrane Gynaecology and Fertility authors for contributing to these reviews. 

Image credit

GettyImages/Sebastian Kaulitzki

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Cochrane Editorial and Methods Department ([email protected])

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