Evidence-based recommendations from ESHRE for 27 IVF add-ons

Researchers in a 2023 study review the use of 27 IVF add-ons and provide recommendations by ESHRE, with only several that are recommended or could be considered for the general infertility population.

Add-ons are optional procedures for IVF that can be added to a cycle, such as PGT-A, the ERA, PRP, reproductive immunology, time-lapse technology, and so on. Doctors may recommended their use for certain patient groups, but how effective they are is still being researched.

This study provides an overview of 27 add-ons for IVF and gives evidence-based recommendations on their use for the general infertility population. These are official recommendations by the European Society of Human Reproduction and Embryology (ESHRE), which included review by 46 individuals.

Note that these recommendations are based on the availability of high quality evidence (randomized controlled trials, or RCTs, and meta-analyses) that demonstrate improvements in live birth/pregnancy rates, as well as safety. Observational studies were included only if RCTs weren’t available.

Generally, high quality data is lacking for the majority of IVF add-ons. As a result, ESHRE doesn’t recommend many of these procedures. Add-ons that are cost-effective, safe, and shown to be effective by numerous high quality studies, are generally what ESHRE is looking for.

They have 4 types of recommendations, which is how I’ll structure this post:

• Recommended for most patients or specific patient groups.
• Can be considered for patients with close monitoring, while informing them of risks.
• Currently not recommended for routine clinical use. Specific groups may benefit, but routine use isn’t recommended without additional evidence.
• Not recommended. There are concerns about the add-on’s safety, effectiveness, and potentially the scientific rationale for its use (ie. the rationale for using the add-on doesn’t make sense based on existing knowledge). In this case, ESHRE recommends that the add-on should only be used in research settings.

It’s important to note that these recommendations are based on current evidence as of late 2022. An add-on may be moved to another category as more evidence becomes available.

For all the details for each add-on, you can check out the original publication. Here I’ll list their recommendations and provide some information alongside select add-ons, along with some concerns raised by reviewers at the end. I’ll also provide links to studies that I’ve covered that discuss some of these add-ons, for more information.

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Add-ons that are recommended

These add-ons are recommended for most patients or specific patient groups.

• Hyaluronic acid (embryo glue) for routine use with fresh transfers. A meta-analysis, including 26 RCTs, have mostly found a benefit, with low risk of side effects. However, there may be a an increase in the risk of multiples. Studies have found no benefit with frozen transfers. I review the latest meta-analysis here.
• Artificial oocyte activation (AOA) for patients with fertilization failure, or <30% fertilization, or some cases of severe male infertility. You can check out a recent RCT on AOA here.
• Artificial sperm activation (eg. pentoxifylline, theophylline) for some male infertility patients. This treatment “wakes up” and causes immotile sperm to move so they can be identified and used for ICSI.

Add-ons that can be considered

These add-ons can be considered for patients with close monitoring, while informing them of risks.

• Screening hysteroscopy for patients with recurrent implantation failure.
• Microfluidics for sperm selection (based on a study using the Fertile Chip device; Zymot is also an example of a microfluidic device).

Add-ons currently not recommended for routine clinical use

These add-ons are currently not recommended for routine clinical use. Specific groups may benefit, but routine use isn’t recommended without additional evidence.

• Screening hysteroscopy
• KIR and HLA genotyping
• AOA
• Rescue IVM
• Sperm DNA fragmentation. The available evidence is low quality and there’s a high amount of variability between studies. Lab conditions when performing tests, like incubation time and centrifugation, can influence the results. Even with this information, there’s no way to identify a sperm that’s free of DNA fragmentation for ICSI.
• Artificial sperm activation
• Sperm hyaluronic binding assay
• PICSI
• MACS
• IMSI
• PGT-A. Limited improvement in live birth rate across studies, despite it’s high cost. Possible reduction in miscarriage and time-to-pregnancy, based on lower quality data in specific patient groups. There may be a benefit for older patients, but more studies are needed. I review a lot of data on PGT-A here.
• Non-invasive PGT
• Mitochondrial DNA measurements with PGT
• Duo-stim
• Intravaginal or intrauterine devices
• Endometrial scratching
• Elective freeze-all (not for PCOS or for OHSS prevention). Evidence shows that freeze-all and fresh transfer cycles are equivalent, possibly with an increased time-to-pregnancy. Freeze-all cycles have a lower risk of OHSS.

Add-ons that are not recommended

These add-ons are not recommended. There are concerns about the add-on’s safety, effectiveness, and potentially the scientific rationale for its use (ie. the rationale for using the add-on doesn’t make sense based on existing knowledge). In this case, ESHRE recommends that the add-on should only be used in research settings.

• The ERA. Higher quality studies have found no benefit. In my opinion, there’s a lack of data for RIF patients, which is the patient group that the ERA is supposed to benefit the most. I cover the most recent and largest RCT here.
• Tests for uterine natural killer cells (only for those without autoimmune disorders, or for those not using immune treatments). The authors state that the idea that uterine NK cells are able to kill the fetus is incorrect, since the fetus is separated from the maternal immune system and uNK cells can’t kill placental cells. The role of uNK cells in endometrial function and implantation is uncertain, with no agreed-upon reference ranges, and changes in these cells may be due to changes in the endometrium by progesterone.
• Immunology treatments like intralipids, IVIG, PBMCs, LIF and anti-TNF. These treatments lack good quality research, and some treatments (like intralipids, anti-TNF and IVIG) can have potentially serious side-effects. I review a recent meta-analysis on this topic here.
• Mitochondrial replacement therapy to improve egg quality
• Growth factor in culture media
• Assisted hatching. No benefit for live birth rate has been shown, and may cause increased risk of monozygotic twinning.
• Time-lapse. Low to very low quality evidence. Available data doesn’t show an improvement over conventional grading.
• PRP administration to the uterus. Variable data, with mostly small studies and mixed patient populations. The authors were also concerned about exposure of the transferred embryo to the administered PRP.
• PRP administration to the ovaries. No high quality data (RCTs) to examine this.
• Ovarian stimulation add-ons, including metformin, growth hormone, testosterone, DHEA, aspirin, indomethacin and sildenafil
• hCG administration to the uterus
• G-CSF administration to the uterus
• Administering embryo culture media to the uterus
• Exposure of seminal plasma to the uterus
• Stem cell therapy for POR/DOR
• Glucocorticoids
• ICSI for non-male factor. No benefit for routine ICSI for non-male factor, but there are additional costs.
• The use of antioxidant supplements. Very low quality evidence for both male and female antioxidant supplements. You can check out the most recent meta-analysis here.
• Acupuncture. Various meta-analyses have shown that acupuncture either improves pregnancy rates or has no effect. The quality of evidence is low. A more recent meta-analysis is reviewed here that found a benefit, however this one wasn’t included in the study and likely wouldn’t have changed their recommendation.

Selected reviewer comments

This review was a massive effort, and included review by 46 experts (who made a total of 274 comments). You can access the reviewer comment pdf here.

• Cristina Magli (pg. 5) commented that the document had an overall negative position for add-ons, and that more studies are needed that target specific patient groups that may benefit.
• Vivienne Raper (pg. 14) commented on the use of immune protocols as an add-on. She comments that women with immune disorders may be undiagnosed, and for these women immune medications may help them treat their underlying symptoms, which may be connected to their infertility.
• Several reviewers (pg. 24) note an inconsistency in recommendations for PRP and microfluidics. For PRP, there are several low quality RCTs that demonstrate a benefit and it was “not recommended for routine use,” while for microfluidics there was only a single RCT that showed a benefit and “can be considered.” The authors reply that there were concerns over the safety of PRP, but not for microfluidics.
• Several authors (pg. 27) point to a study where aneuploid embryos were transferred and demonstrated a 0% live birth rate, thus showing the benefit of PGT-A in avoiding the transfer of such embryos. This study ultimately wasn’t included because it wasn’t an RCT. I review that study here (Tiegs et al. 2021).
• There are about 10 pages of reviewer comments for PGT-A!
• General comments start on pg. 53, which are overwhelmingly positive.

Conclusions

Only a few IVF add-ons were recommended or could be considered for use, by ESHRE:

• Hyaluronic acid (embryo glue)
• Artificial oocyte activation for patients with low/no fertilization.
• Artificial sperm activation for select male infertility patients.
• Screening hysteroscopy for patients with RIF.
• Microfluidics for sperm selection (based on a study using the Fertile Chip device; Zymot is an example of a microfluidic device).

The rest of the add-ons were either not recommended for *routine* clinical use, but could be used for certain patient groups (eg. sperm DNA fragmentation, PICSI, PGT-A), or not recommended for any patient groups (eg. ERA, immunology testing/treatments, assisted hatching, supplements).

For immune testing/treatments, this was in the context of patients without autoimmune disorders. One reviewer commented that women with undiagnosed immune disorders may benefit from immune treatments, however there is a lack of data for this patient group. 

This highlights the point that although certain patients may benefit from a treatment, without adequate evidence that shows this benefit, ESHRE can’t recommend use of the add-on. More research is needed to show that add-ons work for certain patients, and ESHRE states that clinics should share their outcome data to help make conclusions.

Overall, ESHRE recommended add-ons that demonstrated a benefit in multiple high-quality studies, were based on solid scientific reasoning, and were safe and cost-effective. Studies that didn’t meet these criteria were generally not recommended.

The original publication by Lundin et al. (2023) has a ton of data, and I encourage you to check it out to learn more! (it’s open access).

Reference

ESHRE Add-ons working group; Lundin K, Bentzen JG, Bozdag G, Ebner T, Harper J, Le Clef N, Moffett A, Norcross S, Polyzos NP, Rautakallio-Hokkanen S, Sfontouris I, Sermon K, Vermeulen N, Pinborg A. Good practice recommendations on add-ons in reproductive medicine†. Hum Reprod. 2023 Sep 25:dead184. doi: 10.1093/humrep/dead184. Epub ahead of print. PMID: 37747409.

 

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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