Study investigates role of intrauterine PRP in improving embryo transfer outcomes

A 2024 study compared outcomes for intrauterine PRP in patients with RIF and unexplained infertility, finding no improvement in implantation rates but improvements in live birth rate, although there were multiple issues with this study.

Platelet-rich plasma (PRP) is used in IVF for various purposes, including intraovarian administration to improve egg quality and intrauterine administration to enhance endometrial receptivity and implantation, particularly in women with recurrent implantation failure (RIF).

This post is a summary of a study by Yahyaei et al (2024), who performed a randomized controlled trial (RCT) used intrauterine PRP in women before their transfer. These women had unexplained infertility and RIF.

Spoiler alert! I had multiple issues with this study, and I normally wouldn’t review a study like this, but I thought I’d walk through it more and point out the flaws. If you’re interested in critically analyzing research, you might enjoy this post! So you’re not left empty handed as far as PRP goes, I reviewed a few meta-analyses at the end to give a good overview of what the researcher says on intrauterine PRP.

This study was an RCT, which is considered the “gold standard” for evidence and are designed to reduce bias and increase the accuracy of results. In an RCT, participants are randomly assigned to different treatment groups, which helps ensure that the groups are similar at the start of the study. This randomization reduces the chance that differences between groups are due to something other than the treatment being tested. For an RCT to be trustworthy, there are certain steps and guidelines that should be followed, such as clearly defining outcomes, registering the study before it begins, and using a sample size large enough to draw meaningful conclusions. Following these guidelines helps produce results that can be confidently applied to larger populations. As we’ll see, there were several issues with this particular RCT, so let’s get to it!

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Study details

• This was a retrospectively registered RCT (more details below), involving patients recruited between 2017 and 2021 at a single center in Iran.
• Inclusions: Women had unexplained infertility with RIF (history of failing to achieve clinical pregnancy after 3 transfers, using at least 4 good quality embryos), <40, BMI between 19-29, blastocyst production.
• Exclusions: No explained cases of infertility (ie. due to some diagnosis or male factor), no pre-existing conditions (cancer history, autoimmune disorders, etc.), endometrial thickness <7 mm, no gamete or embryo donation. There were a variety of exclusions relating to inflammation — no fevers/anti-inflammatories/garlic, onion and omega 3, 6 supplements before PRP. It’s unclear what the mechanism of PRP is, although some research suggests it could benefit implantation by reducing inflammation.
• Only blastocysts were transferred (2-3). There was no mention of the quality.
• The primary outcome was the implantation rate (the number of gestational sacs divided by the number of transferred embryos).

Sample size: There were 697 patients enrolled in the study, with 617 excluded. A total of 80 patients were randomized to the intervention and control group, with 10 being excluded due to failed blastocyst formation or thin endometrium. There were both fresh and frozen transfer groups. The study didn’t mention a power calculation for determining the sample size, which raises concerns about whether they had enough participants for statistical analysis. The final sample size was:

• Intrauterine PRP group: 34 (fresh transfer 18, frozen transfer 16)
• Control (no PRP): 35 (fresh transfer 18, frozen transfer 17)

Patient baseline and characteristics (between the PRP group and control group): No differences in age, BMI, infertility duration, previous failed cycles, irregular menstruation, primary/secondary infertility, FSH, LH, E2, P4, gonadotropin dose, stimulation duration, endometrial thickness.

Additional info on the retrospective registration:

• RCTs are designed to minimize bias by planning every aspect of the study ahead of time and registering before they begin for transparency. Registration ensures the study’s design, goals, and methods are publicly available. The reason for this is to prevent researchers from selectively reporting favorable results or changing their study’s design after seeing the data.
• This study was retrospectively registered in June 2019, even though it started in August 2017, raising concerns about whether the original study design was changed.
• And it was changed! There are multiple examples, but let’s consider one. The “no garlic, onion and omega 3, 6 supplements before PRP” exclusion was in the published paper but not in the registration. For some reason, at some point between the time the study was registered to the time it was published, they felt it was important to exclude these patients. Why? Maybe they wanted to control for possible inflammatory effects on endometrial receptivity, but they didn’t provide any explanation. This raises questions about whether this decision was based on new information, biases, or unforeseen results during the trial.
• It’s concerning that the protocol was altered, and makes you wonder if they changed things after seeing the data. This undermines the reliability of the study.

Study results

In this study, they compared pregnancy outcomes for patients that transferred 2-3 blastocysts. The patients did or didn’t have intrauterine PRP before the transfer.

The implantation rate was similar between the intrauterine PRP and control groups (57% vs. 59%). However, the clinical pregnancy rate was much higher in the PRP group (55.8%) compared to the control group (20%). This suggests that there was a large number of losses between implantation and clinical pregnancy.

The study defined the implantation rate as the number of gestational sacs per embryo transferred, which typically forms around 4 weeks, but they didn’t define clinical pregnancy. Some studies use the presence of a gestational sac to indicate clinical pregnancy, but since the implantation and clinical pregnancy rates were so different here, they probably used fetal heartbeat (measured around 6 weeks). As far as I can tell (and after doing all kinds of math), the large difference in pregnancy and implantation rates in the control group (59% to 20%) seems to be due to a high number of losses within the two-week period between the gestational sac and heartbeat. Unfortunately, the authors didn’t expand on this.

The miscarriage rate was also lower in the PRP group (5.3% vs 57.1%, p= 0.0001). The 57.1% miscarriage rate in the control group is unusually high, which could be due to the small sample size—there were only 7 clinical pregnancies in the control group, and 4 of them ended in miscarriage. With such a small number of pregnancies, even a few miscarriages could result in a high miscarriage rate.

Small sample sizes can distort the accuracy of study results. In studies with small groups, even a few extreme outcomes can create misleadingly high or low rates, which might not accurately reflect what would happen in a larger, more representative population. In this study, the control group had only 7 pregnancies and 4 of them ended in miscarriage, resulting in an unusually high miscarriage rate of 57.1%, when 10-20% is more typical. In general, small sample sizes reduce the statistical power of a study, making it harder to draw valid conclusions from the data.

The live birth rate was higher for the PRP group vs the control (52.9% vs 8.6%, p= 0.0001). This isn’t surprising when you consider all the losses the control group had.

They also found a higher rate of pregnancy complications (gestational diabetes and hypertension) for the PRP group vs the control group (15.8% vs 0%, p= 0.0001). This might also be due to the low number of pregnancies in the control group.

Conclusions

For the implantation rate, there was no difference between patients who had intrauterine PRP or didn’t.

However, the live birth rate was higher for the PRP group, and this was because of the high number of losses in the patients that didn’t do PRP (specifically between implantation and fetal heartbeat, if the assumptions I made earlier are correct). These RIF patients had a history of not achieving clinical pregnancy, so it seems like intrauterine PRP protected these patients from a loss during this time and allowed them to continue to clinical pregnancy.

In my opinion, there were multiple problems with the study that put into question its reliability.

• The retrospective registration and changes made between the RCT registration and the published data. I listed one example above, but there were many.
• No blinding. The researchers knew who got what treatment. This is a problem because it opens the door to potential bias in how they assess and report the outcomes, as they might unintentionally (or intentionally) influence their observations or interpretations based on the treatment group.
• No focus on the primary outcome. A key limitation of the study is the lack of focus on the primary outcome, the implantation rate, which was similar between the PRP and control groups (57% vs 59%). Instead of discussing this finding, the authors emphasized the clinical pregnancy and live birth rates, which are secondary outcomes. This shifts the interpretation of the results to make PRP look more effective than it may be.
• No power calculation and low sample size. We don’t know if their sample size was adequate for what they were measuring. The results on pregnancy complications was based on only 7 pregnancies in the control group. The low sample size may also be why there’s a high miscarriage rate in the control group.
• No clear definitions for outcomes. I’m not sure how they defined clinical pregnancy.

So I hoped you enjoyed this summary! It’s a bit different from my usual approach. This study had a bunch of problems and I would have normally skipped over it, but I felt like this one had a lot of examples for what to look out for in an RCT.

I hope this analysis gives you a better understanding of the role of RCTs in minimizing bias and providing reliable evidence. A good RCT is carefully planned to ensure that the treatment effect is measured accurately, free from any interference or preconceptions. When done properly, RCTs are one of the most powerful tools for understanding the effects of a treatment!

Not sure if this is interesting for everyone, and if it isn’t I’ll just focus on usable studies in the future. I put together a super short survey so you can let me know how you feel about this.

And just so you don’t leave empty handed, for those looking for more intrauterine PRP information I’ve put together a tiny review of recent meta-analyses on the topic:

• Vaidakis et al. (2024), in their Cochrane review, combined the results of 9 RCTs on intrauterine PRP. With PRP, there was a 2.38-times higher odds of live birth/ongoing pregnancy and 2.22-times higher odds of clinical pregnancy rates, with no change in miscarriage rates. There was an 8.02-times higher odds of preterm delivery, but no difference in multiple pregnancies or ectopic pregnancies. I reviewed this study in my post Meta-analysis combines results of 12 intrauterine, intraovarian PRP studies.
• Maged et al. (2023) combined the results of 6 RCTs and 4 non-RCTs that focused on intrauterine PRP in women with previous implantation failure. They found that there was a 2.62 and 2.06 times increase in the odds of implantation, from the RCT and non-RCT studies respectively.
• Shalma et al. (2023) combined the results of 23 studies (RCTs and non-RCTs) that investigated intrauterine PRP. In their subgroup looking at women with RIF, there was 2.54 higher odds of live birth with PRP than without it (based on 6 RCTs).
• A point that was frequently mentioned in these meta-analyses is that the included studies were low quality, so better designed studies should be performed.

Reference

Yahyaei A, Madani T, Vesali S, Mashayekhi M. Intrauterine infusion of autologous platelet rich plasma can be an efficient treatment for patients with unexplained recurrent implantation failure. Sci Rep. 2024 Oct 29;14(1):26009. doi: 10.1038/s41598-024-77578-1. PMID: 39472511; PMCID: PMC11522411.

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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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