Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. And today, we have with us Dr. Elnur Babayev. He's a physician scientist, an assistant professor, and a specialist in Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology at Northwestern Medicine. He's here to discuss a case that centers on a patient with diminished ovarian reserve and advanced reproductive age, who delayed evidence-based fertility care while pursuing unproven interventions, which can raise important concerns about counseling, prognosis and reproductive aging.

Dr. Babayev, thank you so much for joining us today. This is a really very interesting patient case we're discussing here. So, can you briefly explain this case and why it was possibly concerning in the context of diminished ovarian reserve and reproductive aging?

Elnur Babayev, MD, MS: Thanks for having me on the podcast, Melanie. I'm happy to talk about this case. This was a case of a 45-year old woman who does have a history of uterine fibroids, ovarian cysts, and dysmenorrhea, painful periods. She sought treatment for infertility and received intra-ovarian platelet-rich plasma injections.

So for the physicians who are not aware of this treatment, this is an autologous blood product. So as the name suggests, platelet-rich plasma, that's rich in growth factors. That is used in many fields of medicine to help with regeneration. And it is something that's being explored in reproductive medicine. And this patient received this treatment. And two weeks after her PRP injections into the ovary, she came to our emergency department with severe lower quadrant pain. And she actually has been symptomatic for about a week before she came to our emergency department. She's been experiencing chills, loss of appetite, worsening pelvic pain. And she was actually started on antibiotics orally by her outside provider.

In our ED, she had significant leukocytosis with white blood cell count over 18,000. She had mild lactic acidosis, and she had bilateral complex cystic adnexal masses in the pelvis. And that was consistent with bilateral tubo-ovarian abscesses. She ultimately required two hospitalizations. And, on the second admission, image-guided transabdominal aspiration of the abscess was performed by our interventional radiology colleagues. And the cultures grew bacteria called Streptococcus anginosus. She ultimately recovered fully, and her pain resolved, her menses returned to normal in about four months after her initial presentation.

Why was it concerning? It was concerning because this was a 45-year-old woman who was facing fertility challenges. And in this age group, the success of in vitro fertilization is 1% or less.

For example, in our center, we do not routinely offer IVF to women at 45 years old or older because the risk of medical intervention generally outweigh the benefits in this age group. We would've had a frank conversation speaking of evidence-based medicine in this age group about the donor eggs with this patient. But ultimately, this patient had an unvalidated procedure elsewhere. And this ended in bilateral tubo-ovarian abscesses, two hospitalizations and, unfortunately, several months of recovery.

And another concerning thing was that, in this case, she had some history that would indicate that she may have had endometriosis, which in this specific case would've increased her risk of getting infected with these platelet-rich plasma injections because the endometriosis of the ovary can become superinfected.

Melanie Cole, MS: Wow, that's fascinating. You know, we think about these unproven interventions. And PRP, as you said, is used in other areas of medicine and orthopedics. And, you know, it's found some success. And it's always interesting to me, Dr. Babayev, how certain things — even like when you look at tamoxifen and such — cross over, right? They cross over from area to area. But this is really interesting.

So along those lines, then when you're thinking about patients with diminished ovarian reserve, you've probably heard misconceptions in your career. What do you see most often? And if you think of this particular patient, why she went to pursue those kinds of interventions?

Elnur Babayev, MD, MS: I think the most consequential misconception is likely the belief that ovarian function can be meaningfully "rejuvenated," that the clock can be wound back. You know, maybe one day that would be the case. And as a scientist who works in this field, I can tell you that this is not where science stands today. There's a lot of work going on in this area. But unfortunately, we cannot at this point rejuvenate the ovarian function. But unfortunately, this is the language that's being used to market intra-ovarian PRP, and it's deeply appealing to patients because it reframes an irreversible biological process as something correctable.

The reality is that ovarian aging involves both the depletion of the egg number, but unfortunately, most critically, also the decline in the quality in the eggs. And this is primarily due to accumulation of miotic errors that lead to the aneuploidies. And unfortunately, no intervention today — again, no intervention today — restores the chromosomal integrity of these aging oocytes.

The second major misconception is conflating the ovarian reserve markers with the fertility prognosis. You know, the commonly used marker that general OB-GYNs are aware, anti-Müllerian hormone or AMH for short. It's a measure of the egg quantity, not the quality. While some observational studies have showed that this intermediate marker may improve with the PRP injections, the randomized control trial that we also referenced in our paper have shown that ultimately the number of eggs retrieved or implantation rates in the IVF cycles do not improve. And in that study, the women were actually younger, less than 38 years old. So, we would expect even worse prognosis in women who are older.

The third misconception is that women may think that the regular menstrual cycles means their fertility is intact. However, even for a 45-year-old woman who still menstruates regularly, who may assume their fertility is normal, their egg quality is still poor and egg quality declines long before menstrual irregularity develops. So, the third misconception is regular menstrual cycles do not equal the normal fertility.

And the final misconception I want to emphasize here specifically is what experimental "means." Patients often hear that treatment is experimental and may interpret this as promising but not yet approved. However, the more accurate framing for a treatment like this, intra-ovarian PRP, that's currently offered commercially, which is that outside of registered clinical trial, is that we do not know how it works, we do not have standardized protocols, we do not know whether it works. Adverse events are under-reported and, as this case demonstrates, serious harm is possible. So, that's a very different message from saying this is cutting-edge, but promising. It's important to frame what experimental really means in these cases.

Melanie Cole, MS: Well, those are all important points. So along those lines, when we think of the key risks that are associated with these approaches, your paper discusses unproven fertility interventions that are marketed to these patients, like the one we're discussing here today. What are some of your biggest concerns for those risks?

Elnur Babayev, MD, MS: Absolutely. Yeah. I mean, this case makes the safety argument in the most concrete way possible, right? The transvaginal access used for the platelet-rich plasma, PRP injections, there's a baseline risk when we access the ovaries with a needle as REI [reproductive endocrinology and infertility] practitioners. In the setting of IVF that we do routinely, that risk is reported to be under 0.5%. So certainly not a high-risk, but not a zero risk.

However, when you are adding PRP into the ovary or injecting PRP into the ovary, that adds a layer of additional complexity. We are introducing a blood product directly into the ovarian tissue, which likely amplifies these risks. Like the bacteria that was isolated in our case, it's classically associated with abscess formation. And it's thought to represent vaginal or skin flora introduced at the time of the procedure. And our patient's history of ovarian cysts and probable endometriosis may have further potentiated that risk. So, infection risk is, obviously, you know, one of the risks of these procedures.

And beyond infections, there are important concerns about the lack of standardized protocols. As I mentioned earlier, for PRP specifically in the context of reproductive medicine, the preparation, concentration, injection volume, what needle you'll use, how many times you'll puncture the ovary, at what point of the menstrual cycle you'll do, there is no standardization on that. And without standardization, there's no way to meaningfully compare outcomes across providers and no way to know what a safe technique may look like.

Additionally, psychological and financial risks are also real. Patients with infertility and diminished ovarian reserve are often emotionally and financially vulnerable. They've been told that their options are limited and they're desperate for solutions. Intra-ovarian PRP is not covered by insurance and is marketed with compelling but unsubstantiated language. When it fails — as the evidence suggests it usually does — the emotional toll compounds the financial loss.

And lastly, and perhaps most critically, the opportunity cost risk, which is time. From the fertility perspective, the lost time in your late 30s and early 40s is not trivial. If the patient wants to pursue IVF using their own eggs, the prospects narrow further while pursuing these invalidated treatments. And so, this is some of the risks that are associated with these invalidated treatments.

Melanie Cole, MS: That's so interesting. And, Dr. Babayev, when you mentioned the emotional aspect and the psychological aspect of hearing that this could give you a chance, that this could reverse some biological aging, as you said, and given that emotional complexity of fertility care in general, we know that that is a very emotional time for couples. How should OB-GYNs approach counseling these patients who are seeking that experimental or non-evidence-based fertility treatments when you are talking to patients about this and telling other providers how to speak with patients about this? What do you want them to know about this?

Elnur Babayev, MD, MS: It's a wonderful question. Our general OB-GYN are colleagues deal with these questions on a daily basis from their patients. The first and most important principle is to recognize the emotional context before engaging the clinical content, I believe. A patient who comes in asking about this treatment is not a naive consumer who needs to be corrected. She's someone who's likely been trying to conceive possibly for years who has researched her condition extensively, who may have received devastating prognosis information, and who is looking for hope. Dismissing her interest without acknowledging that emotional reality will end the conversation, in my opinion, before it begins and will likely not prevent that patient from pursuing the treatment elsewhere.

Once we validate that emotion, the conversation should truly move forward towards honest, specific and evidence-based information. Unproven should not be used as a generic dismissal. We need to really explain what it means concretely. We need to walk the patient through what the best available evidence actually shows. You know, in a case like ours, we can say that observational studies, which had several flaws or biases reported modest improvements in surrogate markers like AMH. But the randomized controlled trial found no improvement in the success rates. We need to tell our patients that case reports, including ours, document serious infectious complications. And these are the specific, grounded, honest statements, not paternalistic dismissals.

And truly, informed consent is the operative framework here. You know, if a patient, after being fully informed of the evidence gaps and the risks and opportunity costs, financial costs, still wants to pursue PRP, that's obviously, you know, her right as an autonomous adult. For our patients, even in our practice who ultimately decide to seek this intervention elsewhere, we truly encourage them to do this within a registered clinical trial, because that's the only context in which this procedure can be ethically offered right now and the only context where we can track and report adverse events.

Finally, I think we should offer alternatives proactively. So as general OB-GYNs, they should be aware of the potential alternatives. Patients often pursue these unvalidated treatments, because they feel medicine has nothing left to offer them. We should make it clear that there are meaningful evidence-based options. And as we discussed earlier, IVF was likely not an option for this patient. However, for a relatively younger patient, IVF with or without an add-on, that's called pre-implantation genetic testing aneuploides — so, the genetic testing on embryos — could be an option. For a patient like this, the donor oocytes, which carry dramatically high live birth rates, can be considered. And they deserve to be framed as a path forward for parenthood rather than a concession of defeat. And connecting patients with reproductive psychologists and peer support communities is also part of a comprehensive compassionate care.

Melanie Cole, MS: Dr. Babayev, you have so much knowledge to share about this. So, offer some guidance for OB-GYNs. I just asked you about offering them guidance to approach counseling patients who are seeking those experimental. Now, I'd like you to give them guidance on discussing prognosis, as you're speaking about age and diminished ovarian reserve, referral timing, and options with patients of advanced reproductive age who have these conditions.

Elnur Babayev, MD, MS: Right, absolutely. I think the most urgent practical message is refer early. For women who are, let's say, over 35, fertility evaluation should start just after six months of unprotected intercourse. So, we don't wait a year that we typically do for younger patients. So, those are the women who are at increased risk of having diminished ovarian reserve. So after six months, if you have a couple in front of you who's over 35, been trying for six months and hasn't been successful, refer them to your reproductive endocrinology colleagues for further evaluation and treatment.

On top of that, if your patient has known risk factors for diminished ovarian reserve, that somebody who had a prior ovarian surgery, one ovary removed, or there were multiple cyst surgeries on the ovaries, or had chemotherapy or have a family history, a mom or a sister who had early menopause, those should be the patients you immediately refer to reproductive endocrinology to make sure that they have further workup and possible treatment if indicated.

And when discussing prognosis with this patient, honesty is definitely a clinical obligation. But honesty that's delivered without compassion is not effective, obviously. You know, being specific what the numbers mean in terms of their likelihood of having a baby or what we call a live birth probability is super important.

I hear a lot from our general OB-GYN colleagues who do that AMH test and it results with a certain number like, say, 0.3. And they sometimes struggle interpreting that number or deciding to refer the patient versus, you know, have them continue on their own for a while longer. So, a patient who's being told, let's say, your AMH is 0.3, you know, doesn't really know what that means for her chances to achieve pregnancy. But if we tell them, "Okay, at your age with this AMH, your probability of live birth is this percent, let's say, A percent. And with this intervention, it may go to B percent. And if you use donor eggs, it's C percent," then the patient has that information and can make an informed decision about her fertility. And we have to be honest and transparent about the options without ranking them emotionally. And IVF is definitely a fantastic option, but it's not right for everyone.

As we talked earlier, like donor egg-based treatments ha e substantially higher success rates, up to 50%, again, depending on some individual characteristics. And it should be presented in cases like this as a legitimate and emotionally valid pass. And OB-GYNs should feel empowered to talk about this option to their patients in cases like ours.

And when it comes timing of referrals specifically in the context of unproven treatments, a patient like ours asking about intra-ovarian PRP or similar interventions is giving their OB-GYN a clinical side. She's certainly worried about their fertility. And OB-GYNs can use that visit obviously to educate the patients about their fertility, offer ovarian reserve testing if it has not been done, and just make the referral to reproductive endocrinology that day. There's no need to wait to have another return visit to discuss it further because the biological cost of the delay is real. So, it can have that conversation with the patient, order ovarian reserve test, and then immediately refer the patient to reproductive endocrinology.

Melanie Cole, MS: Dr. Babayev, thank you so much. You've given us so much to think about. Our final question here, what would you like the key takeaways to be from this case report that you really want OB-GYNs to take away for managing infertility and reproductive aging in their practices? What would you like them to know about what you're doing at Northwestern that's so exciting and helpful for these women?

Elnur Babayev, MD, MS: I think the central lesson in cases like this is that the absence of evidence is not the evidence of absence of harm. What I mean by that is it hasn't been proven dangerous yet, in quotes. It's not an acceptable standard for a procedure being offered commercially to vulnerable patients outside of any clinical trials.

Specifically, for our general OB-GYN colleagues, I think there are three actionable takeaways. First, being the informed first responder, our general OB-GYN colleagues are often the first clinician that their patients discuss their fertility concerns with. So, knowing the current evidence landscape well enough to have that substantive specific conversation when a patient asks about these kind of treatments, including PRP and other treatments that are unvalidated but certainly commercially offered will be very helpful.

The second, as we discussed earlier, is referring early and referring specifically to reproductive endocrinology. This timely referral is one of the highest impact interventions an OB-GYN can make for their patient.

Lastly, I would say maintaining a high index of suspicions for complications like this, infection complications in our case, in a patient who presents with a pelvic pain where there's been a procedure into the ovary, it is extremely important for the OB-GYNs to be aware of these practices.

Melanie Cole, MS: Great information. Thank you so much, Doctor, for joining us today and sharing this case and your incredible expertise. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/obgyn to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.