More good news about the safety of the COVID-19 vaccines and male fertility: a study published in JAMA documented semen analysis parameters before and after the COVID-19 vaccine. I referred to it in a previous post when the study was still ongoing.

The findings were enlightening:

Men ages 18-50, provided sperm samples before vaccination, then about 70 days after the second dose. Of the 45 volunteers who bravely ejaculated twice in the name of science, 21 received the Pfizer vaccine and 24 received Moderna. 

After the second vaccine dose, the median sperm concentration, total motile count, semen volume, and sperm motility all significantly increased. Furthermore, of 8 men who had low sperm counts in their first sample, 7 had concentrations improved to the normal range after the vaccinations.

Does that mean the COVID-19 vaccines improve sperm counts? Probably not, and the authors were smart to point that out. To be transparent, the data documented that were some men in the study whose concentrations did decrease somewhat. The authors state that “the magnitude of change is within normal individual variation and may be influenced by regression to the mean.”   

The moderation in their conclusion is admirable. If there was any other intervention  (think vitamins, supplements, etc) that led to a statistical improvement in sperm counts, we would be quick to declaring a miracle cure. Certainly, if the opposite were true and the numbers went in the wrong direction, critics would be quick to vilify the vaccine.

At the very least, this study confidently reassures us that the vaccine did not harm the sperm counts. Let the data speak for itself.

The safety of the COVID-19 vaccines in the context of fertility and pregnancy has been endorsed repeatedly by the World Health Organization and all of the important professional societies (SGOC, CFAS, ASRM, ACOG, ESHRE, yada yada). I have blogged on this a few times: link here, here, and here for my thoughts. However, it is always nice to have logic and reason supported by data, and a new study published in Fertility & Sterility Reports does just that: 

Dr. Randy Morris compared 3 groups of patients: 1) vaccinated against COVID-19, 2) previously infected with COVID-19 virus, and 3) neither infected nor vaccinated.  Antibodies to the COVID-19 spike protein were measured in all patients to confirm their immunity status. In the vaccinated group, patients received either the Pfizer or Moderna vaccines, both mRNA-based. The design of the study was simple and elegant: outcomes were compared after frozen embryo transfer of a single embryo.  

The data from the paper is copied below, but here’s the bottom line: implantation and ongoing pregnancy rates were identical in all 3 groups. (Actually, point values were better in the vaccination group, but statistically speaking, there were no differences.) Furthermore, miscarriage rates were not higher in those who were vaccinated compared to others (again, at face value results were better in the vaccinated group). 

Perhaps even this will not convince those that are entrenched in the anti-vax conspiracy theories. However, for the reasonable people out there who were just nervous about jeopardizing their fertility and were waiting for data, I hope you find this evidence enlightening. For those of you who already been vaccinated, good on you. You are saving lives, not the least of which is your own. 

Dare we say that we are emerging from the worst of the pandemic. At least in our little slice of the universe, infection rates have declined again, and vaccines are finally becoming more available. With sunshine and warm weather upon us, “normal” life looks like it is soon to return. Hopefulness and optimism notwithstanding, lest we forget this pandemic claimed nearly 4 million lives worldwide and taken an immeasurable toll in so many other ways.  

Furthermore, it is clear that there are long-term health consequences for some COVID-19 survivors. Post-acute COVID-19 syndrome is the emerging diagnosis recognizing the multi-system, chronic effects we are seeing in “long-haulers.” 

In honor of Men’s Health Week (which is the week leading up to Father’s Day, and not to be confused with Movember), let’s discuss the one very specific concern with COVID-19: can it affect male reproductive health?  

We know that many infections, due to the fevers that they cause, can at least temporarily result in a decline in sperm count. Mumps is perhaps the most well-known example of a viral infection that can cause acute testicular damage (aka, orchitis), rendering some men sterile.  

It turns out that COVID-19 also has a special affinity for the testicles: the portal of entry into the lung tissue, the ACE2 receptor, is also highly expressed in the testicles, specifically on the Leydig cells which are critical for hormone production, and the Sertoli cells which are required for spermatogenesis.  

Men recovering from COVID-19 infection demonstrated lower semen volume, sperm concentration, motility, morphology as well as elevated markers of inflammation and oxidative damage.  Post-mortem studies have demonstrated the COVID-19 infection has caused destruction of the testicular tissue.  A  study from Italy showed that some men infected with COVID-19 will develop hyogonadism (aka, testicular failure), with the associated lower testosterone levels predictive of a poorer prognosis and greater mortality from the infection. 

To add insult to injury, COVID-19 infection in men may also be associated with erectile dysfunction. The “cytokine storm” caused by the infection is responsible for the life-threatening damage in the respiratory and cardiovascular systems, but also damages the endothelial cells that line blood vessels throughout the body, including the penile tissue. In turn, the presence of erectile dysfunction is also associated with other health consequences such as heart disease, a classic vicious cycle.  

But is it safe to get the vaccine? The experts certainly believe so, demonstrated by a joint statement from the Society for Male Reproduction and Urology and the Society for the Study of Male Reproduction. While it is true that about 16% of patients will develop a brief fever after vaccination, it is not necessarily severe enough to cause a decrease in sperm count. Even so, such an effect would be temporary, in contrast to the potentially more severe and long-lasting destructive effects of the virus itself. A soon to be concluded study will reveal more objective data on the effects of the COVID-19 vaccine on semen parameters.  

So if you are a person with testicles and a penis, protect them from COVID-19. Get vaccinated, which by the way, might also save your life. 

Most people are familiar with the fact that our gastrointestinal systems are colonized by bacteria. All the way from the mouth to the anus, the long tube known as the “gut” is full of bugs! Your skin is also covered. In fact, it has been estimated that there are more than 10 times as many microbes that live in/on our bodies than our bodies’ own cells. Gross, right?

The microbiome is the environment within our bodies comprised of trillions of other living organisms (and BTW, it’s not just bacteria). Eubiosis is the condition of harmony with our microscopic friends; dysbiosis is an imbalance of the microbiome with an overabundance of unwelcome guests.*

It has become apparent that a proper balance is not only important to prevent infections and maintain healthy digestion but can also influence the immune system and even neurological diseases like Parkinson’s syndrome. Click here for an interesting review on the topic. If you want to dive deeper into the geeky rabbit-hole, read about the concept of the hologenome. It’s fascinating!

We also know that the vagina hosts a variety of normal flora. Lactobacillus is the dominant species, named for its production of lactic acid that maintains a healthy pH, defending against pathogenic microbes. Yeast infections and bacterial vaginosis occur when the balance of normal bacteria is disrupted. Furthermore, vaginal dysbiosis increases risks for sexually transmitted infections, pelvic inflammatory disease, and even gynecological cancers. During pregnancy, dysbiosis can cause miscarriage and preterm labor. In addition, a mother’s microbiome can potentially have long-term health effects for her offspring [1].

On a related note, we have long since appreciated that infections in the reproductive tract can cause infertility. For example, sexually transmitted infections like chlamydia can destroy fallopian tubes; tuberculosis (luckily not common in our part of the world) can irreversibly damage the endometrium. Pathological bacteria secrete toxins and create a biofilm that is hostile to sperm, eggs, and embryos (not to mention your overall health!). In turn, the immune system is activated to fend off the attackers, but the inflammatory state causes collateral damage to the tissues.

It turns out that a healthy uterus doesn’t just require the absence of bad, it also needs the presence of good: the uterus has its own microbiome. Once again, lactobacillus is the good stuff, although in a much lower density than the vagina. A study with IVF patients demonstrated that patients with >90% lactobacillus concentration in their microbiomes had significantly higher implantation and live birth rates than those who were non-lactobacillus dominated [2].

A trickier condition is chronic endometritis (CE): a low-level infection that does not usually cause any noticeable symptoms.  One study demonstrated that up to 42% of women with recurrent implantation failure after IVF had CE [3].  Unfortunately, diagnosing CE has also been traditionally challenging since it relies on the microscopic identification of plasma cells with H&E staining and cell culture, both of which are plagued with inaccuracy, often leading to misdiagnosis. Hysteroscopy is helpful but also of limited value since we simply can’t see all infections [4]. Carpet-bombing with antibiotics to try to kill the bad bacteria has been proposed but is problematic for obvious reasons.

Fortunately, we have new way to assess the uterine microbiome: EMMA (Endometrial Microbiome Metagenomic Analysis) and ALICE (Analysis of Infectious Chronic Endometritis). Cute names aside, these tests leverage a high-tech approach called metagenomic sequencing to comprehensively evaluate bacterial diversity. This technique identifies organisms that can not be studied with conventional tests.  

Sometimes the results will reveal low biomass: a reduced concentration of the healthy bacteria, which can then be overrun by the troublemakers. Occasionally, a specific infection will be revealed. The results will determine if treatment with probiotics, antibiotics, or both/neither are justified.

To perform the test, an endometrial biopsy is required. For our IVF patients, we will usually combine the ALICE & EMMA with the ERA (read about it here), for the hattrick cleverly named EndomeTRIO. Like the ERA, there are downsides: 1) a month is required to perform the tests, and occasionally another month is necessary to verify adequate treatment, 2) the biopsy can be uncomfortable, 3) there is a financial cost.

Has it made a difference for our patients yet? Too early to say. We have been offering ALICE & EMMA for about 1 year (in contrast we have been using ERA for more than 5 years), and we are still gathering data. In my humble opinion, I believe that there is an ample body of evidence supporting the significance of chronic infections and dysbiosis as they relate to infertility, and ALICE & EMMA appear to be better ways to diagnoses these conditions.

What about just loading up on probiotics? That seems reasonable, but 1) the probiotics should contain only lactobacillus species, 2) they should be administered vaginally, so as not to disturb the gut microbiome, and 3) maybe it’s possible to have too much of a good thing. To be honest, there is no evidence to support that just prescribing probiotics to all-comers will make a difference for fertility outcomes, but it seems like there is little downside. We will have to wait and see…

*Bonus- a gut busting joke as a reward for making it to the end of this extra-long post:

Q: What’s the opposite of dysbiosis?

A: Datbiosis!

References:

[1]       R. Tomaiuolo, I. Veneruso, F. Cariati, and V. D’argenio, “Microbiota and human reproduction: The case of female infertility,” High-Throughput, vol. 9, no. 2. MDPI AG, 01-Jun-2020.

[2]       I. Moreno et al., “Evidence that the endometrial microbiota has an effect on implantation success or failure,” in American Journal of Obstetrics and Gynecology, 2016, vol. 215, no. 6, pp. 684–703.

[3]       R. Romero, J. Espinoza, and M. Mazor, “Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization?,” Fertil. Steril., vol. 82, no. 4, pp. 799–804, 2004.

[4]       I. Moreno et al., “The diagnosis of chronic endometritis in infertile asymptomatic women: a comparative study of histology, microbial cultures, hysteroscopy, and molecular microbiology,” Am. J. Obstet. Gynecol., vol. 218, no. 6, pp. 602.e1-602.e16, Jun. 2018.

Doctors love to share clinical anecdotes. I am no exception:  

The year was 2014, and I was treating a young and healthy woman whose only reason for IVF was because her partner’s sperm count was low.  She wanted to make sure we were picking the best embryos, so we took the extra step of PGT-A (back when it was still called CCS, or comprehensive chromosomal screening). Six of her embryos were found to be normal, an outstanding result we were all very excited about! A sure thing, I thought, given that the implantation rate for chromosomally normal embryos is typically 75% in our clinic. 

In preparation for her embryo transfer, everything looked great: the endometrium was more than 8mm thick with a trilaminar pattern. Her transfer procedure was simple, but alas it failed. Disappointed, but still encouraged by how many embryos she still had left, we just tried again.  Unfortunately, the second transfer failed too. Let’s add some extra treatments, I suggested, such as aspirin, heparin, prednisone, and intralipid. These are controversial, but sometimes seem to help patients with unexplained implantation failure. Yet her third cycle also failed despite “the kitchen sink” approach. 

This lovely patient had done everything I counseled her to do, spent thousands upon thousands of dollars, and suffered immense heartache, especially since little hope was apparent going forward. By far, the most common reason for implantation failure can be ascribed to unhealthy embryos, but hers were highly graded and chromosomally normal. We had also added all the “extras” too, and still no avail. I was at wits end to the say the least. 

It was at that time I learned about a test called the Endometrial Receptivity Array (now the A stands for Assay), or ERA for short. This was the first time we tried it at Olive (and perhaps one of the first in Canada). The ERA requires a dress rehearsal of sorts: a mock cycle is performed to prepare the endometrium for an embryo transfer. However, instead of the transfer, an endometrial biopsy taken, and the tissue sample is sent to a company called iGenomix where the RNA is extracted and an expression profile is performed for 238 genes that are known to be important for implantation. 

The rationale for the test is based on the fact that the endometrium will only allow the implantation during a finite time frame known as the window of implantation (WOI). If the embryo is delivered to the uterus too early or too late, when the window is closed, implantation cannot occur. The concept of the WOI has been recognized for decades. However, until the ERA test was developed, there was no meaningful way to measure it in any given individual. More importantly, the ERA was actionable: if the endometrium was found to be non-receptive a plan to optimize receptivity was provided. I was not convinced by the data I had read at the time but given that we had exhausted all our traditional options we decided to give it a try. 

Sure enough, the ERA showed that her WOI was shifted 24 hours later than we thought, a diagnosis we would have never made otherwise. We made the suggested adjustments, and low and behold, she conceived with her subsequent transfer, had a successful pregnancy and a beautiful baby, then two more over the next few years! 

In 2018 we published a review of our data with the ERA for patients who had previously experienced implantation failure with chromosomally normal embryos. We found that if the ERA results were non-receptive, and we made the appropriate adjustments, patients were more likely to conceive with the next transfer. (If you would like a copy of the paper, email me: gnakhuda@olivefertility.com). 

We have used the ERA hundreds of times over the years for patients with a history of implantation failure, but a question that has always lingered: should we be using the ERA for all patients?  Why wait until implantation failure has already occurred and precious embryos have been wasted? 

The bottom line is that ERA test was designed specifically for those with a history of implantation failure, not all comers. Most patients will have the typical WOI, thus for the majority the ERA won’t offer any actionable results. Some would suggest that normal results would at least offer reassurance even if they don’t change the treatment which may be true, but it is also important to consider what is involved in the ERA: 1) it requires a dedicated month which delays the transfer cycle, 2) an endometrial biopsy needs to be performed, which is usually quick, but can be uncomfortable for many patients, and 3) there are financial costs involved.  

A recently published study did in fact suggest that the ERA may add value for patients from the get-go. The designs and conclusions of the study are not perfect for many reasons, but at least it offers some evidence that the usefulness of the ERA may extend beyond implantation failure. We are also participating in an ongoing clinical trial further investigating the value of the ERA for patients who have had PGT-A. (If you are an Olive patient who has had IVF with PGT-A, ask your care team about the “PEAR study” if you are interested). 

(As a newish twist, we can also perform 2 more tests at the same time as the ERA, called the EMMA and ALICE, which analyze the microbiome and chronic endometritis, respectively. I will discuss these in a future post.) 

If you have the ERA, we find the problem and fix it, is implantation guaranteed to happen with the next transfer? Unfortunately, no. The ERA doesn’t give us all the answers.  However, in our experience, it can be a helpful tool for many patients. Talk to your Olive team to determine if the ERA is right for you. 

I previously discussed the safety of COVID-19 vaccination during pregnancy here. Since then, the Society of Obstetricians and Gynecologists  of Canada has updated their stance to more specifically endorse the approved COVID-19 mRNA vaccines during pregnancy and breastfeeding. The World Health Organization also endorses the use of the vaccines in pregnancy. It bears repeating: the COVID-19 vaccines (both Moderna and Pfizer/BioNTech) are safe and recommended during pregnancy.

However, a related concern has stirred a significant amount of controversy and is specifically relevant to our patient population trying to conceive: do the COVID-19 mRNA vaccines cause infertility?

Let’s unpack the origins of this rumor. It began when a German doctor and a former Pfizer employee wrote a letter to the European Medical Agency in December to delay the study and approval of the Pfizer/BioNTech vaccine. This went viral (no pun intended) through a blog with a funny name called “Health & Money News” since taken down but archived here. First of all, they state that the vaccine contains the syncitin-1 protein, which is clearly inaccurate. Both of the approved viruses are mRNA-based, thus do not contain any viral protein. Secondly, they argued that the target of the vaccines, the COVID-19 spike protein, was similar to syncytin-1, a human protein that is crucial to the connection between the placenta and the uterus. Therefore, they claimed, the antibodies produced against the COVID-19 would also attack syncitin-1 and could lead to “female sterilization”.

Fake news, or more specifically, fake science. While it turns out that the target of the vaccines, the COVID-19 spike protein, bears a passing resemblance to syncitin-1, there is no evidence that the antibodies elicited by the vaccine will even recognize the placental protein. An eloquent explanation by well-respected fertility experts illustrates that the amino-acid sequences of COVID-19 spike protein and syncitin-1 have very few similarities. The lack of homology between the COVID-19 spike protein and syncitin-1 is counterfactual to the baseless claim that the antibodies will cross-react and attack the developing placenta.

It is true that the vaccines were not tested on pregnant women or those trying to actively conceive, but there was some incidental evidence from the Pfizer/BioNTech trial: 23 women did get pregnant after the vaccine was administered, probably inadvertently. Twelve of these were in the vaccine group, and 11 in the placebo group. The only miscarriage occurred in the placebo group (see page 42 of the Pfizer/BioNTech FDA briefing), meaning this patient did not receive the actual vaccine.  Furthermore, according to this study even pregnant women actually infected with COVID-19 in the first trimester do not seem to be at higher risk for miscarriage, making the risk of miscarriage with the vaccine seem even less likely.

The bogus blog lacked evidence and distorted facts, but most importantly, has done a disservice to those who could be protected by the potentially life-saving vaccine. The risks of COVID-19 are real, and the benefits of the approved vaccines are proven. Trust science, not pseudoscience.

There are two important concepts about eggs when it comes to fertility: 1) quantity, and 2) quality. Both inevitably decline with age. However, as we would expect, there is variation between individuals, so tools to assess personalized levels are very useful.

The ovaries contain the maximum amount of eggs before birth, with the numbers rapidly declining over the years, such that by the age of 35 only 10% of the eggs that were initially present remain. Once the number of eggs reaches a minimal lower threshold, menopause ensues. While we can never directly measure the absolute number of eggs remaining (ovarian reserve in medical lingo), tests such as antral follicle count, or Anti-Mullerian Hormone (AMH) level are helpful in comparing an individual’s relative egg quantity to what we would be typically expected for their age.

Egg quality (oocyte competence in technical parlance) is much more elusive. What we really want to know is the egg’s ability to mature properly, fertilize normally, and develop into a healthy embryo. The decline in egg quality is one of the major reasons that it is harder to become pregnant, but also why the risks of pregnancy losses increase, as well as the chances of pregnancies affected by chromosomal disorders such as Down syndrome. Unfortunately, poor egg quality can be a significant factor even in young patients who are struggling with infertility. Yet, there is no blood test or imaging study that can tell us how good your eggs are.

It is not until one undergoes IVF that we can get some insight into egg quality, and even then, simply observing the eggs themselves under the microscope is not terribly informative. We have to attempt to fertilize with sperm and observe embryo development. Only then, once we have put the eggs to the task, can we make some inferences about quality. (Of course, sperm quality also plays a role, a topic for another day).

This puts our egg freezing patients in a tricky situation: because we will not be fertilizing the eggs until some uncertain time in the future, it is difficult to say how good their eggs really are. If we wait until years later, only to find out then that the eggs are not healthy, valuable time would have been lost. We do try to make some predictions using age and the number of frozen eggs to estimate the probability of eventually leading to live birth (check out our egg freezing estimator here), but accounting for only these two factors, all patients of the same age and same egg number together are clumped together. For example, all 35-year-olds with any 10 eggs will be given the exact same odds for success. Such estimations, while better than nothing, are admittedly very crude and may not be too meaningful for any given individual.

Wouldn’t it be great if we had a tool that actually allowed us to make more personalized predictions, not just based on age and number of eggs, but also on the characteristics of individual eggs?

Well, maybe we do: introducing Violet, an image analysis tool from the Canadian start-up, Future Fertility, that leverages the power of artificial intelligence to noninvasively assess oocyte quality. Violet’s algorithm is based on hundreds of thousands of images in the training dataset. Each egg is analyzed independently and a probability distribution is generated to predict its chances to develop into a blastocyst and result in a live birth. Check out these images from a sample Violet report: