Tag Archive for: fertility

In-vitro Fertilization and Heart Disease: Is There a Link?

Author: Elaha Niazi, University of Calgary, Libin Cardiovascular Institute, BHSc Health Sciences Editors: Romina Garcia de leon & Shayda Swann (Blog Co-coordinators)

Published: December 2nd, 2022

Note: When using the term ‘woman’ in this blog, it is to remain consistent with terms used in published literature. While ‘female’ refers to biological sex and ‘woman’ refers to gender identity, much of the medical literature currently reports findings on ‘women’ from samples of female participants. 

What comes to mind if I asked you to name a few risk factors for heart disease? Smoking? Obesity? Diabetes? What about in-vitro fertilization? 

In-vitro fertilization (IVF), a form of assisted reproductive technology, has risen in popularity since its first successful cycle in 1978. Currently responsible for approximately 2% of live births in Canada, IVF is a source of hope for families struggling with biological and/or social infertility. Biological infertility is the inability to achieve pregnancy after one year of unprotected sex and implies a sexual relationship between a male and a female, whereas social infertility applies to those who cannot conceive through intercourse due to factors related to sexual orientation.

Recent studies demonstrate that females treated with IVF may have increased cardiovascular risk compared to those who conceived naturally. The underlying mechanism of this association has not yet been determined, but it is critical to investigate to optimize patient care for females undergoing IVF treatment. But before we dig any deeper into this, we must first examine female cardiovascular disease.

Female cardiovascular disease: an overlooked and under-researched issue

Cardiovascular disease is the leading cause of death in women (shocking – I know!), yet women with cardiovascular disease remain underdiagnosed, undertreated, and undersupported. Research shows that heart attack signs are missed in more than 75% of women. Sex differences exist in mortality rates as well; after experiencing a heart attack, women have a higher chance of dying than men. 

But despite the risk of cardiovascular disease being similar between males and females, less than half of women are actually aware of their risk.

You would hope this would mean that both sexes would be equally represented in cardiovascular research, right? Unfortunately, not. Female systems and women have been historically under-represented in cardiovascular disease research, from the cellular level to animal research and human clinical trials.

Female sex- and gender-specific factors in cardiovascular health

We are now beginning to uncover that sex differences exist in the risk factors, presentation, progression and response to treatment in cardiovascular disease. An important identified contributor to these differences is sex hormones. Female sex hormones are known to directly interact with the cardiovascular system, and consequently, we see cardiovascular implications of experiences unique to females. Specifically, female sex hormones involved in menstruation, menopause, fertility and pregnancy all affect an individual’s cardiovascular risk. Furthermore, exogenous hormone administration, such as hormonal contraception or hormone replacement therapy, influences the development of cardiovascular disease and risk factors. When considering health determinants that disproportionately burden females, such as socioeconomic status and stress levels, it becomes clear that we must examine the sex and gendered factors related to female cardiovascular disease much more closely.

What happens to female sex hormones in IVF?

During IVF, female patients are treated with high doses of female sex hormones to stimulate their ovaries and promote the development of their eggs. This is called ovarian stimulation and is necessary for the subsequent steps of IVF, including egg retrieval, fertilization with sperm, and transfer of the embryo into a uterus to begin pregnancy. Many female sex hormones increase substantially during ovarian stimulation; for example, estrogen levels can increase by over 20x!  

Where does IVF fit into cardiovascular health?

Given what we already know about female sex hormones and cardiovascular disease, it is reasonable to wonder how ovarian stimulation impacts cardiovascular health. However, this has not yet been adequately studied. While we must strive to empower and expand a range of female reproductive choices, it is also important that we consider their cardiovascular implications to protect all aspects of health. To address this critical knowledge gap, I have initiated a study designed to investigate the effect of ovarian stimulation on cardiovascular risk in females treated with IVF, under the supervision of Dr. Sandi Dumanski at the University of Calgary. Healthy, pre-menopausal females planning IVF treatment will be invited to participate in this study. We will monitor changes in their hormone levels and vascular health (predictors of cardiovascular disease) as they undergo ovarian stimulation. This work will provide foundational knowledge that will play a key role in optimizing the care of females treated with IVF.

Where do we go from here?

It cannot go without saying that IVF treatment has provided hope and care for millions of families worldwide and has undergone incredible advancements in past decades — remaining a promising option for those challenged with infertility. However, the implications of this important treatment on cardiovascular health have not yet been fully elucidated. In the era of personalized medicine, and with consideration of the effects of sex and gendered factors on health, it is critical that we investigate health within female-specific contexts like IVF. I believe it is important that healthcare providers and scientists have (and use!) the tools to paint a clearer picture of unique female experiences so they can better inform the reproductive and lifestyle choices of females everywhere.

COVID-19 Vaccines and Infertility: Fact or Fiction?

Authors: Alex Lukey, RN, WHRC Blog Co-coordinator; Arrthy Thayaparan, BSc, WHRC Blog Co-coordinator; Liisa Galea, PhD, WHRC Lead; Deborah M. Money, M.D., F.R.C.S.C.

Published: July 2nd, 2021

It can be difficult to separate fact from fiction when it comes to COVID-19 vaccines, particularly in relation to fertility and reproductive health. This blog will dive into the scientific findings of these claims and bust some of the many myths circulating about the vaccines’ impact on fertility. 

Myth #1: The vaccines haven’t been tested for pregnant people or those trying to conceive

In the earlier stages of vaccine trials, people who are pregnant or trying to conceive are not included for safety. However, in large trials, such as those for the COVID-19 vaccines, there are often accidental pregnancies. While not initially planned, this data provides a natural fertility experiment.

In a paper published by Nature, “Are COVID-19 vaccines safe in pregnancy?” the control groups had 28 accidental pregnancies, and the vaccinated groups had 29 pregnancies. The vaccinated groups received Pfizer/BioNTech, Moderna and AstraZeneca vaccines in these trials.

If the COVID-19 vaccine decreased fertility, there would be fewer accidental pregnancies in the vaccinated groups than the control groups. But it turns out the chances of pregnancy were the same. Since accidental pregnancy rates were similar between groups, there is no evidence that COVID-19 vaccines decrease a person’s fertility. The problem here is that the numbers in this comparison are not sufficient to state that there is no impact, but there is no biological reason to suspect that there would be an impact and no data to support this claim.

Myth #2: The COVID-19 vaccines cause miscarriages

Not only were there no differences in the numbers of conceptions in the vaccine trials, but there was also no difference in the number of miscarriages between participants in the control and vaccinated groups.

Based on the latest research, there is no reason to believe that the COVID-19 vaccine could increase the risk of a miscarriage.

Myth #3: The COVID-19 vaccine damages the placenta

This myth is false–it rests on the belief that after receiving the COVID-19 vaccine, the body’s immune system might attack syncytin-1, a key protein necessary for the placenta’s formation. There is also the claim that the spike protein of the COVID-19 virus and syncytin-1 are so similar that the immune system might mistake one for the other. 

This claim was tested in a recent study that showed no immune cross-reaction between the spike protein and syncytin-1, dispelling the claim that there is a risk of placental injury after taking the COVID-19 vaccines.

Myth #4: mRNA vaccine technology hasn’t been tested long enough to know if it causes infertility

While mRNA is a new technology compared to other vaccine delivery methods, there have been numerous human trials using mRNA vaccines for Influenza, HIV-1, Zika, Ebola and rabies virus well before the COVID-19 pandemic.

In fact, the first human trial of an mRNA vaccine began in 2006, giving researchers almost 15 years of follow-up data. There has been no evidence suggesting long-term fertility concerns arising from the use of mRNA vaccines based on current research. 

Myth #5: mRNA vaccines change your DNA and could impact fertility

To impact DNA, a substance must enter the nucleus, or control centre, of the cell, where DNA is stored. mRNA from vaccines is not able to enter the nucleus and therefore cannot impact DNA. 

Rather, the body uses mRNA as a template to create proteins that teach the body how to fight the COVID-19 virus. 

Take-Aways

The known risks of COVID-19 to pregnant people are severe, including increased rates of intensive care admissions and more premature births. In weighing these risks alongside the latest research, professional associations are making a strong recommendation for people planning a pregnancy to receive the vaccine.

As stated by the Canadian Society of Obstetrics and Gynecology: “There is absolutely no evidence, and no theoretic reason to suspect that the COVID-19 vaccine could impair male or female fertility. These rumors are unfounded and harmful.”

The evidence is clear. The best thing to do to protect your health and the health of those around you is to get vaccinated as early as possible. 

Menstrual Irregularities and the COVID-19 Vaccine

Authors: Romina Garcia de Leon, Neuroscience MSc student, Faculty of Medicine, UBCJennifer Richard, PhD, Department of Psychology, UBC;  Liisa Galea, PhD, WHRC Lead | Editors: Alex Lukey and Arrthy Thayaparan (Blog Coordinators) 

Published: June 18th, 2021

“Imagine if you didn’t know that fever could be a vaccine side effect? You might be concerned that something untoward was happening to your body when all you were experiencing was a typical post vaccine fever. That is exactly the same with menstrual irregularities.” (Gunter, 2021).

There is a growing concern that the COVID-19 vaccine is causing disruptions to menstrual cycles and questions as to why the vaccine may have this effect have been raised by women awaiting their vaccines. Valid, as these questions are, we have few answers as there has been very little to no research in this area. In fact, most of these concerns have been reported through social media and voluntary self-report on databases such as the United States’ Vaccine Adverse Event Reporting System (VAERS) and the Canada Vigilance Adverse Reaction Online Database.

Yet, to date, there have been no systemic studies to examine whether the COVID-19 vaccine – or other factors – are causing these irregularities. So, short of an actual study to show that there is any effect of the COVID-19 vaccine on menstrual cycles, what can we infer?

Unfortunately, given the dearth of research into women’s health, it is not altogether surprising that we do not have this information at the ready. Studies looking at females alone make up only about 6% of the literature. Male-only studies make up approximately 40% of the total studies, although the total number varies by discipline. Women’s health includes studies that would examine how hormonal contraceptives influence mood, or how menopause influences memory in middle age or – you guessed it – how vaccines affect the menstrual cycle or even whether there is a time during your menstrual cycle that the vaccine could cause the fewest side effects. The disparity in women’s health research is no exception in COVID-19 literature.

Thus far, studies examining the main receptor that SARS-CoV-2 binds to in order to enter cells, and infect the body, angiotensin-converting enzyme 2 (ACE2), have been predominantly conducted in males. In fact, a recent study showed the extent of the disparity with 70% of the research conducted involving male-only studies, and only 11% involving females. As a result, it is not surprising that we know so little about how COVID-19 or the COVID-19 vaccines may affect menstrual or menopausal symptoms.

Certainly, many people will already be aware that menstrual cycle variations occur naturally (with more regular cycling often achieved through taking steps to control the menstrual cycle – e.g. taking hormonal contraceptives) and that menopausal symptoms can vary dramatically. Generally, cycle lengths vary in the general population because of many factors including biological and environmental factors. So, with this in mind, what science is there to show what we might expect post-COVID-19 vaccination?

Plausible Theories 

A recent study showed that COVID-19 infection itself influences menstruation. Specifically, a research group in China analyzed data from 177 menstruating people diagnosed with COVID-19, and found that a quarter of all participants had a change in menstrual pattern. In this study, researchers identified that nearly all participants returned to their normal menstrual pattern 1 to 2 months following their COVID-19 diagnosis. However, based on these findings, it is clear that further research is also needed to investigate whether the COVID-19 vaccine also affects menstruation.

In the meantime, there are theories that may provide insight into what may be happening to the menstrual cycle, and why, in response to COVID-19 vaccination.  But before we begin it is important to acknowledge that the entire female reproductive tract (vagina, cervix, uterus, endometrium) is a system that responds to immune challenges (think yeast infections and pelvic inflammatory disease) but this system also needs to show immune tolerance (as is the case in pregnancy – the fetus is a foreign body that we don’t want the body to reject). It shouldn’t surprise us that some changes occur in the reproductive tract when the immune system is challenged…like with infections or vaccine stimulations.

Environmental: Stress

Stress itself can challenge our immune system. A stress response, much like a foreign body, can cause an immune response (and this makes perfect sense from an evolutionary perspective as stress and infection were often seen together!) In doing so, disruptions to our menstrual cycle and menopausal status may occur with stress. Throughout the COVID-19 pandemic, many of us have undoubtedly experienced higher levels of stress. Moreover, women around the world have reported a disproportionate amount of stress, compared to men, for example, due to the added challenges imposed by school closures and daycare closures. If women have been reporting high-stress levels – and a lot of stress can affect the menstrual cycle – is the stress of the pandemic resulting in abnormal periods?

In May 2020, a research group analyzed data from 263 participants and found that an increase in COVID-19 pandemic-related stress was correlated with an increase in menstrual irregularities. Similarly, preliminary data from Canada showed that 27.8% of women experienced menstrual irregularities after receiving the COVID-19 vaccine (unpublished data). This leads us to question whether the changes seen in menstruation are an indirect result of higher levels of stress due to the ongoing pandemic or a direct response to vaccination, or perhaps a combination of the two!?

Biological: A direct link

Vaccines (for example, against rubella) can trigger menstrual irregularities depending on what stage it is received during the menstrual cycle. The endometrium, which is the lining of the uterus, is part of the immune system. This complex reproductive organ is host to a multitude of immune cells and offers protection from infections. These immune cells also vary cyclically, according to the phase of the menstrual cycle. This makes sense: the lining of the uterus sheds tissue which results in menstrual bleeding (and builds tissue too). It may be that when an immune response is mounted post-vaccination, the endometrium reacts by adapting its immune environment to protect the uterus. This abrupt change may trigger abnormal menstrual changes such as an increase (or decrease) in menstrual length and blood volume. 

Interestingly, the ACE2 receptors involved in COVID-19 infection are found on the reproductive tract – including the endometrium and ovaries. The presence of this receptor in the ovaries modulates the production of sex hormones, estradiol and progesterone, which in turn can increase or decrease cells on the endometrium. If this theory checks out, does the time the vaccine is administered during one’s cycle change the probability of having menstrual irregularities? A research group in Spain looked at just this. They found that ACE2 receptors increase in the endometrium during the luteal phase (the time between ovulation and the start of menstruation), suggesting a higher risk for viral infection during this time. Meaning that menstrual side effects may be dependent on cycle stage at the time of vaccine administration. But until this is examined and tested in a research setting, this will remain simply a theory.

The COVID-19 Vaccine and Post-menopausal symptoms

What about people reporting bleeding after menopause?

Just like there is a lack of research into the impact of COVID-19 infection/vaccination on menstruation, even less is known about how this may affect post-menopausal women. Could the vaccine or infection be directly impacting the reproductive system? Recently, post-menopausal women have taken to social media to report abnormal bleeding following a COVID-19 infection or vaccination. Although there are reductions in some immune cells in the endometrium post-menopause, immune cells are still reactive across the reproductive tract. There is, however, a scarcity of research on this subject.

Although we do not yet know if COVID-19 vaccines are the cause of the reported incidents of post-menopausal bleeding, there may be several other reasons for bleeding to occur, such as hormone therapy or medication-related changes in the endometrium.  Regardless, risk of postmenopausal bleeding after vaccination seems to be low as it was not reported in initial trials, and few incidents have been reported so far (27 cases of postmenopausal hemorrhage have been reported in VAERS) with about 50% of women (almost 83 million!) in the USA already having received at least one vaccine against COVID-19. It should, however, be noted that this is a voluntary self-report system for recording adverse events and it is unclear whether all women would consider post-menopausal bleeding as a vaccine-related event.

Is there a direct link to the female reproductive system through ACE2 receptors in menopause as well?

Considering that knowledge on immune changes during pre-menopause is still growing, information about the levels of ACE2 receptors (reminder, these are the receptors that allow for COVID-19 infection) in the endometrium post-menopause is unknown. However ACE2 receptors are linked to levels of estrogens so it may not be surprising that menopausal status is related to COVID-19 outcomes, with postmenopausal people having more severe outcomes compared to pre-menopause. Intriguingly, women over 50 that receive hormone therapy are at reduced risk of mortality due to COVID-19. ACE2 receptors are found in numerous tissues and the distribution of these receptors does change with age in females in the heart and possibly lung, but there are few studies in this area. However, the potential connections between COVID-19 vaccination and effects on the endometrial immune system, and ACE2, will require further study. But it is important to recognize that the female reproductive tract is actively involved in immune challenges even post-menopause.  

Let’s get vaccinated!  

In sum, we know very little of the side effects of any vaccine, let alone the current vaccines available for COVID-19, on menstruating and post-menopausal women. Yet, we know for sure that these risks are far smaller than the risk of becoming severely ill from COVID-19 itself. Although the risk of mortality from COVID-19 is higher in males, the incidence of COVID-19 infection is actually higher in females and although it needs more study, long-haul COVID symptoms (those that last post infection) is more common in women than in men. That’s why more than ever it is important to be vaccinated.

The bottom line as we see it: There is no evidence that the COVID-19 vaccine alters menstruation or menopause long-term. Whether COVID-19 vaccination is behind the reported cases of postmenopausal bleeding, or menstrual changes, remains to be investigated. And this again highlights the need for additional research on women’s health, in general. For example, had there been more concerted research efforts examining menstruation and menopausal physiology, the current issue of possible vaccine side effects may have been avoided (or at least better understood!). As a whole, however, the take-home message is that although there may be potential side effects on menstruation and menopausal status as a result of the COVID-19 vaccine, these, like other vaccine side effects, appear to be temporary. It is therefore important to follow health guidelines and get vaccinated as soon as possible.

If you are interested in participating in a study, Dr. Kate Clancy at the University of Illinois has a survey open documenting any menstrual cycle abnormalities following the vaccine: https://redcap.healthinstitute.illinois.edu/surveys/index.php?s=LL8TKKC8DP 

More reading? – Check out these blogs on the COVID-19 vaccine and menstrual irregularities or bleeding post menopause by Jen Gunter.