Is Long COVID the Match That Will Finally Light a Fire Under Research Into Women’s Reproductive Health?

“Sometimes just standing line in the pharmacy is enough to put me in bed. I can’t do anything for several days,” she says.

Due to reduced mobility and symptoms including severe fatigue, pain, and migraines, Soares was unable to continue her studies. Her visa was revoked, and she was forced to return to her home country of Brazil in November 2021.

Soares began logging her symptoms. Among the more than 200 she observed, the bizarre changes in her menstrual cycle caught her attention. She’d had a Mirena intrauterine device (IUD) since 2012, replacing it in 2018, and was among the 20 percent of people with the device who stopped having a period. But a year and a half after getting COVID, Soares’ periods mysteriously returned, with heavy bleeding and excruciating cramps. She also noted that her long COVID symptoms seemed to worsen around her period.

“It’s almost like somebody got the controls, and all the different types of pain that I feel with COVID just level up,” during that time of the month, she says.

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Soares, who holds a PhD in biology and is a patient-researcher with the long COVID activist group Patient-Led Research Collaborative (PLRC), decided to do some digging. “There was my just intrinsic curiosity as a scientist of just, ‘What is going on?’” she says. With the support of the PLRC, she and several other researchers published a literature review¹ in April 2023 suggesting long COVID could be associated with reproductive health issues in people with ovaries, from endometriosis to fertility issues and more.

Soares is far from the only one who’s noticed a link. Alba Azola, MD, the co-director of the Johns Hopkins Post-Acute COVID-19 Team and an assistant professor of physical medicine and rehabilitation, says irregular periods and menstrual-related symptom flares are “common” in her long COVID patients. Other patients, she says, experience perimenopausal symptoms, like hot flashes, that suddenly begin in their late 30s or early 40s—several years earlier than the average onset.

Victoria Male, PhD, a senior lecturer in reproductive immunology at Imperial College London, in the United Kingdom, was studying² the effects of COVID vaccination on the menstrual cycle when a flood of long COVID patients began reaching out to tell her their symptoms got worse during their periods, too. This struck her, she says, because symptoms of autoimmune diseases like multiple sclerosis, lupus, and inflammatory bowel disease also fluctuate with the menstrual cycle.

“I was like, hmm, that’s really interesting,” she says. “And it might make sense with what we know about immunology and what we think about long COVID. So let’s try to study this formally.”

What we know so far about long COVID and reproductive health

Long COVID appears to affect roughly ³twice as many women as men, especially premenopausal women⁴. To Beth Pollack, a co-author of Soares’s review and a research scientist at the Massachusetts Institute of Technology’s Department of Biological Engineering, this “suggests⁵ that sex hormones or pathological female immune responses to infection may play important roles.”

Pollack studies infection-associated chronic illnesses including long COVID, and the lab where she works, the MIT Tal Research Group, is looking into sex differences in immunity.

Most studies so far involve only a few or even just single patients, so we’re far from having a smoking gun. But some 2021 observational research⁶ suggests people’s long COVID symptoms do seem to worsen just before or during their periods. One 2022 study⁷ found that around half of the nearly 500 women included experienced changes in their menstrual cycles after having COVID, including irregular cycles and heavier periods.

Male is currently working on two studies to explore this observation. In one—part of a larger ongoing study on the immunological effects of long COVID—people with and without long COVID will give blood samples throughout their menstrual cycles, so researchers can track fluctuations in their immune markers. In a second study, people with and without long COVID will log their periods alongside how they generally feel and any other symptoms they’re having (breathlessness, brain fog, rashes, fatigue, etc.). Male and her team hope this will help to identify patterns and confirm if and how much long COVID affects the menstrual cycle-related changes people notice in their health.

Other research suggests long COVID might have consequences for fertility. One January 2022 study⁸ of 80 women undergoing assisted reproductive technology procedures (such as IVF) found that a history of COVID-19 decreased the chances of successfully retrieving a mature egg. Some case ⁹reports¹⁰ have also linked long COVID to primary ovarian insufficiency (POI, also known as premature menopause), or a loss of normal ovary function before the age of 40. In addition to infertility, POI may be associated with chronic conditions including osteoporosis and heart disease.

Kathryn Terry, ScD, an associate epidemiologist in the OB/GYN Epidemiology Center at Brigham and Women’s Hospital in Boston, became interested in researching the link between long COVID and endometriosis because the conditions share symptoms, notably fatigue. In endometriosis, tissue that normally lines the inside of the uterus grows outside of it, mainly in the ovaries and fallopian tubes. Beyond painful and heavy periods, endometriosis has been linked to infertility and a higher risk¹¹ of pregnancy complications such as preeclampsia, preterm birth, and placental abruption.

Terry’s study¹², published last March in the American Journal of Obstetrics and Gynecology, looked at 386 women who were diagnosed with endometriosis before the pandemic and found they were 22 percent more likely to have long COVID than those without an endometriosis diagnosis. This doesn’t mean endometriosis causes long COVID, but it confirms earlier research¹³ suggesting it could be a risk factor.

“Considering the history of research in reproductive health for women and nonbinary people,” or, more accurately, the lack thereof, “I think we have to fight for recognition that we have an issue that is urgent and worth investigating.” —Letícia Soares, PhD, long COVID activist and researcher

Theories about long COVID’s link to reproductive health

Plenty of yet-unproven theories might eventually help explain why people with ovaries tend to have specific health effects following a COVID infection. Both Male and Pollack say it’s possible that a live but undetected virus may lurk in the body. This persistent infection could cause some people’s immune systems to produce chronic inflammation that keeps the body from repairing itself and drives long COVID and reproductive health issues.

Similarly, because symptoms of autoimmune conditions also fluctuate with the menstrual cycle, Male says long COVID might actually be an autoimmune condition. Other researchers have been exploring a potential COVID-autoimmune link; some have found that people are more likely to be diagnosed with an autoimmune condition, such as rheumatoid arthritis, lupus, or irritable bowel disease, after having COVID.

Immune system differences might play a role as well: People with endometriosis have more inflammation and immune dysregulation, for example, which “could be contributing to their higher risk of having long COVID,” says Terry. (Researchers are also exploring¹⁶ whether, similar to long COVID, endometriosis might be caused by an infection.)

The female sex hormones estrogen and progesterone are known to¹⁷ increase blood clotting. Microclots seem to be relatively common¹⁸ in patients with long COVID and may contribute to circulation issues and many long COVID symptoms¹⁹, says Pollack.

Researchers hope to explore these and many other theories, including microbiome dysbiosis (or abnormal changes in bacteria), which seems more common in people with long COVID²⁰ and endometriosis²¹.

For now, they say we need to keep digging. “People really have a tendency to think they see a pattern and then make everything fit the pattern they think they see,” says Male. That’s where research plays a crucial role: It offers subjective facts that help prove—or debunk—these explanations. And, once the truth is uncovered, it could eventually lead to improved treatments.

Where do we go from here?

Long COVID isn’t going away anytime soon, and it affects a lot of people. Getting to the bottom of exactly how it’s linked to reproductive health, including why symptoms tend to flare around a person’s period, can lead to better treatments for people who deal with these mysterious fluctuations every month.  “That’s actually my main driving goal,” Male says.

What’s more, if long COVID turns out to affect fertility or menstrual cycles, it could influence how people plan their families and seek fertility counseling, Male adds.

Doctors already have some effective treatment options. Azola says hormone replacement therapy often helps patients with early perimenopausal symptoms, for example. For those whose long COVID symptoms flare during their periods, taking a hormonal contraceptive and skipping the placebo week—which suppresses ovulation and evens out hormone fluctuations—may be a solution, say Azola and Male.

Because it can take time (and potentially many doctors) to get a diagnosis for long COVID, you have to be your own advocate, Azola says. Find a provider who seems open and listens to you, and be ready to potentially educate your doctor by sharing the latest research. “Most clinicians in general are curious and want to help people,” she says.

Most importantly, believe what your body is telling you. “You are not supposed to feel debilitating pain in your period. Sometimes I think that we just lose perspective of what is normal,” Soares says. “Considering the history of research in reproductive health for women and nonbinary people,” or, more accurately, the lack thereof, “I think we have to fight for recognition that we have an issue that is urgent and worth investigating.”

—medically reviewed by Andrea Braden, MD

Source: Well and Good