How COVID-19 can harm pregnancy and reproductive health

Lisa O'Brien fell ill just after arriving home in Utah following a Hawaiian vacation in March 2020. She was among the earliest COVID-19 cases in her state. Though she didn't land in the hospital, she's never really recovered. Her heart beats with wild irregularity, she's fatigued, she's had blood clots. And even though she once had a clockwork-like menstrual cycle, she's had only five periods in nearly two years. She was 42 when she got sick, so the change was surprising: She's very young to be going through menopause.

After she launched a private Facebook group in June 2020—the Utah COVID-19 Long Haulers—she realized that many others also had lingering symptoms, a phenomenon now referred to as long COVID. That included dramatic shifts to their menstrual cycles. Nationwide, thousands more people have since reported that the virus has affected their menstruation—and that was just one early sign that long COVID may take a toll on women's reproductive health.

An assessment of 2,000 couples showed that vaccination for COVID-19 does not lower fertility, contrary to claims that tore across social media. However, new studies have revealed that SARS-CoV-2 infections can endanger the lives of both mothers and their unborn babies. Research funded by the National Institutes of Health (NIH) found that pregnant individuals were 40 percent more likely to have very serious complications than the uninfected. Another study revealed that the virus can decimate the placenta, cutting off the oxygen supply to the fetus and causing stillbirth.

Researchers are still teasing out the intricacies of how this virus disrupts monthly cycles, why it lands more pregnant women in intensive care or on ventilators than any other adult cohort, and how to intervene to prevent stillbirths.

"The science is evolving, this virus is really unique, and I don't think we have enough data to say exactly how it impacts reproductive issues," says Lucinda Bateman, an internal medicine specialist and medical director of the Bateman Horne Center in Utah. "That's going to take some time."

On a quest for post-viral answers

O'Brien says doctors initially dismissed her post-infection symptoms, which has not been an uncommon reaction.

"Long COVID affected predominantly women, and they were not listened to," says Bateman. "They were told it was all an emotional response to the pandemic."

A quest to understand post-viral syndromes, particularly in women, has driven Bateman's career. It was also personal. Just as she was graduating from medical school, her sister developed myalgic encephalomyelitis, previously known as chronic fatigue syndrome. She has treated patients with poorly understood conditions like fibromyalgia and ME/CFS for decades, which may prove to be autoimmune or neuroimmune conditions," and are more common in women. She opened the Bateman Horne Center in 2015 to also pursue research.

So far she's found what she calls "a distinct parallel" between long COVID and those with ME/CFS in terms of inflammation and possible autoimmune characteristics. One of the reasons may be that the female immune system is deeply interlinked with hormones, particularly estrogen. So, understanding the virus means understanding how the immune system responds to this pathogen.

The virus can trigger an incredibly complex web of hormonal shifts, making it hard to pinpoint the origin or cause of these changes, Bateman says. It's especially difficult for women, who have fluctuating hormones, not only during a single month but also throughout their lives: adolescence, pregnancy and post-pregnancy, during infertility treatments, and midlife changes.

Some of the earliest comprehensive reports on long COVID came in May and December 2020 from the Patient-Led Research Collaborative, a group of researchers who themselves have the condition. In a global online survey, they documented at least 205 symptoms that may linger in any of 10 organ systems—including the reproductive and endocrine systems.

Three-quarters of the 3,762 respondents were women; about 25 percent experienced abnormally irregular periods, a ratio corroborated by other research. About 5 percent experienced early menopause (during or before their 40s); another 5 percent had breakthrough periods even though they'd already gone through menopause. Symptoms sometimes persist six months or more post-infection.

Women seem to be more affected than men, says Jeanette Brown, an intensive care doctor and medical director of the University of Utah's COVID-19 Long-Hauler Clinic. Most range in age from their 20s to their 50s, were healthy before infection, and have had symptoms that appear, disappear, wax, or wane.

Determining the implications of an infection on fertility and pregnancy is especially tricky because the health consequences are slow to emerge, says David A. Schwartz, an Atlanta-based placental pathologist and epidemiologist.

"It can take many months to determine if a new infection causes pregnancy complications because of the length of gestation," Schwartz says. "But we've seen increasing data telling us that if a woman is infected with the virus in pregnancy, she's at risk for an adverse outcome."

The pregnancy risks of infection

That first pandemic summer and fall of 2020, obstetricians started seeing a spike in preterm births. "And then we started to see maternal deaths," Schwartz remembers.

This wasn't completely unexpected; influenza, acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), and other viral infections have led to dire outcomes for mothers and their babies, including miscarriage, restricted fetal growth, and stillbirth.

Only now are physicians gaining a more complete picture of how COVID-19 infections during pregnancy can affect mother and child.

A new retrospective study led by Torri D. Metz, a maternal fetal medicine specialist at the University of Utah, quantifies how pregnant women fared between March 2020 and December 2020—before vaccination was available. Metz teamed up with colleagues at 16 other hospitals to examine medical records of 14,000 women who gave birth during that period. Of that group, 2,352 tested positive for COVID-19; the rest were uninfected.

The results were sobering. Overall, those who had the virus were at 40 percent higher risk of complications and were at greater risk of landing in intensive care, ending up on a ventilator, or dying when compared with uninfected pregnant women. Most of those who experienced severe problems had been hit hard by the virus. "For those with moderate or higher [COVID-19] disease severity, they had a doubling—100 percent increase—in risk," Metz says. That group also had more Cesarean sections.

Some pregnancy complications such as high blood pressure, preeclampsia (a condition involving hypertension and problems with kidney or liver function), life-threatening postpartum hemorrhage, or infection progressed to much more serious illness for those with COVID-19. Those pregnancies also resulted in more babies born prematurely and admitted into neonatal intensive care. Physicians say this could have lifelong consequences; preterm babies face significant risk for lowered IQ and attention deficit disorder, and they may struggle with social interactions and emotional control.

"COVID is much more dangerous in a pregnant woman due to a suppressed immune system and lower lung capacity," says Paula Brady, a reproductive endocrinologist at Columbia University. That at least partly explains why a notable number of pregnant women who fall ill with the virus land in the hospital.

The viral attack on the placenta may also possibly explain some of these complications, Metz says. "It's been known for some time that high blood pressure and preeclampsia in pregnancy are closely linked with placental function," Metz says. COVID-19 may result in areas with poor blood flow through the placenta, and the mother's blood pressure may rise to dangerous levels, depriving the fetus of nutrients and oxygen.

As a next step Metz and her consortium plan to follow these patients and their children over the next four years to document whether they endure persistent health problems.

What COVID does to developing babies

Contracting COVID-19 also seems to put a developing baby at risk. Some of the earliest clues pointing to why this was happening came from County Cork, Ireland, where there was a cluster of misfortune. Over the course of three months in early 2021, six pregnant women who'd contracted the virus birthed stillborn babies, and another miscarried during her second trimester. Scientists found that their placentas were infected and damaged by the virus.

That prompted Schwartz to launch an international investigation to figure out why. He, along with colleagues examined 68 placentas from 64 stillborn fetuses and four newborns who died soon after birth in 12 countries. In each of these cases, the mothers were not vaccinated and contracted COVID-19 while pregnant.

The placenta is the baby's organ, developing during pregnancy and attaching to the uterine wall. Oxygen and nutrients from the mother's bloodstream travel through the placenta and reach the fetus via the umbilical cord. Maternal blood flow is also the most likely route of placental infection.

Pathologists in each country first evaluated the size, shape, and overall health of the infected placentas before slicing off tiny samples to examine under a microscope. All were grossly abnormal. A healthy placenta, Schwartz says, is reddish and easily compressible, a little bit like a kitchen sponge. The coronavirus radically altered the tissue, making it firm, rubbery, and dense. Under magnification, researchers observed dark swirls of necrotic tissue.

Every one of the placentas had excessive fibrin—a fibrous mesh that aids in blood clotting. This seems to have obstructed blood flow into the organ, choking off the oxygen supply and killing placental tissue.

"What we found was an enormous surprise," Schwartz says. On average 77.7 percent of the placenta was destroyed, making it incapable of meeting the basic survival needs of a fetus. "It was highly consistent from case to case, far beyond coincidence. This is an unheard-of level of placental destruction for a viral infection," he says.

"From a clinical standpoint, it will be important to track how long this process takes from the time mom is infected for this terrible process to occur and lead to stillbirth," Schwartz says. This knowledge could reveal a window for intervention, saving babies that have reached viable age in utero.

In November 2021 the U.S. Centers for Disease Control and Prevention published a large national study definitively showing that being infected with COVID-19 during pregnancy raised the risk of stillbirth, and that risk increased with the appearance of the more virulent Delta variant. The CDC expects to have data on the Omicron variant soon.

"The good news is that [placental damage] is probably a very uncommon occurrence," Schwartz says. "Most women who have COVID-19 while pregnant will do well, and most of their babies will, too."

Meanwhile, reports remain mixed on miscarriage. Some studies have found greater incidence; others didn't. But even if the overall number of miscarriages did not increase, one study noted that in severe COVID-19 cases with high viral load and pregnancy risk factors, there was greater miscarriage risk. But the real impact will be hard to assess, says Brady, because miscarriages are underreported, and some COVID-19 infections are asymptomatic.

Planning for the long haul

There is even some evidence that COVID-19 may be reactivating other viruses that can affect reproductive hormones, particularly Epstein-Barr virus, a herpesvirus that causes mononucleosis. Kelsey Ursenbach, a 26-year-old member of O'Brien's Facebook group, personally documented this and other metabolic changes to her health.

Ursenbach had a routine blood test four months before she got sick. All was normal until she picked up a relatively mild case of COVID-19 over Thanksgiving dinner in 2020. She still suffers chronic exhaustion, loss of smell and taste, brutal menstrual cramps, and periods that come weeks late.

Lab tests revealed that her thyroid wasn't functioning properly, her testosterone levels were high, and her progesterone was imperceptible. She wasn't ovulating. Notably, her Epstein Barr antibodies were "through the roof." Ursenbach has one child but may want others. Her gynecologist assured her that if she wants to have another, she may need medical intervention.

Last week O'Brien posted an informal poll on her Long Haulers Facebook page—which now has 4,200 members—asking for feedback from others who've had women's health issues post-infection. The 69 responses she received covered the gamut.

Some reported that their cycles stopped altogether, were intermittent, irregular, or light. Others had heavier periods, flamed with hot flashes, or had a range of long COVID symptoms worsen during their cycle. Some went into early menopause; others somehow emerged from menopause, again having periods.

For women with long COVID, the most widely reported reproductive health issue is altered menstrual cycles.

Since the lining of the uterus is part of the immune system, it's not so surprising that an immune disruption or medical illness could affect women's cycles, says Columbia University's Brady. "The body has a finite amount of energy, and one of the first places it will divert energy away from is from reproduction. "Menses are a bit like a vital sign," she says, an indicator of overall health.

"Because there are legitimate concerns about the virus and reproduction, I definitely advocate for patients to be vaccinated to protect themselves," Brady says.

O'Brien adds a different warning. "There's just no way to predict which version of COVID that you'll get," she says. "You might not die, but you might not go back to living the life that you planned to live."

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