Drucilla Roberts and Vanda Torous stared at the placental tissue of two babies—fraternal twins—and were stunned by what they saw. The twins had shared the same womb and obviously the same mother, who’d tested positive for SARS-CoV-2 during delivery, yet the babies’ individual placentas looked very different, Roberts recalls. The tissue of one of the placentas was severely inflamed, riddled with immune cells. The other one looked healthy. When Roberts and Torous, who are both pathologists at Massachusetts General Hospital in Boston, ordered tests of the placental tissue for markers of SARS-CoV-2, the inflammation-riddled organ appeared to be heavily infected with the virus, while the other one had relatively little viral RNA.

Neither twin tested positive for the novel coronavirus after birth, Roberts tells The Scientist. “The babies are fine.” The fact that one placenta was heavily infected by the virus...

At the time that Roberts and Torous identified the twins’ surprisingly distinct placentas, researchers had begun to gather data suggesting that the virus could indeed pass to a fetus during pregnancy. The most persuasive evidence came from a 23-year-old mother in France. At the time of delivery, her nasal swab, blood, and amniotic fluid all tested positive for the virus, and so did the baby’s nasal swab. The baby boy also developed symptoms of COVID-19, and scans of his brain revealed the organ to be inflamed, with damage to the white matter, similar to what had been reported in adults who suffered encephalitis after SARS-CoV-2 infection.

Not only did that case study demonstrate that a pregnant mom could in fact pass the virus on to her unborn child, it also highlighted concerns that such transmission could have devastating consequences for the baby, says Roberto Romero, the chief maternal-fetal medicine specialist at the Detroit-based Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). After that study was published in July, he explains, one of the most pressing questions in understanding COVID-19 and pregnancy became: “What is the frequency with which mothers pass the virus to the fetus?”

The current data indicate that infected moms-to-be pass the virus to their babies relatively infrequently, perhaps only in about 1 percent of pregnant women who contract COVID-19, though some estimates are as high as 30 percent. With Zika virus, the rate of maternal-fetal transmission is, at a minimum, 10 percent, and with cytomegalovirus, a type of herpes virus, it’s roughly 30 percent in the first and second trimester and as high as 70 percent in the third trimester. The placenta, Roberts’s and others’ studies indicate, may be a better buffer against transmission from mother to baby in cases of SARS-CoV-2 than when the woman is infected with those other viruses. 

Just because the baby doesn’t contract the novel coronavirus in utero doesn’t mean there’s no risk of complications after birth. If a fetus is exposed to inflammation because of the mother’s viral infection, there could be long-term effects, explains Diana Bianchi, a medical geneticist and neonatologist and the director of NICHD. “We don’t know yet.”

Cells in a placenta infected with SARS-CoV-2 (red)

Tracking SARS-CoV-2 transmission via the placenta

From the moment she wakes up until seconds before she goes to sleep, pediatrician Elisha Wachman combs the medical records of pregnant mothers slated to deliver their babies at Boston Medical Center, where she works. The instant she sees one of the moms has delivered, she arranges childcare for her kids, coordinates with her collaborators, and rushes to the hospital to retrieve the placenta from a dedicated fridge in the Labor & Delivery ward of the hospital. 

“This has been a nonstop, twenty-four-seven ordeal . . . with many, many nights, weekends, four am stints in the lab,” Wachman says, “because, you know, women do not deliver between nine and five, Monday through Friday.”

Wachman and her collaborator Elizabeth Taglauer, who is also affiliated with Boston Children’s Hospital, want to know more about the vertical transmission of SARS-CoV-2. Since early on in the pandemic, Wachman, Taglauer, and their research assistant have been collecting and analyzing placentas from women who tested positive for COVID-19 while pregnant. In August, based on PCR tests for viral RNA and examinations of the organs under a microscope, the team reported that all 15 placentas they’d collected from these mothers showed signs of SARS-CoV-2 infection, and in five cases, the virus was passed to the baby—a transmission rate of  about 30 percent.

This result stands in stark contrast to much lower estimates of other studies. In a paper published the month before Wachman and Taglauer’s, Roberts’s team examined 19 placentas from moms who were carrying the virus at the time they gave birth, and only two showed signs of SARS-CoV-2 infection, while none of the babies tested positive for the virus. Since then, Roberts has looked at more than 50 additional placentas of infected moms and identified five others, including both twins, that showed signs of SARS-CoV-2 infection, and each of these babies except the twins tested positive for the virus—a transmission rate of 4.3 percent. In Italy, pathologist Fabio Facchetti of the University of Brescia and colleagues found a comparable rate—of 15 women who got a positive SARS-CoV-2 test at the time of delivery, only one (6.7 percent) transmitted the virus to her child—and Facchetti says that additional data he has since collected suggest that this may be an overestimate. An NIH-funded study published in December found no evidence of vertical transmission in babies born to 64 women who tested positive for the virus at the time of delivery.

To better understand how SARS-CoV-2 can pass from a pregnant mother to her unborn child, researchers have been taking a closer look at the placenta under the microscope. They’ve analyzed the fetus-supporting tissue not only for the viral infection but also for immune cells that may be trying to prevent transmission. So far, the data suggest that the virus can pass through the placenta and into the fetal blood, but this type of viral transmission is rare.

See full infographic: WEB

An estimate of SARS-CoV-2 infections in newborns from the US Centers for Disease Control and Prevention (CDC) seems to agree with Facchetti’s analysis. Released in November, the data show that, of 610 babies tested for the virus at birth, 16 (2.6 percent) were infected. The babies that were infected were primarily born to mothers who tested positive for the virus within a week of delivery. However, the report did not include information on whether or not the placentas of the babies were infected, so it’s not clear that the infants contracted the virus in the womb. 

Researchers haven’t yet figured out why Wachman and Taglauer’s team found such high transmission compared with other estimates to date. It could have to do with the demographics of the women in the study or some other factor, says Roberts, who has reached out to collaborate with the other researchers. She says their findings about the location of inflammation in the infected placentas align with her own.

A closer look at SARS-CoV-2 infection in placentas

When Romero learned about cases of transmission of SARS-CoV-2 from mother to fetus over the summer, he and his colleagues began investigating in healthy placental cells the levels of transcription of ACE2, the gene encoding the cell receptor that the virus uses to gain entry into human cells, and TMPRSS2, the gene than encodes an enzyme that cleaves the virus’s spike protein and helps with viral entry into the cell. In the RNA sequencing data, he and his colleagues found transcription of both ACE2 and TMPRSS2 was exceedingly low, far lower than the transcription of the receptors for Zika or cytomegalovirus. Such low activity of these genes in the placenta, he says, could help to explain why transmission of SARS-CoV-2 from mother to baby is relatively uncommon. 

However, examining the abundance of ACE2 and TMPRSS2 proteins in SARS-CoV-2–infected and healthy placental tissue seems to tell a slightly different story, according to Wachman and Taglauer’s study. In their infected tissue samples, ACE2 was prevalent, while TMPRSS2 was completely absent in both infected and control samples. Both Romero and Wachman note that the low TMPRSS2 levels might indicate that the virus could be using alternative cellular entry molecules to get into placental cells. ACE2 was even more abundant in healthy tissue than in the placental tissues of infected moms, Wachman and Taglauer found. This pointed to the possibility that the placenta could be downregulating ACE2 during SARS-CoV-2 infection, possibly to prevent further viral spread. But, the researchers write, “the findings from this limited descriptive analysis are not sufficient to make any true conclusion on this point.” 

Looking at the spatial distribution of cells in the placenta, Wachman and Taglauer’s team found that cells carrying ACE2 were most prevalent in the outer layer of the syncytiotrophoblast, the protective, glove-like epithelial covering of the placenta that sits closer to the mother’s uterine lining than it does to the developing fetus’ amniotic sac. That’s also where most of the SARS-CoV-2–infected cells were found. Keeping the virus localized there, away from the fetus, Wachman says, may help to explain why transmission rates from mother to fetus are often low, even when the placenta is infected. 

ACE2 (brown) is present in the glove-like syncytiotrophoblast of the placenta. The receptors are clumped along the inner sides of the syncytiotrophoblast cells, away from the maternal blood that bathes the outside of the placental villi. Cell nuclei are stained purple.

Facchetti’s team also found evidence of the virus in the syncytiotrophoblast of the mom-baby pair in which both tested positive for SARS-CoV-2. There were also signs of inflammation in other parts of the placenta. In the intervillous space, which surrounds the finger-like chorionic villi that house the maternal and fetal blood vessels, for example, the researchers found activated innate immune cells from the mother, hinting they’d come to the placenta to combat infection.

Roberts thinks the buildup of these immune cells might be a distinct histological footprint of SARS-CoV-2–infected placentas. She saw it in many of the placentas she studied, as did Wachman, who had some samples with so much inflammation that the placentas had large, easily visible chunks of white or gelatinous scar tissue that uninfected placentas lacked. Because that kind of inflammation, what’s called intervillositis, in the placenta is rare, “to see it in a SARS-CoV-2–infected mom is a red flag that you might have placental infection,” Roberts says. “And if you have placental infection, you might have fetal, or neonatal, infection.”

In the placenta Facchetti’s team studied, there was a clue as to how SARS-CoV-2 might sometimes spread from mother to the baby. Examining ultrathin slices of the placenta with an electron microscope, he and his colleagues spotted a viral particle inside a white blood cell in one of the fetal capillaries, hinting that the virus was in the mother’s blood that was sent to the fetus. At first, “I did not believe it,” Facchetti says, “since it is not so easy to find.” But slowly, with more imaging, the team became convinced of what they were seeing, and they concluded that the virus was getting into the mother’s blood, probably through the lungs, and then circulating throughout her body and into her baby.

Immediately after birth, that newborn’s lungs didn’t appear to be infected with SARS-CoV-2 (a nasal swab gave an inconclusive result), but hours later, the baby boy tested positive for the virus and soon suffered lung damage consistent with COVID-19 pneumonia and pneumonia-related symptoms. Facchetti and his colleagues were curious as to why there was a delay in the viral spread after birth. A possible explanation, he writes in an email to The Scientist, is that the fetal lungs are dormant during gestation, with the mom’s lungs working to oxygenate her blood, which is then shared with her baby. After birth, a baby takes his first breaths, and the lungs begin expanding and contracting and pumping blood in and out. Because the baby was quarantined from his mother after birth, his illness indicates that the virus was probably circulating in the baby’s blood and moved into the lungs after birth, Facchetti says. “However, I admit that this is quite speculative.”

Risks to baby of mom’s SARS-CoV-2 infection

The baby in Facchetti’s case recovered quickly, as did the five in Wachman and Taglauer’s study. Others have taken longer to recover. The boy born with neurological abnormalities still had residual injury to the white matter of his brain months after birth, though it was less severe, and preliminary evidence indicates that if a woman gets infected with SARS-CoV-2 earlier in pregnancy, the outcome could be more dire. 

In June of last year, for example, David Baud of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, reported on a second-trimester miscarriage potentially tied to COVID-19. The 28-year-old mom-to-be was 19 weeks pregnant when she came to the hospital with a high fever, dry cough, mild pain when swallowing, and diarrhea. She tested positive for SARS-CoV-2 through a nasal swab, was given oral acetaminophen, and was discharged. Two days later, she returned, with all the same symptoms and now having labor contractions. Ten hours later, she delivered a stillborn child who tested negative for the virus. The placenta, however, tested positive. 

Two days after the birth, the mother again tested positive for SARS-CoV-2 via nasopharyngeal swab, but her blood, urine, and vaginal swab were all negative. Because her blood tested negative for the virus, it’s unclear how it would have made it to the placenta, Roberts says, and it’s a reason why so many more detailed examinations of afterbirths began.

Immunohistochemistry staining for the SARS-CoV-2 spike protein (brown) showing intense infection in the syncytiotrophoblast, the protective layer of cells covering the placenta. 

It’s unclear if the mother’s infection caused the miscarriage, Baud concedes. A June study tracking 427 women in the UK who contracted SARS-CoV-2 while pregnant noted that three suffered stillbirths, though a JAMA report published in December found no increase in stillbirths regionally or nationally in the UK during the pandemic. A study published in the same edition of JAMA on two Philadelphia hospitals also found no increase in stillbirths or preterm births. Recently released CDC data, however, show that SARS-CoV-2 infection is associated with preterm birth. Of 3,912 babies born to mothers with SARS-CoV-2 infection, 12.9 percent came earlier than 37 weeks gestation. Typically, only 10 percent of babies are born that early in the US. In addition to the spread of the virus from mother to fetus, a maternal infection has the potential to generate antibodies that could be shared across the placenta. However, a study published in December showed that in the third trimester, transfer of antibodies against SARS-CoV-2 from mother to fetus was significantly lower than the transfer of influenza- and pertussis-specific antibodies.

The data are concerning, Baud says. In a report published in October, he noted that MERS and SARS infections during pregnancy were linked with restricted fetal growth and miscarriage, something his team is now watching for in their pregnant patients. They have been testing their pregnant patients monthly for SARS-CoV-2, and for those who do contract the virus, “so far, it seems there is no increased risk of abnormality,” he writes in an email to The Scientist. A smaller study published in JAMA in November backs Baud’s observations: in an analysis of 252 women who tested positive for SARS-CoV-2 while pregnant, the study authors found no association with adverse outcomes when the women gave birth. Still, Baud notes, “long-term impact and risk of growth retardation need further investigations.”  

Part of the concern is that studies in mice have connected maternal infections with autism-like behaviors in their offspring. And other research has shown that babies born to human moms infected with Zika during pregnancy have suffered from microcephaly. Because there is little known about COVID-19, the long-term effects of being infected while pregnant are unknown, which led the US National Institutes of Health to launch a study of COVID-19 and pregnancy near the start of the pandemic. From March to December, doctors at 12 sites across the country reviewed the medical records of pregnant women; now they’re comparing outcomes of those pregnancies to data from 2019. In addition to the risks that infection may pose to fetuses, the researchers leading the study, called GRAVID (the Gestational Research Assessments for coVID), hypothesize that there will be more complications, such as hypertension and blood clots, in pregnant women. Already, data show that if pregnant women do contract COVID-19, expectant mothers are more likely to be admitted to the intensive care unit, require mechanical ventilation, and die than are women of similar age who are not pregnant.

“What’s been terrifying for all of us is that we are essentially learning on the fly,” Bianchi says. “This is a new disease, and it’s vitally important to collect as much data as we can so that we can understand it.”

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