Anasthasia Shilov, Illustrations Editor

A study by researchers at the Yale School of Medicine analyzed the placental tissue of pregnant women infected with SARS-CoV-2, testing whether the virus could infect the placenta itself.

The study was published on April 22 in the journal Med and examined the impact of COVID-19 infection during pregnancy — specifically its effect on the placenta. The researchers analyzed placental tissue taken from pregnant women infected with COVID-19 to see if the SARS-CoV-2 virus was present in the placenta. The study also looked at the immune activity in the placentas, as well as the presence of the ACE2 receptor, a feature of human cells that the SARS-CoV-2 virus interacts with to infect these cells, at different stages of pregnancy.

“We wanted to understand the impact of COVID-19 during pregnancy, particularly at the maternal-fetal interface,” senior paper author Akiko Iwasaki, Waldemar Von Zedtwitz Professor of immunobiology, told the News in an email. “The biggest take away is the finding that respiratory infection with SARS-CoV-2 has impact within the placenta, to trigger interferon and inflammatory responses.”

The lead author of the study, MD/Ph.D. student Alice Lu-Culligan GRD ’22, recalled that data began to emerge early in the pandemic suggesting that pregnant women are at an increased risk for severe COVID-19, adding that the CDC has since classified pregnancy as a risk factor for severe illness. One of the biggest questions for researchers was whether or not SARS-CoV-2 could cross the placenta and infect the fetus. According to Lu-Culligan, this phenomenon is very dangerous to fetal development and is found in viruses called TORCH pathogens.

Lu-Culligan recalled one pregnant woman who was admitted to Yale New Haven Hospital in March of last year with a COVID-19 infection — a case that partially inspired the work in this study. The woman was in her second trimester of pregnancy and ended up losing the pregnancy due to a complication known as preeclampsia. Lu-Culligan contributed to this particular case study, which found that SARS-CoV-2 was present in the woman’s placenta.

“We didn’t know if that was going to be representative of the cases that were to come or if that was an unusually bad outcome,” Shelli Farhadian, assistant professor of internal medicine and neurology and senior author on the paper, told the News. “So we started to approach and consent hospitalized pregnant women who had COVID-19 and asked them if they were willing to donate their blood and their placenta for us to study the effects of the virus on the pregnancies.”

According to the paper, during the study period from March 27 to June 1, 2020, pregnant women admitted to Yale New Haven Hospital for delivery were routinely tested for SARS-CoV-2 by nasopharyngeal swab. Women who tested positive were given the opportunity to donate their placenta to be analyzed in the study following their delivery.

The first thing they looked at, Farhadian explained, was whether SARS-CoV-2 itself was present in the placenta. While the case study of the earlier pregnancy found the presence of SARS-CoV-2 in the placenta, the virus was rarely found in those taken from women with full-term pregnancies during the larger study.

Researchers then began looking for the ACE2 receptor in the placental tissue. According to Lu-Culligan, the team acquired placental samples from different stages of pregnancy to test for the receptor.

According to Farhadian, the ACE2 receptor was found in the placenta during earlier stages of the pregnancy but was less likely to be found in later stages of pregnancy. The researchers therefore speculated that these patterns could explain why the virus was not found in all placental samples.

Lu-Culligan echoed these findings, noting that they could also help to provide a better understanding of the vulnerability of the placenta to SARS-CoV-2.

“We hypothesize that actually the maternal-fetal interface is most vulnerable earliest in pregnancy,” she told the News. “That vulnerability, by the time you have a full-term pregnancy, has declined to its lowest levels by the third trimester.”

The researchers also looked at the immune response in the placenta to the mother’s SARS-CoV-2 infection. Although most of the placentas were not infected with SARS-CoV-2, there could still be immune activity in the placenta in response to the infection elsewhere in the body.

“In this small study, we did find evidence for immune activity in the placenta in women who had COVID-19,” Farhadian told the News. “What this tells us is that the placenta is still sensing and responding to mom’s respiratory infection even though the virus itself is not present or replicating in the placenta.”

The focus of many researchers early in the pandemic was determining whether the placenta could become infected with SARS-CoV-2, according to Lu-Culligan. Although this question is still an important one, it is also necessary to focus on the risks of the immune response that occurs in the placenta, she explained.

Lu-Culligan hypothesized that this immune response could be responsible for some of the poor pregnancy outcomes linked to COVID-19, as maternal immune activation has been correlated with poor pregnancy outcomes. Lu-Culligan, Farhadian and Iwasaki all indicated that further research will need to be done studying COVID-19 in pregnant women.

“I think it’s really going to be important to monitor women who had COVID-19 earlier in pregnancy and then recovered,” Farhadian told the News, adding that it will also be important “to try to understand what, if any, might be the consequences of infection earlier in pregnancy.”

Farhadian emphasized that vaccination is the best way to protect pregnant women and their babies from the potential risks that come with infection, and she noted that an increasing number of pregnant women are choosing to get vaccinated.

She also expressed her gratitude toward the women who consented to the study and provided the placental tissue that the researchers analyzed.

“Even during the very high-stress scenario of having COVID-19 during pregnancy, these women were still so generous in contributing to something bigger than themselves,” she said.

The National Institutes of Health and the Emergent Ventures Fund at the Mercatus Center at George Mason University provided funding for the study.