COVID-19 during pregnancy: Effects on the placenta and stillbirth risk

• Cases of mother-to-fetus transmission of SARS-CoV-2 are low, but rates of stillbirth nearly double if pregnant women develop COVID-19 during pregnancy.
• Though the risk of stillbirth increases for women who contract SARS-CoV-2 while pregnant, many mothers and their babies are fine.
• Previously, researchers understood very little about the mechanisms leading to stillbirths in pregnant people with COVID-19 or how the pregnant body responds to SARS-CoV-2 infection.
• Two recent studies looking at the placentas of women who had COVID-19 while pregnant have attempted to shed some light on the effect of the virus on this organ and on maternal and perinatal outcomes following SARS-CoV-2 infection.

At the beginning of the COVID-19 pandemic, it was unclear how the virus affected pregnant people and their fetuses.

At first, though many pregnant people who contracted SARS-CoV-2, the virus that causes COVID-19, had a mild form of the disease, it soon became clear from a cohort study in England that pregnant women who contracted the virus were more likely to have a stillbirth and other adverse outcomes.

In the United States, the Centers for Disease Control and Prevention (CDC) later confirmed this, saying that the risk of stillbirth nearly doubled for women who developed COVID-19 while pregnant. Additionally, the CDC reported that this likelihood was even higher during the Delta variant surge.

Pregnant people who contract certain viruses, such as rubella, cytomegalovirus, herpes, and more recently, Ebola and Zika, have an increased risk of stillbirth, mostly through the fetus acquiring the infection in the uterus. However, the mechanism behind the increase of stillbirths for pregnant people with COVID-19 was unknown.

Now, an international study of placentas of babies stillborn to women who had COVID-19 has proposed that rather than fetal infection, the effect of the virus on placentas can be responsible for causing deaths of fetuses and newborn babies from a lack of oxygen.

The study was an international effort by 44 researchers in 12 countries, led by Dr. David A. Schwartz, M.D., MS Hyg., a perinatal pathologist and medical epidemiologist based in Atlanta, GA. The results appear in the journal Archives of Pathology and Laboratory Medicine.

“We wanted to understand the mechanisms of fetal demise and neonatal deaths in women who had COVID-19 and infected placenta,” he told Medical News Today in an interview.

Studying placentas

As part of the effort, researchers studied sixty-four placentas from stillborn fetuses and four from babies who had died very soon after birth. To the authors’ knowledge, all of the women affected were unvaccinated. The stillbirths occurred at an average of 30 weeks of gestation.

The researchers collected data on the mothers’ health, weighed the placentas, and visually studied them. They also took samples for microscopic tissue analysis and checked some for the presence of the SARS-CoV-2 virus.

They found that all 68 placentas had increased fibrin deposition and villous trophoblast necrosis, which refers to cell death. Fibrin is a protein often found at sites of bleeding or tissue damage. It can cause stiffening and death of the tissue, and deposits of this in the placenta can reduce the amount of oxygenated blood circulating through the placenta.

The trophoblast is the protective cell layer of the placenta. Sixty-six placentas also had chronic histiocytic intervillositis, an unusual inflammatory condition.

These three findings together are termed “SARS-CoV-2 placentitis,” which reduced the blood flow and oxygen in the placenta and led to low oxygen levels in the fetus.

Ultimately, this caused the death of placental tissues in all 68 of the placentas studied. An average of 77% of the placenta was destroyed by these processes, which the researchers believe to be responsible for the death of the fetuses and newborns from a lack of oxygen.

An examination of 30 autopsies showed some fetuses with the virus, but there was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

“[Other viruses] typically harm the fetus by crossing through the placenta, infecting the fetal body, and then causing pathology changes in the fetal organs. And the classic example, of course, is Zika virus, which causes central nervous system injury and malformation syndromes in the developing fetus,” explained Dr. Schwartz.

“But what we’re seeing in these cases of mothers who had [SARS-CoV-2] infection while pregnant — who then had placentas that were infected — is this uniform finding from case-to-case of SARS-CoV-2 placentitis, which is a very destructive abnormality that, in most cases, is destroying the majority of the placenta.”

– Dr. Schwartz

“And when that occurs, it prevents blood flow, both from the fetus and the mother through the placenta, and is significantly hampering oxygen exchange between the mother’s bloodstream and the fetal bloodstream, and as a result, we believe these fetuses are becoming hypoxic,” said Dr. Schwartz.

Can the placenta protect the fetus?

In another recently published study, researchers wanted to investigate why the transmission of SARS-CoV-2 from mothers to fetuses was so low. This study also looked at placentas, this time in women at different stages of their pregnancy, both from women who had COVID-19 and those who did not. These findings appear in the American Journal of Pathology.

For the study, researchers collected blood from 24 pregnant women who attended Boston University Medical Center between July 2020 and April 2021. Eight of these women had confirmed cases of COVID-19 in their third trimester, eight in their second trimester, and eight in the control group did not contract SARS-CoV-2 at all while pregnant. Just one of the women had been hospitalized with COVID-19, with the rest having mild cases.

The team took blood samples from the women within 24 hours before or after delivery, and they also collected placentas after delivery.

They then looked at the angiotensin-converting enzyme 2 (ACE2) receptor, the main receptor for SARS-CoV-2. They also looked for the activity of the genes responsible for the production of these receptors. The ACE2 receptor is found on the cell surface of many types of cells in the human body, and the SARS-CoV-2 virus uses it to gain access to our cells.

In fact, results showed a significant decrease in ACE2 receptor expression in the third trimester in women who had COVID-19 compared with the second trimester or in controls. Conversely, there was a significant increase in ACE2 protein levels in the blood serum in the third trimester of women who had COVID-19, compared with those who had the disease in the second trimester and controls. This suggested that ACE2 receptors were being shed, presumably to minimize the ability of the virus to cause infection in placental tissue.

Dr. Elizabeth Taglauer, first author of the study and assistant professor of pediatrics at Boston University School of Medicine, explained: “Our results suggest that the placenta is somehow sensing the mother’s infection and guarding against fetal transmission. If we understand how the placenta is naturally protecting babies from COVID-19, this may provide important information for therapies and strategies to help prevent other SARS-CoV-2 infections from continuing to spread.”

The study’s sample size was small and more research is necessary to determine the origin of the ACE2 found in the blood serum of the pregnant women, but the results suggest the placenta is staging a protective response in the presence of SARS-CoV-2.

In an email to MNT, Dr. Taglauer explained: “The placenta is likely putting many defense mechanisms in place to combat SARS-CoV-2 at the maternal-fetal interface. We are just beginning to understand the effects of these placental responses on infants born to mothers with SARS-CoV-2 in pregnancy.”

“These consequences are actually the main focus of our perinatal COVID-19 moving forward. We will be following infants born to mothers with SARS-CoV-2 in pregnancy for up to 2 years, studying their long-term health, whether they have any changes in their immune systems, and their ability to fight infections, especially respiratory infections.”

Both her own and Dr. Schwartz’s papers underlined the importance of vaccination. Dr. Taglauer told MNT in an interview:

“The most important thing that pregnant women can do to keep their babies healthy in this pandemic is to get vaccinated.”

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