C.Liniker in Ireland are warning of a spate of stillbirths in the first few months of 2021 that they have linked to SARS-CoV-2 infections. There were six women in the country who had stillbirths and one who miscarried, each a few weeks after they had COVID-19. Five of the cases so far concerned variant B.1.1.7, which now dominates cases in Ireland, Great Britain, large parts of Europe and the USA.
In all cases the placenta was badly damaged. “The placentas look completely burned out, just incredibly necrotic and damaged,” says Keelin O’Donoghue, obstetrician at Cork University Maternal Hospital in Ireland who is part of the team that manuscripts the cases. “You have all sustained acute injuries, thus having an acute impact on fetal compromise or death.”
In addition to stillbirths and miscarriages so far this year in Ireland, there have been three cases of expectant mothers diagnosed with COVID-19 having emergency deliveries and severely deteriorated placentas. The babies survived.
“There is a very abnormal appearance” on the surface of the placenta when it is cut for examination, says Brendan Fitzgerald, a pathologist at Cork University Hospital who examined five of the affected placentas, “with white streaks and nodules covering large parts the placenta occupy the placental disc. It is a very unusual finding that we would rarely see in routine practice. ”
Immunohistochemical tests showed the presence of SARS-CoV-2 in the placenta and in some cases the virus was detected by PCR. Researchers are writing down their results for a peer-reviewed publication, and Irish clinicians alert colleagues to their observation of stillbirths. The Royal College of Physicians in Ireland issued a statement on April 13th: “The six cases are against the background of a total of 11 cases of SARS-CoV-2 placentitis identified in Ireland since the start of the pandemic. The results of the baby’s death so far suggest a connection with the worrying variant B.1.1.7, which may explain why this finding was not an essential feature for the 1st and 2nd waves in 2020. ”
Estimates are pretty difficult at the moment to determine the true risk, but we believe we will see one in one hundred to one in two hundred cases [of stillbirth] in women with [COVID-19].
– Keelin O’Donoghue, Cork University Maternity Hospital
The B.1.1.7 variant, originally identified in the UK in 2020, was first discovered in Ireland in December 2020. It now accounts for 94 percent of cases in Ireland, according to Cillian de Gascun, director of the National Virus Reference Laboratory. Fitzgerald says that placenta disease is unlikely to be specifically related to the B.1.1.7 variant, but that the condition appears to be more severe after B.1.1.7 infection compared to other variants.
Massachusetts General Hospital perinatal pathologist Drucilla Roberts is waiting for more published results on cases related to different types of SARS-CoV-2 and says, “It makes sense that the placenta has an exercise-related effect.” Pandemic reveal that the placenta is somewhat resistant to infection and can help protect a fetus from the virus. Roberts adds, “Maybe these women [with B.1.1.7] are more viremic, so they have more virus in the blood so it can get to the placenta. ”
This remains speculative, and epidemiological studies from the US and England have so far found no increase in stillbirths in women who had COVID-19 while pregnant. A study of 4,005 pregnant women with suspected or confirmed SARS-CoV-2 infection also found that infection during pregnancy did not appear to be associated with a higher stillbirth rate, although preterm births in infected women were more common than expected. and the mother’s death was unusual, but higher than expected.
“Estimates are pretty difficult at the moment to determine the true risk, but we believe we will see one in one hundred to one in two hundred cases [of stillbirth] in women with [COVID-19]”Says O’Donoghue. She believes it is time to change the advice to pregnant women so that they let doctors know if they have COVID-19 and make doctors aware of this possible complication. Fitzgerald adds that his experience of seeing three stillbirth cases in quick succession warrants action without waiting for epidemiological trends.
The pregnant women O’Donoghue saw with affected placentas had moderate or no symptoms of COVID-19 and were not unwell enough to be hospitalized. There was no evidence that the fetus had the disease, says O’Donoghue. “All infants were usually adult and otherwise normally shaped,” she explains. The damage to the placenta “occurs within two to three weeks of the mother’s positive COVID-19 test.”
O’Donoghue’s group first reported placental damage related to COVID-19 in May 2020, before variant B.1.1.7 emerged. The researchers published a single case study of a 26-year-old woman who tested positive for SARS-CoV-2 at 36 weeks of pregnancy. She felt uncomfortable and reported reduced fetal movements. A caesarean section was performed later after the fetal heartbeat monitor raised concerns and the baby survived.
The placenta showed extensive cell injury and inflammation. This, says Fitzgerald, is similar in all the cases he has seen. The most commonly affected part of the placenta is the syncytiotrophoblast, a layer of epithelial cells that covers the placental villi and is a crucial part of the protective barrier between the mother and fetus. This is where ACE2 receptors are expressed, which the virus uses to enter human cells. A mutation in the receptor binding domain of B.1.1.7 likely increases the specificity of binding to ACE2, adds immunologist Michael Eikmans of Leiden University Medical Center via email. “This viral mutation could explain increased deposition of particles at the maternal-fetal interface, which can lead to clinical complications.”
The upper field shows the cut surface of a normal placenta with a spongy texture. The lower panel shows a placenta affected by SARS-CoV-2 placentitis. The unusually pale and firm appearance is due to clumping of the placental villi and the accumulation of substances such as fibrin and necrotic material.
In late December 2020, clinical pathologist David Schwartz of the Medical College of Georgia and 18 other perinatal specialists reported pathological findings in 11 placentas from infants in five countries believed to have acquired SARS-CoV-2 infection prior to delivery had previously published criteria.
The team found SARS-CoV-2 infection of the syncytiotrophoblast in all 11 placentas. All of them also had a rare abnormality called chronic histiocytic intervillositis (CHI), which involved the build-up of immune cells and cell death of syncytiotrophoblasts. These abnormalities were present in the placenta of the five live and six stillborn or terminated infants. “The 11 infected placentas in this study showed remarkable consistency of pathological findings,” the report said.
“It’s exactly the same result,” says Schwartz, referring to O’Donoghue’s May 2020 report, adding that he has seen similar published and unpublished reports. In cases where the virus has been transmitted from mother to fetus, infants typically only test positive for a day or a few days. “It’s hard to say that someone shouldn’t be overly concerned if it’s your baby, but I don’t think it’s something they should be very worried about because it seems rare,” says Schwartz.
Another common observation by Fitzgerald, Schwartz, and others is excessive build-up of fibrin, a blood clotting protein, in the placenta. Schwartz examines an autopsy in which the placenta of a stillborn child was heavily infected with SARS-CoV-2. “There’s a massive build-up of fibrin in the placenta,” he says, which may have cut the blood supply and oxygen levels to the fetus.
Roberts says the case reports collection so far “is a real placenta footprint of SARS-CoV-2”.
Roberts has studied a somewhat similar placental CHI disorder in which the mother’s immune system appears to have targeted the placenta. There is a pronounced number of maternal inflammatory cells (histocytes) in the space, but no necrosis of the synctiotrophoblasts in contrast to the SARS-CoV-2 placental infection, which has both. “There is an inflammatory response in the placenta that necroses trophoblasts, which is likely to lead to placenta dysfunction,” says Roberts. She suspects that the virus itself is damaging the placenta. “I don’t think it was just the inflammatory cells that caused the trophoblastic necrosis, as the common type of non-infectious CHI is not associated with trophoblastic necrosis.”
Last December, just before Schwartz and his co-authors published their analysis, another group reported trophoblast damage and placenta disruption from SARS-CoV-2. Larisa Debelenko, a pathologist at Irving Medical Center at Columbia University in New York, and her colleagues examined the placenta of 75 women infected with the virus and 75 control subjects. “In our experience, only about 1% of the placenta of women who tested positive by PCR at the time of delivery show this pathology,” she stated in an email.
Debelenko acknowledges that pathogens such as malaria, enteroviruses and cytomegalovirus can and do infect the placenta, but is cautious about attributing placental inflammation to SARS-CoV-2. She says it can be difficult to confirm the presence of the virus in placental tissue vascularized with maternal blood just by PCR. She also notes that the frequency of the ACE2 receptor in the placenta was discussed in 2020 and could be very different between placentas. “Proper statistical analysis comparing the incidence of spontaneous abortions[COVID-19] and during the epidemic may provide a better understanding of the effects of the virus on pregnancy outcomes. ”
The clinicians in Ireland have contacted British colleagues who are doing similar tests on stillbirths. “Pathologists in the UK are seeing the same results,” says O’Donoghue. “There are a number of cases that are being investigated.” While there were few reports in the literature in 2020, O’Donoghue predicts there will be many more in the near future. She would like to see more pregnant women offered vaccines for COVID-19.
Fitzgerald says “we don’t want to scare people,” but if a risk is identified, there is an opportunity to intervene and hopefully prevent stillbirths associated with SARS-CoV-2. O’Donoghue agrees, “There is potential here for an opportunity to save babies.”
Schwartz, who studied the effects of HIV, Ebola, Zika, and other viruses in pregnant women, says the focus on pregnancy is warranted. “Pregnant women and their infants are very often among the most vulnerable groups when they have a new, emerging drug like Zika or SARS-CoV-2 and are a major concern from a public health perspective.”
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