During pregnancy, a mother’s life is ever-changing as she develops the fetus and prepares for birth. With these changes come alterations in the immune response and nutritional interactions between the mother and fetus. As the fetus relies on the placenta to bridge the mother’s blood, nutrients, oxygen, and other essential components for growth, this can also introduce the fetus to infectious agents the mother is exposed to. Multiple infectious diseases have been found to impact a fetus during pregnancy to varying degrees, from no impact to deformities or even stillbirths.
During the COVID-19 pandemic from 2020 to 2024, its effects on pregnant women and the developing fetus were not well understood. As vaccines for the virus were rolled out en masse, guidelines were established to best administer them to pregnant women based on their immune status and stage of fetal development. Despite these vaccinations, pregnant women still got infected with the virus, with medical professionals unsure of how the virus affects the fetus. Researchers from the University Hospital of Würzburg, Germany, have shed some light on the interaction by detecting the COVID-19 spike protein in placenta samples collected between 2020 and 2022.
The placenta plays a critical role as a barrier, preventing maternal infections from entering the developing fetus. As the fetus grows, it develops its own immune system through immature macrophages (their name meaning “big eaters”), called Hofbauer cells. It’s these cells that offer protection to the fetus during infection, but they aren’t fully functional like mature macrophages seen after birth. This still leaves the fetus vulnerable to infections that can cross the placenta from the mother, and medical professionals were unsure if COVID-19 was able to make this cross over.
During the pandemic, several studies from the Xiangya Hospital in China, Renmin Hospital of Wuhan University, and the Maternal and Child Health Hospital of Hubei Province found that the risk of COVID-19 transmission from mother to fetus was low. A study from the Yale School of Medicine confirmed that, finding that when the mother tested positive for COVID-19 by PCR, the placenta was negative. However, the Yale study also found an immune response at the maternal-fetal interface, indicating that the fetus was being attacked by the virus. In subsequent case studies, viral RNA (the genetic material of COVID-19) and the spike protein were detected in the placenta, but the impact on the fetus wasn’t significant.
When vaccines for COVID-19 became available, they were administered to pregnant women without complete approval by medical legislation. The vaccines contained the segment of the COVID-19 RNA that produced the spike protein during infections. When administered, the vaccine would be taken in by cells, and the cells would produce only the spike protein instead of the full virus. This allowed the immune system to encounter a part of the virus without the full virus present, thereby preventing major complications or disease. The reasoning for administering vaccines to pregnant women without full approval was that pregnancy itself was a major risk factor for severe outcomes during COVID-19 infection. Initial studies from Harvard and Tel Aviv University found that antibodies that targeted the COVID-19 spike protein were present in the placenta after maternal vaccination, suggesting some protection for the fetus. However, there was no confirmation that the spike protein or protective proteins were present in the fetus itself.
The researchers from the University Hospital of Würzburg sought to answer the question by looking at placenta samples from 106 women who gave birth from 2020 to 2022. Using the samples and the mothers’ medical history of COVID-19 infection and vaccination, they looked for the presence of the spike protein in the Hofbauer cells to determine if the spike protein was able to cross the placenta and interact with the fetus. The idea was that if the spike protein was present, then the virus and vaccine could access the fetus, resulting in disease outcomes or protection, respectively.
From their results, the researchers were able to detect the spike protein in the Hofbauer cells, confirming that it was able to cross the placenta. On top of this, the team also found lingering COVID-19 RNA delivered by the vaccine in Hofbauer cells, suggesting that the vaccine could also cross the placenta. How the spike protein (and more specifically, the virus) and vaccine cross the placenta still remains a mystery, and further research needs to be conducted to explain the exact mechanism.
Another question that remains to be answered is how this crossing affects the fetus. Currently, there is some debate, and it needs to be researched further, as studies from Massachusetts General Hospital found that maternal infection with COVID-19 resulted in inflammation of the placenta, which led to disastrous outcomes like stillbirths. Contrary to this study, studies from Karolinska University Hospital in Stockholm and the Post Graduate Institute of Medical Education & Research in India found the risk of COVID-19-induced pregnancy complications to range from non-existent to 25 percent. Even the researchers from Würzburg were unable to detect placental inflammation from their samples.
In retrospect, the researchers from Würzburg acknowledge that their study had its flaws. These include a relatively small sample size of unvaccinated mothers for the Würzburg, Germany region, and women who had complicated births declined to participate in the study, while miscarriages were excluded. Despite these flaws in their methodology, the Würzburg researchers still shed light on the possibility and confirm that the COVID-19 virus and vaccine are able to cross the placenta and reach the fetus. Depending on which accesses the fetus first can determine if the fetus suffers or survives during pregnancy, and further research is needed to provide a better chance for the latter outcome.
References
Bartmann C, Schmidt V, Mörz M, Schwab M, Rehn M, et al. (2026) Detection of spike protein in term placentas of COVID-19 vaccinated and/or SARS-CoV-2 infected women. PLOS ONE 21(3): e0344185. DOI
Kumar, M., Saadaoui, M., & Al Khodor, S. (2022). Infections and pregnancy: effects on maternal and child health. Frontiers in cellular and infection microbiology, 12, 873253.
Reyes L, Golos TG. Hofbauer Cells: Their Role in Healthy and Complicated Pregnancy. Front Immunol. 2018;9:2628. pmid:30498493
Zhang L, Dong L, Ming L, Wei M, Li J, Hu R, et al. Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection during late pregnancy: a report of 18 patients from Wuhan, China. BMC Pregnancy Childbirth. 2020;20(1):394. pmid:32641013
Zhang L, Jiang Y, Wei M, Cheng BH, Zhou XC, Li J, et al. Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province. Zhonghua Fu Chan Ke Za Zhi. 2020;55(3):166–71. pmid:32145714
Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, et al. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr. 2020;9(1):51–60. pmid:32154135
Lu-Culligan A, Chavan AR, Vijayakumar P, Irshaid L, Courchaine EM, Milano KM. SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface. medRxiv. 2021.
Dong L, Pei S, Ren Q, Fu S, Yu L, Chen H, et al. Evaluation of vertical transmission of SARS-CoV-2 in utero: Nine pregnant women and their newborns. Placenta. 2021;111:91–6. pmid:34217121
Patanè L, Morotti D, Giunta MR, Sigismondi C, Piccoli MG, Frigerio L, et al. Vertical transmission of coronavirus disease 2019: severe acute respiratory syndrome coronavirus 2 RNA on the fetal side of the placenta in pregnancies with coronavirus disease 2019-positive mothers and neonates at birth. Am J Obstet Gynecol MFM. 2020;2(3):100145. pmid:32427221
Taglauer E, Benarroch Y, Rop K, Barnett E, Sabharwal V, Yarrington C, et al. Consistent localization of SARS-CoV-2 spike glycoprotein and ACE2 over TMPRSS2 predominance in placental villi of 15 COVID-19 positive maternal-fetal dyads. Placenta. 2020;100:69–74. pmid:32862058
Li A, Schwartz DA, Vo A, VanAbel R, Coler C, Li E, et al. Impact of SARS-CoV-2 infection during pregnancy on the placenta and fetus. Semin Perinatol. 2024;48(4):151919. pmid:38897829
Watkins JC, Torous VF, Roberts DJ. Defining Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Placentitis. Arch Pathol Lab Med. 2021;145(11):1341–9. pmid:34338723
Schwartz DA, Mulkey SB, Roberts DJ. SARS-CoV-2 placentitis, stillbirth, and maternal COVID-19 vaccination: clinical-pathologic correlations. Am J Obstet Gynecol. 2023;228(3):261–9. pmid:36243041
Joshi B, Chandi A, Srinivasan R, Saini SS, Prasad GRV, Puri GD, et al. The placental pathology in Coronavirus disease 2019-infected mothers and its impact on pregnancy outcome. Placenta. 2022;127:1–7. pmid:35917629