To the Editors:
I read with great interest the findings presented by Patberg and colleagues.1 They reported findings of a higher rate of villitis of unknown etiology and fetal vascular disruption in the placental tissues taken from term deliveries of pregnant women with COVID-19. This makes it reasonable to assume that there are pathologic changes in the fetal-maternal interface and the endometrium and their potential implication in the decidualization, placentation, and trophoblast invasion if pregnant women had COVID-19 just before pregnancy or during the first trimester. Whether these pathologic changes are driven by SARS-CoV-2 viremia or as a result of a heightened inflammatory response associated with COVID-19 is unknown.1
The process of placentation begins early after implantation when the trophoblast cells begin to invade the decidua and the uterine wall. The SARS-CoV-2 virus attaches to the angiotensin-converting enzyme 2 (ACE-2) receptor that is expressed in the human endometrium, and its knockdown can result in impaired decidualization, as shown in an in vitro study.2 In addition to the ACE-2 receptor, the formation of normal decidua requires certain levels of immune markers.3 Alternatively, the process of normal trophoblast invasion is regulated by the balance of the decidual antiinflammatory and proinflammatory cytokines.4 Once SARS-CoV-2 attaches to the ACE-2 receptor, it could down-regulate this receptor and elicit a cascade of inflammatory reactions, which (if present in the endometrium early in pregnancy) can disrupt the immune balance required for normal decidualization and trophoblast invasion.
Defective decidualization and abnormal trophoblast invasion can be implicated in the development of placenta accreta spectrum (PAS) and preeclampsia, respectively. The pathogenesis of PAS remains uncertain, but there is more evidence to support the involvement of thin decidua rather than excessive trophoblast invasion.5 It is postulated that the presence of thin decidua, as present in a cesarean scar, would allow excessive extravillous trophoblast invasion into the myometrium. Further, excessive trophoblast invasion as a primary culprit, regardless of decidual thickness, might also contribute to the development of PAS.5 In contrast, shallow extravillous cytotrophoblast invasion into the spiral arteries can result in hypoxia with the subsequent development of preeclampsia.4
COVID-19 infection just before pregnancy or during the early first trimester could disturb the local endometrial immune response that could subsequently lead to abnormal decidualization and trophoblast invasion. This could potentially result in PAS and preeclampsia. Therefore, pregnant women who present with a history of COVID-19 infection just before pregnancy or during early pregnancy should be carefully monitored. More studies are needed to understand this hypothesis regarding COVID-19 infection just before pregnancy or during early pregnancy and the potential risk of PAS or preeclampsia.
Acknowledgments
Special thanks to Dr Hugh S. Taylor (Anita O’Keeffe Young Professor of Women’s Health, chair of the Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, and the current president of the American Society of Reproductive Medicine) for his scientific opinion.
Footnotes
The author reports no conflict of interest.
This study did not receive any financial support.
References
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