key: cord-0895882-dizhms9a authors: Komine-Aizawa, Shihoko; Takada, Kazuhide; Hayakawa, Satoshi title: Placental barrier against COVID-19 date: 2020-07-25 journal: Placenta DOI: 10.1016/j.placenta.2020.07.022 sha: 179caff456452f918863b90601342746b6bde9de doc_id: 895882 cord_uid: dizhms9a Vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and possible induction of pregnancy complications, including miscarriage, fetal malformations, fetal growth restriction and/or stillbirth, are serious concerns for pregnant individuals with COVID-19. According to clinical information, the incidence of vertical transmission of SARS-CoV-2 is limited to date. However, even if a neonate tests negative for SARS-CoV-2, frequent abnormal findings, including fetal and maternal vascular malperfusion, have been reported in cases of COVID-19-positive mothers. Primary receptor of SARS-CoV-2 is estimated as angiotensin-converting enzyme 2 (ACE2). It is highly expressed in maternal-fetal interface cells, such as syncytiotrophoblasts, cytotrophoblasts, endothelial cells, and the vascular smooth muscle cells of primary and secondary villi. However other route of transplacental infection cannot be ruled out. Pathological examinations have demonstrated that syncytiotrophoblasts are often infected with SARS-CoV-2, but fetuses are not always infected. These findings suggest the presence of a placental barrier, even if it is not completely effective. As the frequency and molecular mechanisms of intrauterine vertical transmission of SARS-CoV-2 have not been determined to date, intensive clinical examinations by repeated ultrasound and fetal heart rate monitoring are strongly recommended for pregnant women infected with COVID-19. In addition, careful investigation of placental samples after delivery by both morphological and molecular methods is also strongly recommended. The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as the most critical global public health problem in 2020. For pregnant individuals infected with SARS-CoV-2, vertical transmission and subsequent pregnancy complications, such as miscarriage, fetal malformations, fetal growth restriction and/or stillbirth, are serious concerns. It is well known that some viral species can cause congenital viral infections and affect the health status of the fetus [1] . For instance, rubella From the limited information, the incidence of vertical transmission of SARS-CoV-2 has been considered rare; however, some cases have been reported [2] [3] [4] . At this time, we do not have specific medicines or effective vaccines for COVID-19. Therefore, to reduce the incidence of vertical transmission of COVID-19, it is important to understand the mechanisms of SARS-CoV-2 intrauterine infection. In this review, we discuss the possibility from 108 pregnancies and found one neonatal death and one intrauterine fetal demise (IUFD), in which vertical transmission could not be ruled out [7] . However, frequent abnormal findings in placental pathology have been reported among COVID-19-positive mothers (Table 1 Table 1 Table 1 Table 1 [10] . The placenta from the patient with IUFD showed villous edema and a retroplacental hematoma [10] . Findings such as thrombosis, intramural fibrin deposition, villous stromal-vascular karyorrhexis, and villous infarction were commonly observed [8] [9] [10] . Interestingly, acute and chronic inflammatory reactions were rarely observed [8] [9] [10] . This finding could be explained by the presence of regulatory cytokines produced by placental and decidual immune cells. Furthermore, the active replication and release of the SARS-CoV-2 cause pyroptosis [11] , which is a highly inflammatory pathway in the infected cells. In human trophoblast, pyroptosis also reported as a critical inflammatory form to induce adverse pregnant outcomes [12] . One possible hypothesis is SARS-CoV-2 can infect and replicate in the trophoblast cells but cannot be released. Therefore, inflammatory findings might be hardly observed in the placenta with SARS-CoV-2. However, the placentas of SARS-CoV-2-positive neonates showed chronic intervillositis with the presence of macrophages [3] . reported that viral spike protein and viral RNA staining within COVID-19-positive placental tissue was rare [8] . These reports suggest that even though SARS-CoV-2 was present in the placenta, the incidence of vertical transmission may be limited. We need to investigate the maternal-fetal interface in SARS-CoV-2 infection cases in more detail. The expression of angiotensin The expression of angiotensin The expression of angiotensin The expression of angiotensin----converting enzyme 2 (ACE2) in the converting enzyme 2 (ACE2) in the converting enzyme 2 (ACE2) in the converting enzyme 2 (ACE2) in the feto feto feto feto----placental unit placental unit placental unit placental unit ACE2 is a zinc metalloprotease attached to the cell membrane. The main function of ACE2 is the regulation of blood pressure by catalyzing the hydrolysis of angiotensin I to angiotensin II. In addition, ACE2 works as a SARS-CoV-2 receptor for cell entry [15, 16] . The expression of ACE2 is observed in various cells, including alveolar epithelial cells, endothelial cells, nephrocytes, and intestinal epithelial cells. Moreover, ACE2 is widely expressed in cells in the female genital tract and feto-placental unit, such as syncytiotrophoblasts, cytotrophoblasts, endothelial cells, and the vascular smooth muscles of primary and secondary villi [17] . A single-cell transcriptome study revealed ACE2 expression at the maternal-fetal interface and in fetal organs [18] . According to RefEx, which is the reference expression dataset, the expression of ACE2 in the reproductive tract is greater than that detected in the lung. Despite the finding that the mRNA expression level of ACE2 was higher in the early gestation placenta than the term placenta [19] , clinical data suggest no evidence of an increase in spontaneous abortion cases in patients infected with SARS-CoV-2 in early pregnancy. The aberrant expression of ACE2 is associated with pregnancy complications. For instance, the expression of ACE2 in the arterial endothelium of the umbilical cord was increased in preeclamptic placentas compared with normal placentas [17] . This finding suggests that preeclampsia patients might be a high-risk group of COVID-19 vertical transmission. The expression levels of ACE2 are variable between trophoblast types and differentiation [19] , further it can be influenced by pathophysiological conditions such as gestational diabetes mellitus (GDM) and preeclampsia. These changes must be examined carefully to evaluate possible risks of vertical transmission. ACE2 is also expressed in the vaginal mucosa; however, SARS-CoV-2 was not detectable in the vaginal fluid of women with severe COVID-19 infections in several studies [20] [21] [22] . [26] . However, the low sensitivity of PCR examination, as well as the financial cost, and limited medical resources make this approach impractical. Another possible mechanism of vertical transmission is via maternal immune cells. SARS-CoV-2 was reported to infect T lymphocytes through spike protein-mediated membrane fusion [27] , and maternal lymphocytes occasionally migrate into the fetal circulation, which is observed as microchimerism. The authors declare no conflict of interest. Vertical transmission of COVID-19 is rare but of serious concern． COVID-19 placentas show various histopathological findings. The precise mechanism of vertical transmission is so far unknown. Though placentas are susceptible to SARS-CoV-2, partially they protect fetuses. 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We thank American Journal Experts for English editing.