key: cord-0741287-mq6qjs2s authors: Mahyuddin, AP; Kanneganti, A; Wong, JLJ; Dimri, P Sharma; Su, LL; Biswas, A; Illanes, SE; Mattar, CNZ; Huang, RY‐J; Choolani, M title: Mechanisms and evidence of vertical transmission of infections in pregnancy including SARS‐CoV‐2 date: 2020-06-12 journal: Prenat Diagn DOI: 10.1002/pd.5765 sha: 16d492b12e64af7b490ce9a472e509e245872dc9 doc_id: 741287 cord_uid: mq6qjs2s There remain unanswered questions concerning mother‐to‐child‐transmission (MTCT) of SARS‐CoV‐2. Despite reports of neonatal COVID‐19, SARS‐CoV‐2 has not been consistently isolated in perinatal samples thus, definitive proof of transplacental infection is still lacking. To address these questions, we assessed investigative tools used to confirm maternal‐fetal infection and known protective mechanisms of the placental barrier that prevent transplacental pathogen migration. Forty studies of COVID‐19 pregnancies reviewed suggest a lack of consensus on diagnostic strategy for congenital infection. While RT‐PCR of neonatal swabs was universally performed, a wide range of clinical samples was screened including vaginal secretions (22.5%), amniotic fluid (35%), breast milk (22.5%) and umbilical cord blood. Neonatal COVID‐19 was reported in eight studies, two of which were based on the detection of SARS‐CoV‐2 IgM in neonatal blood. Histological examination demonstrated sparse viral particles, vascular malperfusion and inflammation in the placenta from pregnant women with COVID‐19. The paucity of placental co‐expression of ACE‐2 and TMPRSS2, two receptors involved in cytoplasmic entry of SARS‐CoV‐2, may explain its relative insensitivity to transplacental infection. Viral interactions may utilise membrane receptors other than ACE‐2 thus, tissue susceptibility may be broader than currently known. Further spatial‐temporal studies are needed to determine the true potential for transplacental migration. This article is protected by copyright. All rights reserved. The current COVID-19 pandemic raises many concerns about its effect on pregnancy. 1 • The placenta is a physical and immunological defence against fetal infection ( Figure 1 ). Maternal natural killer (NK) cells, decidual macrophages, and T cells co-inhabit the placental decidua. Immune cells in the decidua are vital in placental remodelling and implantation; deficiencies are associated with miscarriage and other adverse pregnancy outcomes. 4 While decidual NK cells are restrained by decidual macrophages via cytokines to prevent cytotrophoblast injury, 5 this protective mechanism may predispose the placenta to infections which would normally trigger a NK cell response. Decidual macrophages perform anti-microbial functions 6 and placental T cells regulate fetal-maternal tolerance while decidual virus-specific CD8 + T cells protects the fetus from infection. 7 Syncytiotrophoblasts (SCTs) and cytotrophoblasts (CTs) act as additional barriers to traversing infections and demonstrate varying resistance to pathogens, 8, 9 mediated by Toll-like receptors which regulate expression of anti-microbial pathways via interferon-β and secretory leukocyte protease inhibitor. 10 Anti-microbial peptides have been identified in the placenta, 11 accounting for protection against transplacental transmission of various pathogens. When the maternal-fetal interface barrier fails, pathogens breach the innate maternal • Pathogens can traverse the placenta and migrate from mother to fetus in several ways ( Figure 1) • The risk of fetal infection depends on gestation at exposure. 14 What do we know about mother-to-child-transmission (MTCT) of SARS-CoV-2? • Thirty-seven studies reported cases in the third trimester while three did so for the first and second trimester. 37,48,49 Not all samples described in Table 2 carry equal weight in proving vertical transmission. • IgM assays are prone to technical errors. 69 82 It is therefore important to understand the immune defence mechanisms at the maternal-fetal interface that prevent transplacental transmission of SARS-CoV-2. • Multiple reports have confirmed that SARS-CoV-2 gains entry into cells utilising the ACE-2 receptor and the serine protease TMPRSS2 for S protein priming. [83] [84] [85] In humans, ACE-2 mRNA gene and receptor protein are highly abundant in the early placenta, especially in SCT and villous stroma. 86 • Another potential route for SARS-CoV-2 transmission to the newborn is via breast milk. Comparing scRNA-seq datasets extracted from The Cancer Genome Atlas and FANTOM5 it was observed that ACE-2 translation in breast tissue was similar to that of the lung tissue. 95 Even though the ACE-2 receptor is expressed in breast tissue, most reports have not detected SARS-CoV-2 in breast milk. 3 9,44,45,51 In one report, a sample from one patient was transiently positive for SARS-CoV-2 on the first day of collection but subsequently tested negative two days later. 96 Although the various guidelines have endorsed the relative safety of breastfeeding whilst infected with COVID-19, more data on breastfeeding safety is still needed. 97, 98 • The This article is protected by copyright. All rights reserved. 2022. 102 Until the many uncertainties regarding MTCT remain unanswered, social distancing, 103 universal testing in high prevalence areas 104 and proper intrapartum infection control 105 will remain mainstays in reducing transmission of SARS-CoV-2 from mother to baby. Separation of infant from mother is controversial and not universally recommended; therefore obtaining conclusive evidence on diagnostic performance of various newborn samples poses a challenge. Biological samples as detailed in Table 1 interface. These comprise a microscopic section of the gross placenta, which is shown, for orientation, together with the fetus inside the uterine cavity (right panel). The possible routes of pathogen migration from mother to fetus, and across the placental barrier, are described in the coloured boxes (1) (2) (3) (4) (5) . The left panel is an expanded view of the cell membrane from a chorionic villus cell depicting the presence of ACE-2 receptor, and the absence of TMPRSS2 in this cell type (the putative location is boxed in and crossed-out). Co-expression of both ACE-2 and TMPRSS2 is required for SARS-CoV-2 virion entry into the cell cytoplasm. S ars-CoV-2 in t he context of past coronaviruses epidemics: Consideration for prenatal care Coronavirus disease 2019 (COVID-19) pandemic and pregnancy Vertical hepatitis C virus transmission: Main questions and answers The role of decidual immune cells on human pregnancy Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy What are the roles of macrophages and monocytes in human pregnancy? 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American family physician Risk of hepatitis B in infancy and childhood Hepatitis B in pregnancy A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy Trans placent al infection with Japanese encephalitis virus Arboviruses and pregnancy: maternal, fetal, and neonatal effects Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome Evidenc e for high levels of vertical transmission in Toxoplasma gondii Pathologic examination of the placenta in human cases of toxoplasmosis Herpes simplex virus infection in pregnancy Syncytiotrophoblast is a barrier to maternalfetal transmission of herpes simplex virus Neonatal airway swabs RT Other neonatal tissues (anal swab/rectal swab/urine/faeces/blood/gastric juice Peri-partum vaginal or cervical secretions RT Peri-partum maternal rectal swab/stool RT-PCR 3 123 Hypoplasia, placentitis, lobular rarefaction, dysmaturity of villous trunci and villus, villitis, villi agglutinated by fibrin, inclusion bodies in fetal and decidual cells. 124 Placenta via cytotrophoblast or invasive cytotrophoblast. 125 Mental retardation, vision loss, sensorineural deafness, prematurity, IUGR.Underdevelopment of the placenta, CMV impairs cytotrophoblast differentiation/invasion, impairs formation of floating and anchoring villi leading to reduced surface area of villous tree. Clusters of cytomegalic cells in villi, massive villous destruction and villitis, fibrotic areas with pigment macrophages and thrombus. 125 Parvovirus B19 Placenta Fetal loss, hydrops fetalis (nonimmune) 126 , congenital anomalies (CNS, craniofacial, eye) and fetal anaemia.Chronic villitis, chorioamnionitis, viral inclusions. Infarction and necrosis, villous oedema, villus immaturity and increased erythropoiesis. 127 Varicella-Zoster Placenta Ascending infection from the cervix. 128 Abortion, stillbirth, congenital anomalies, cataract, skin lesions, CNS damage, cranial calcifications and skeletal anomalies.Diffuse basal chronic villitis, widespread infiltration of lymphocytes, histiocytes and multinucleated giant cell. 129 Placenta: Coxsackie B-3. 130 Stillbirth, possible congenital anomalies, hand-foot-and-mouth disease, hepatitis, meningoencephalitis, myocarditis, pneumonia, coagulopathy, rashes. 130 Coxsackie B-3 placenta -inflammation of villi, chronic monocytic villitis, increase in Hofbauer cells, presence of myeloid cell populations. 130 Human Immunodeficiency Virus (HIV) Placenta cells expressing CD4, Fc receptors on syncytiotrophoblast, Hofbauer cells, placental tears, chorioamnionitis. 131 Abnormalities in the thymus and spontaneous fetal loss. 132 Placenta of fetal demise and fetus HIV positive: acute and chronic deciduitis, endometritis, areas of infarct and haematoma, small or oedematous placenta.Placenta of fetal demise and fetus HIV negative: funisitis, Contact with maternal secretions acute and chronic deciduitis, chorioamnionitis. 132 Droplet, airborne transmission Fetal demise (27%) 133 preterm delivery Placental abruption, which can be caused by maternal infection. 134 SARS-CoV-1 Droplet, airborne transmission.Spontaneous miscarriage (first trimester), preterm delivery. 76 Oligohydramnios, IUGR, and small for gestational age. 75 Placentae showed greater amounts of subchorionic, intervillous and perivillous fibrin, avascular fibrotic villi, perivillous calcification, accelerated villous maturation and areas of infarct. 75 Droplet, airborne transmission.Increased incidences of preterm births; higher rates of miscarriage, perinatal death, pre-eclampsia, caesarean section deliveries; and no increased incidences of fetal growth restriction compared to general population. 82 Intrauterine fetal distress, PROM, low birth weight, feeding intolerance and respiratory distress. 138, 139 replicate in all cells of the maternal-fetal interface. 140 Lassa fever Intrauterine Miscarriage, intrauterine death, stillbirth. 141 Replication in placental cells. 141 Japanese Encephalitis Miscarriage, stillbirth. 142 Infection and replication in placental cells. 142 Zika virus Intrauterine Microcephaly, ventriculomegaly, intracranial calcification. 143 Malformations of cortical development, abnormalities of corpus callosum and posterior fossa, eye abnormalities, arthrogryposis, anaemia and IUGR. Infants may present with neurological, motor and auditory problems and epilepsy. 144 Infect and multiply in resident macrophages (Hofbauer cells) and endothelial cells of placenta. 16 Intrauterine Spontaneous abortion and fetal loss, CNS calcifications, CNS/cranial abnormalities, retinochoroiditis. 145 Infection of placenta, low grade chronic villitis, mononuclear inflammatory infiltrate. 146 Herpes-Simplex Intrapartum (majority) Intrauterine (less)Congenital infection (rare), abortion, stillbirth, congenital anomalies (eye, CNS, skeletal), growth restriction. 147 Inflammation of placental cells affects placentation. Infection of extravillous trophoblast cells. Syncytiotrophoblast prevents entry of virus limiting transplacental transmission. 148 IUGR: intrauterine growth restriction, PROM: premature rupture of membrane, CNS: central nervous systemAccepted Article