Table 2.
SARS-CoV-2 detection in the placenta, placental pathology and vertical transmission in COVID-19-positive mothers.
| Author | No. of cases | Patient Characteristics (Gestational age at infection/Symptoms (weeks); Disease severity; Days of infection/Symptoms until delivery (range); Delivery mode | Investigations | SARS-CoV-2 Placental Infection | Placental Pathology | Vertical Transmission |
|---|---|---|---|---|---|---|
| Baud D et al., 2020 | 1 | 19 w; Mild; 4 days, VD. | Placenta RT-PCR, histology and IHC, and fetal autopsy. | Placental submembranes and cotyledons positive for SARS-CoV-2. | Acute subchorionitis (macrophages and neutrophils) and increased intervillous fibrin deposition and synctial knots. Funisitis and umbilical cord vasculitis. | Maternal blood, urine and vaginal swab were negative for SARS-CoV-2. Fetal swabs (axillae, blood, meconium, mouth), lung, liver, and thymus were negative for SARS-CoV-2. |
| Penfield CA et al., 2020 | 32 | 26-41 w (range); 6 mild, 2 severe, 3 Mild; 0–15 days; 4 CS, 7 VD. | RT-PCR (11 placentas). | 3 placentas from women with severe to critical COVID-19 were positive for SARS-CoV-2. | N/A | Fetal swabs were negative for SARS-CoV-2. |
| Kirtsman M et al., 2020 | 1 | 35 w, Mild, 1 day; CS. | Placenta PCR and histology. | Placental swabs and placental parenchymal and chorion tissues were positive for SARS-CoV-2. | Multiple areas of infiltration by inflammatory cells (mainly CD68-positive macrophages) and extensive early infarction. Only scattered T-cells (CD3), B-cells (CD20) and neutrophils (CD15) were identified on IHC. The inflammatory infiltrate was largely confined to the intervillous space, consistent with chronic histiocytic intervillositis. | Breast milk and vaginal swab were positive for SARS-CoV-2. All 3 of the neonate's nasopharyngeal swabs were positive for SARS-CoV-2 gene targets via RT-PCR testing; neonatal plasma tested positive on day 4, and stool was positive on day 7. |
| Patanè L et al., 2020 | 22 | Third trimester; 1 case Mild; 1 CS, 1 VD. | Placenta RT-PCR ISH. |
2 positive placentas; In situ hybridization for SARS-CoV-2 spike protein mRNA, highlighting the presence of SARS-CoV-2 spike antigens in villous STBs. | Case 1: Chorionic villi showing chronic intervillositis with macrophages; Macrophages in the intervillous spaces highlighted by anti-CD68 IHC in 2 cases that were positive for SARS-CoV-2. | Case 1: The newborn had a positive result for COVID-19 from NP swabs that were obtained immediately after birth, 24 h later, and after 7 days. Case 2: The NP swab obtained at birth from the neonate was negative for SARS-CoV-2, but a follow-up test of an NP swab that was obtained on day 7 was positive for SARS-CoV-2. |
| Schoenmakers S et al., 2021 | 1 | 31 + 4 w; Mild, 8 days; CS. | Maternal, placental, and neonatal swabs for RT-PCR, serology, IHC, ISH, TEM. | Positive placenta RT-qPCR; SARS-CoV-2 RNA ISH demonstrated predominant localization of SARS-CoV-2 in the STBs; Electron microscopy confirmed the presence of SARS-CoV-2 particles in the STBs, whereas villous and fetal parenchyma showed no evidence of SARS-CoV-2 infection on IHC, ISH, or TEM. | Presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the STBs associated with an intervillous inflammatory infiltrate, characterized by IHC as M2 macrophages (CD163+ and CD68+), cytotoxic (CD8), and helper T-cells (CD4) as well as activated B-lymphocytes (PAX5 and CD38) | RT-qPCRs of the maternal blood, vagina, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples (umbilical cord blood, urine, feces, blood, nasopharynx, and sputum from a deep tracheal aspirate) tested negative over a period of 9 days. Paediatric multisystem inflammatory syndrome—temporally associated with SARS-CoV-2 (PIMS-TS). |
| Hosier H et al., 2020 | 1 | 22 w; Severe; 10 days; Termination. | Placenta, umbilical cord, fetal heart and lungs RT-PCR, Histology, IHC, ISH, TEM and WGS, and maternal serology. | Placenta and umbilical cord positive for SARS-CoV-2 RNA; SARS-CoV-2 localized predominantly to STBs on IHC and ISH; viral particles seen within the cytosol of placental cells. | Marginal adherent clot with focal placental infarct; Diffuse pervillous fibrin and inflammatory infiltrate (macrophages and T cells) demonstrated by IHC for CD68 and CD3, consistent with histiocytic intervillositis | Maternal saliva and urine positive but oral and nasal swabs tested negative postoperatively. Fetal heart and lung were negative for SARS-CoV-2. |
| Pulinx B et al., 2020 | 1 | 22 w; Mild; 15 days; VD. | Placenta and amniotic fluid RT-PCR, IHC, and histology. | Positive placenta RT-PCR; viral localization in the placental STBs confirmed by IHC. | Chronic intervillositis and extensive intervillous fibrin depositions with ischemic necrosis of the surrounding villi. Aggregates of histiocytes and cytotoxic T lymphocytes in the intervillous space were also present and confirmed with IHC stainings for CD68, CD3, and CD8; chronic intervillositis and extensive intervillous fibrin depositions with ischemic necrosis of the surrounding villi. In the fetal circulation, there was nuclear debris and an increase in erythroblasts, as can be seen in fetal hypoxia. |
Amniotic fluid was positive for SARS-CoV-2. |
| Richtmann R et al., 2020 | 5 | 21-38 w (range); Mild-Moderate; 1–22 days (range); 2 CS 3 VD. | Placenta and amniotic fluid for RT-PCR and histology, and fetal autopsy (1). | SARS-Cov-2 was detected by RT-PCR in placental specimens in two cases. | Acute chorioamnionitis in all five cases. Two cases had massive deposition of intervillous fibrin associated with mixed intervillitis and villitis, and intense neutrophil and lymphocyte infiltration. These findings are described as villitis of unknown etiology (VUE). | SARS-Cov-2 was detected by RT-PCR in amniotic fluid. Fetal deaths. One fetus had neutrophils inside alveolar spaces, suggestive of fetal infection. |
| Vivanti AJ et al., 2020 | 1 | 35 + 2 w; Mild; 3 days; CS. | Placenta and amniotic fluid RT-PCR and histology. | RT-PCR on the placenta was positive for both SARS-CoV-2 genes. An intense cytoplasmic positivity of peri-villous trophoblastic cells was diffusely observed performing immunostaining with antibody against SARS-CoV-2 N-protein. | Diffuse peri-villous fibrin deposition with infarction and acute and chronic intervillositis. | Amniotic fluid collected before rupture of membranes tested positive for both the E and S genes of SARS-CoV-2. Blood and non-bronchoscopic bronchoalveolar lavage fluid were collected for RT-PCR and both were positive for the E and S genes of SARS-CoV-2. NP and rectal swabs were first collected after having cleaned the baby at 1 h of life, and then repeated at 3 and 18 days of postnatal age: they were tested with RT-PCR and were all positive for the two SARS-CoV-2 genes. Neurological symptoms and inflammatory findings in CSF. |
| Hsu AL et al., 2021 | 1 | 40 + 4 w; Mild; 2 days; VD. | Placenta for IHC, histology. | Placenta was positive for SARS‐CoV‐2 antigens in the umbilical cord, central and peripheral disc, chorionic villi endothelial cells and rarely in trophoblasts. | Normal gross morphology. Acute uterine hypoxia (hypertrophic arteriopathy, subchorionic laminar necrosis) superimposed on chronic uterine hypoxia (extravillous trophoblasts and focal chronic villitis). |
Neonate RT-PCR negative. |
| Facchetti F et al., 2020 | 101 | 37 + 5 w; Moderate; 0 days; VD. | Placentas for IF, IHC, ISH, RT-PCR, and TEM. | SARS-CoV-2 N and S proteins in the STB; viral RNA detected in the cytoplasm of the STB, fetal capillaries endothelium, fibroblasts, and fetal intravascular mononuclear cells; S protien and intense signal detected in the STB on IHC and ISH respectively; viral particles detected in the cytoplasm of the STB, fetal capillaries endothelium, fibroblasts, and cytoplasm of intra-capillary cells, likely corresponding to monocytes (1 placenta). | COVID-19-positive placenta: Gross: weight 448 g (25–50 percentiles for age), no significant abnormalities were detected on cord insertion, cord vessels, fetal surface and membranes, the chorionic parenchyma was dark brown and contained multiple small pale areas Histology: histiocytic-neutrophilic intervillositis; avascular and fibrotic villi and stroma-vascular karyorrhexis, accelerated villous maturation; chorangiosis. |
Newborn tested positive for viral RNA at 36 and 72 h, and 17 d and developed COVID-19 pneumonia and severe respiratory distress 24 h after birth. |
| Mongula JE et al., 2020 | 1 | 31 + 4 w; Moderate; 1–13 days; CS. | Placenta for PCR, IHC. | Fetal side of the placenta was positive for SARS-CoV-2. | Abnormal gross (not described). Histology: Increased perivillous fibrin deposition leading to trophoblast necrosis and intervillositis (chronic (histiocytes) and acute (granulocytes)); increased villi maturation |
Vaginal swab positive. Neonatal NP swabs negative on days 4 and 7. |
| Menter T et al., 2021 | 5 | 35 + 5–40 + 5 w (range); Asymptomatic-Mild; 35-(-1) days; 2 CS 3 VD. | Placenta and umbilical cord for RT-qPCR, histology, and ISH. | 1 placenta and umbilical cord positive; viral RNA visualized in the decidua by ISH. | Umbilical cord hypercoling in 3 placentas. Prominent lymphohistiocytic villitis and intervillositis; signs of maternal and fetal malperfusion in 100% and 40% of cases, respectively. |
Amniotic fluid, breast milk and umbilical cord blood negative for SARS-CoV-2 in all cases. |
| Fenizia C et al., 2020 | 31 | 34.4–41.4 w (range); 26 mild, 4 severe; 1–17 days; 6 CS, 25 VD. | Maternal and newborn NP swabs, vaginal swabs, maternal and umbilical cord plasma, placenta and UC biopsies, amniotic fluid and milk for serology, inflammatory gene expression analysis (RT-PCR). | 2 positive term placentas. Inflammatory hyperactivation upregulated for effector cytokines and chemokines (CXCL10, CXCL8, CCL5, CCL3, and CCL2), adaptive immunity mediators, downstream signaling molecules and TLRs. |
N/A | SARS-CoV-2 genome detected in 1 UC blood and 1 vaginal swab. Anti-SARS-CoV-2 IgM and IgG antibodies in 1 milk specimen and UC blood (whose placenta tested positive). 2 fetuses NP swabs tested positive but one tested negative after 48 h. |
| Schueda Stonoga ET et al., 2021 | 1 | 26 + 5 w; Severe; 8 days; CS. | Placenta for RT-PCR, IHC and histology, and fetal autopsy. | SARS-CoV-2 RNA in cotyledons and membranes. | The placental disc was round, and had tan and glistening membranes peripherally attached. The umbilical cord had 3 vessels; it was 28 cm long, inserted eccentrically, and under coiled. The fetal surface was gray with normal chorionic plate vessels. The trimmed placental disc weighed 135 g and measured 12 × 12 cm (<3rd percentile). Chronic histiocytic intervillositis, maternal and fetal vascular malperfusion (infarcts, decidual vasculopathy, accelerated villous maturation). |
SARS-CoV-2 RNA in umbilical cord blood aspirate. Fetal tissue samples tested negative for SARS-CoV-2. Microglial hyperplasia, mild lymphocytic infiltrate, and edema in skeletal muscle. |
| Shende P et al., 2021 | 1 | 8 w; Asymptomatic; 35 days; termination. | Amniotic fluid and placenta (villi) for FISH, RT-PCR, Histology. POC for routine examination and SARS-CoV-2 testing. |
SARS-CoV-2 RNA for E, N, and RdRp genes detected in the placenta villli; S1 and S2 proteins localized in the cytoplasm of CTB and STB cells and fetal membranes. | Avascular villi with extensive perivascular fibrin deposition; Decidua had fibrin deposition with extensive leucocyte inflitration in the intravillous spaces and decidua, and lysis of the STB of the villous cells. | Viral RNA in amniotic fluid. Hydrops fetalis (non-autoimmune and placenta disomic for chromosomes 13, 18, 21 and X). |
| Zhang P et al., 2020 | 74 | 38-40 w; 20 CS, 54 VD. | Placenta for ISH, IHC and histology. | Viral particles in the STB, atrophic endometrial glandular epithelium, and subchorionic plate (Langhan's fibrinoid) 2 (ISH) placenta. | Weight mean 437 (390–519); Vasculopathy (classic type (33.8%), mixed type (9.5%), and mural hypertrophy (5.4%)); Infarcts (9.5%); chorioamnionitis (64.9%); meconium (32.4%); thrombosis (24.3%); villitis (23%); cord issue (1.4%); MFI (97.3%); avascular villi (93.2%). | No viral signals in maternal or fetal tissues. Newborn tested (whose placenta tested positive for SARS-CoV-2 by ISH) positive by swab PCR at 24 h, 48 h and 7 days, but was asymptomatic. |
| Feitosa Machado SS et al., 2021 | 1 | 35 w; Mild, 0 days; CS. | Placenta for RT-PCR, and fetal autopsy. | Positive placental cut surface | Placenta had an irregular shape, weighed 245g, below the percentile 3, about one eighth of fetal weight, and measured 17.5 × 14.5 × 1 cm. The maternal surface of the placenta had some lobes with little distinct borders, presenting an area of previous infarction and an area of recent infarction, peripheral, making up about 20% of the organ. The fetal membranes had thickened and yellowish areas and umbilical cord had peripheral implantation. | NP swab of the fetus was negative for SARS-CoV-2. Histological sections of the lung was impaired due to autolysis, but the presence of a mixed inflammatory infiltrate was noticeable. |
| Michel AS et al., 2021 | 1 | 16 + 4 w; Moderate; 7 days; VD. | Amniotic fluid and placenta for RT-PCT, IHC and histology, and fetal autopsy. | Placenta tested positive (twice same day). | Reactive villitis (histiocytes) specifically in infected villi but no intervillitis. | Amniotic fluid positive for SARS-CoV-2. Negative RT-PCR for SARS-CoV-2 in the fetal liver and lung. |
| Cribiù FM et al., 2021 | 21 | 37 + 3 w (median); Mild-Moderate; 9 days; 9 CS, 12 VD. | Placenta for RT-PCR, ISH, and gene expression. | 10 placentas positive for SARS-CoV-2. Signature enrichment and differential expression analyses showed that genes implicated in innate antiviral immunity, chemotactic and inflammatory response, and adaptive response (such as CXCL9, CXCL10, CXLC11, CCL2, CCL7, IL6, IL21R, CD8A, GZMA, PRF1, CD68, and CD163.) were highly expressed in the placenta in 1 patient and the infected lungs, compared with the rest of the placenta samples. |
Non-specific features indicative of maternal inflammation rather than direct viral infection except in one placenta with massive fibrin deposition and necrosis of the STB layer of the villi. | N/A |
| Sanchez J et al., 2021 | 2 | Case 1: 36 w, Case 2: 37 w; Asymptomatic; 1–2 days; 2 CS. | Placenta for IHC, RT-PCR, and WGS. | 2 placentas positive in the fetal side, endothelial cells of chorionic villi vessels proximal to both maternal and fetal sides (A1 and B1 lineage with A to G nucleotide mutation at position A23403G (D614G) and G11803T in both genomes). | Dense infiltrate of lymphoid cells around decidual vessels and endothelial cells with cytopathic changes karyomegaly and hyperchromia, especially on the maternal side. | NP swabs from the ingants negative for SARS-CoV-2 at 24 h. |
| Lu-Culligan A et al., 2021 | 39 | 22-40 w (range); Asymptomatic-Severe; 0–27 days; 13 CS. | Maternal plasma and placentas for IF, IHC, hstology, RT-qPCR, serology, and single-cell transcriptomics. | Viral RNA found in 1 placenta on RT-qPCR and CTB in vitro. | Increased intervillous fibrin (33%) but none in controls. | Noenate NP negative (whose placenta tested positive). |
| Zaigham M et al., 2021 | 1 | 34 + 1 w; Mild; 0 days; CS. | Maternal blood, neonatal NP swab and placenta for RT-PCR, serology, WGS, histology, IHC, and ISH. | SARS-CoV-2 RNA was positive in the cytoplasm and nucleus of CTBs and STBs in areas with intervillositis and fibrinoid depositions, with positive staining in the villous stromal cells; ds-RNA detected in the vCTB and STB by ISH (genetic seq placenta (clade 20B/GR/B.1.1 with 11 SNPs and 1 MNPs from the reference Wuhan genome). | Gross: membranes had normal color without signs of meconium staining, placental weight 342 g, within the 10th-90th percentile for GW 34 + 0–34 + 6; UC: 3 vessels; fibrinoid depositions (50%). Intervillous fibrinoid deposition accompanied by denudation of the villi from trophoblasts and STB with dislocated STB visible in the fibrinoid; multiple regions of dense intervillous infiltrates of neureophilic granulocytes and macorphages. Chorangiosis in areas devoid of fibrinoid depositions. IHC confirmed inflammatory cell component of the intervillitis was dominated by myeloperoxidase-positive granulocytes and CD-68-positive macrophages with sparse amounts of CD3− and CD-20-positive lymphocytes |
Maternal blood positive for SARS-CoV-2. Neonate positive for SARS-CoV-2 at 48 h and IgM- and IgG-seropositive at 14 days. |
| JAK B et al., 2021 | 1 | Asymptomatic; 10 days; VD. | Placenta for ISH, RT-qPCR, nested PCR, and fetal autopsy. | Positive placenta on nested RT-PCR. | Gross: placenta and umbilical cord weighed 416g and measured 42*12*4 cm, discoid in shape with a firm reddish-colored maternal surface, spongy in appearance, and adherent clots and diffuse whitish areas; fetal surface smooth and opaque and evident vessels Intervillous and subchorionic fibrin; recent infarcts, villous agglutination, and narrowing of the intervillar spaces, an increase in synctial nodes; fetal thrombotic vasculopathy. | Fetal brain, heart, liver, and lung positive for SARS-CoV-2 on nested RT-PCR. Left fetal lung showed intense and extensive bronchopneumonia with numerous neureophis and pyocytes filling the alveoli, along with abundant amniotic fluid, fibrin deposits, and Gram-positive bacterial growth in blood culture. Right lung showed intense capillary and vascular congestion, with amniotic fluid and meconium in the alveoli. |
| Valdespino-Vazquez MY et al., 2021 | 1 | 13 w; Mild; 5 days; VD. | Placental and fetal autopsy for IF, IHC, histology RT-qPCR, and TEM. | SARS-CoV-2 N protein and viral particles found in the placenta; viral dsRNA. | Gross: bichorial, biamniotic. The placental weight was 25 g with measurements of 8 × 7 × 1cm with parenchymal infarcts in 25% of the examined surface. Placental infarction, with diffuse perivillous fibrin, active chronic intervillositis, and subchorial inflammation; CD163 positivity in the villous stroma and intervillous space |
Positive signal to N protein detected in the placenta; dsRNA detected in the fetal and kidney; viral particles in the cytoplasmic vacuoles of lung cells. |
| Sinaci S et al., 2021 | 48 | 38 w (median); Mild-Moderate; 38 CS, 10 VD. | Amniotic fluid, cord blood, placenta, and vaginal secretions for serology, and RT-PCR. | 1 positive placental sample. | N/A | Vaginal secretions positive for SARS-CoV-2 in two cases. Two newborns screened positive for IgG-IgM at 24 h but RT-PCR were negative. 1 newborn had a positive NP RT-PCR but the amniotic fluid, cord blood, placenta and vaginal secretions were negative. |
| Garcia-Ruiz I et al., 2021 | 45 | Median: 34.7 w (range: 14–41.3 w); 29 Mild, 12 Severe, 3 Critical; Median: 21.5 days (range: 0–141 days); 15 CS, 29 VD. | Amnitoic fluid, UC blood and placenta for IHC, ISH, RT-PCR, and serology. | 1 positive placenta on IHC and ISH. | N/A | 1 case positive for SARS-CoV-2 in amniotic fluid and UC blood but negative NP. 1 case negative at birth returned positive at 24–48 h. |
| Karade S et al., 2021 | 1 | 39 w; Moderate; 2 days; VD. | Amniotic fluid, breast milk and placenta swab for RT-PCR. | Placenta positive for SARS-CoV-2 ORF 1b and RDRp. | Grossly normal. Histology not done. | Amniotic fluid positive for SARS-CoV-2 ORF 1b and RdRp. Neonate NP positive RT-PCR but returned negative on DOL 5. |
| Husen MF et al., 2021 | 36 | 269.5 days (39 median); 28 Asymptomatic/Mild, 8 Moderate/Severe; 19.5 days (median 33); 22 CS 14 VD. | Fetal, maternal blood, feces, and urine, placental samples for serology, IHC, RT-PCT, and histology. | Positive SARS-CoV-2 on RT-PCR and IHC. | Perivillous fibrin (23.1%), fibrinoid necrosis (10.3%); maternal CD20+ B-cell infiltrate (12.8%). | N/A |
CS: cesarean section; CSF: cerebsrospinal fluid; CTBs: cytotrophoblasts; DOL: day of life; dsRNA: double-stranded RNA; IF: immunofluoresence; IHC: immunohistochemistry; ISH: in situ hybridization; MFI: massive perivillous fibrinoid deposit; N/A: not available; NP: nasopharyngeal; POC: products of conception; RdRp: RNA-dependent RNA polymerase; RT-PCR: reverse transcriptase polymerase chain reaction; STBs: synciotrophoblasts; TEM: transmission electron microscopy; UC: umbilical cord; VD: vaginal delivery; WGS: whole genome sequencing.