key: cord-0949865-jhuhcber authors: BOUACHBA, Amine; ALLIAS, Fabienne; NADAUD, Beatrice; MASSARDIER, Jerome; MEKKI, Yahia; BOUSCAMBERT DUCHAMP, Maude; FOURNIERE, Benoit DE.LA.; HUISSOUD, Cyril; TRECOURT, Alexis; COLLARDEAU-FRACHON, Sophie title: Placental lesions and SARS-Cov-2 infection: Diffuse placenta damage associated to poor fetal outcome date: 2021-07-15 journal: Placenta DOI: 10.1016/j.placenta.2021.07.288 sha: 3fbf21606c338281857387ce730c090c38a11731 doc_id: 949865 cord_uid: jhuhcber INTRODUCTION: Pregnant women with covid-19 are more likely to experience preterm birth. The virus seems to be associated with a wide range of placental lesions, none of them specific. METHOD: We collected cases of Covid-19 maternal infection during pregnancy associated with poor pregnancy outcomes, for which we received the placenta. We studied clinical data and described pathological findings of placenta and post-mortem examination of fetuses. We performed an immunohistochemical study and RT-PCR of SARS-Cov-2 on placenta samples. RESULTS: We report 5 cases of poor fetal outcome, 3 fetal deaths and 2 extreme premature neonates, one with growth restriction, without clinical and biological sign of SARS-Cov-2 infection. All placenta presented massive perivillous fibrin deposition and large intervillous thrombi associated with strong SARS-Cov-2 expression in trophoblast and SARS-CoV-2 PCR positivity in amniotic fluid or on placenta samples. Chronic histiocytic intervillositis was present in 4/5 cases. Placental ultrasound was abnormal and the sFLT1-PIGF ratio was increased in one case. Timing between mothers’ infection and the poor fetal outcome was ≤10 days in 4 cases. The massive placental damage are directly induced by the virus whose receptors are expressed on trophoblast, leading to trophoblast necrosis and massive inflammation in villous chamber, in a similar way it occurs in diffuse alveolar damage in adults infected by SARS-Cov-2. DISCUSSION: SARS-Cov-2 can be associated to a rare set of placental lesions which can lead to fetal demise, preterm birth, or growth restriction. Stronger surveillance of mothers infected by SARS-Cov-2 is required. Introduction: Pregnant women with covid-19 are more likely to experience preterm birth. The 29 virus seems to be associated with a wide range of placental lesions, none of them specific. 30 Method: We collected cases of Covid-19 maternal infection during pregnancy associated with 31 poor pregnancy outcomes, for which we received the placenta. We studied clinical data and 32 described pathological findings of placenta and post-mortem examination of fetuses. We 33 performed an immunohistochemical study and RT-PCR of SARS-Cov-2 on placenta samples. 34 Results: We report 5 cases of poor fetal outcome, 3 fetal deaths and 2 extreme premature 35 neonates, one with growth restriction, without clinical and biological sign of SARS-Cov-2 36 infection. All placenta presented massive perivillous fibrin deposition and large intervillous 37 thrombi associated with strong SARS-Cov-2 expression in trophoblast and SARS-CoV-2 PCR 38 positivity in amniotic fluid or on placenta samples. Chronic histiocytic intervillositis was 39 present in 4/5 cases. Placental ultrasound was abnormal and the sFLT1-PIGF ratio was 40 increased in one case. Timing between mothers' infection and the poor fetal outcome was 41 ≤10 days in 4 cases. The massive placental damage are directly induced by the virus whose 42 receptors are expressed on trophoblast, leading to trophoblast necrosis and massive 43 inflammation in villous chamber, in a similar way it occurs in diffuse alveolar damage in adults 44 infected by SARS-Cov-2. Introduction 55 Since late 2019, SARS-Cov-2 has been circulating all over the world infecting more than 70 56 million people and causing more than 2 million deaths [1] . Since the beginning of the 57 pandemic, some authors tried to assess the transplacental transmission of the virus and its 58 effects on both pregnancy and fetus [2, 3] . It is now known that SARS-Cov-2 requires 2 59 receptors to infect a cell: the ACE2 and the TMPRSS2. Both are expressed in the 60 syncytiotrophoblast. According to some authors, the low co-expression profile of those two 61 receptors in the placenta probably explain the low risk of vertical transmission of SARS-CoV-62 2 from mother to fetus during pregnancy [4] . However the potential adverse effects of the 63 virus on maternal and perinatal outcomes are of concern [5]. Indeed, pregnant women with 64 covid-19 are at increased risk of admission to an intensive care unit and are more likely to 65 experience preterm birth. [6] . There are growing arguments for an increased risk of fetal death 66 (2) and hypertensive complications of pregnancy [7] . Intra-uterine growth restriction (IUGR) 67 seems to be three times more frequent than in COVID negative patients [ Table 1 . Clinical and biological data of mothers and pregnancies 125 Mean age of mothers was 36,4-year-old (26 to 43 years old). All were Caucasians and had no 126 peculiar past medical history, except one who had a gastric bypass surgery for obesity (case 127 5). Three were primiparous. Regarding obstetrical history, one had a background of genital 128 herpes (case 1) which was absent at the time of the delivery, and one had 3 previous 129 unexplained first trimester miscarriage (case 5). No mother presented with predisposing 130 factor of severe COVID-19, except case 5 who still had a high BMI despite gastric bypass 131 surgery. 132 Prenatal US findings: second trimester prenatal US suggested fetal growth restriction in case 133 5 and were normal in other cases. Furthermore, an abnormal heterogeneous aspect of the 134 placenta was noted in case 5 at 26GW placenta with coexistence of hypo and hyperechoic 135 areas, suggestive of infarction and calcification respectively. (Fig .1A, 1B) . This lead to test sFlt- 136 1/PIGF which was increased (116 pg/mL). None of the five mothers presented with 137 preeclampsia or HELLP syndrome. Coagulation tests were normal and Factor V Leiden mutation 138 has been investigated in one patient (case number 1) and was negative. Delay between maternal nasopharyngeal swab PCR positivity and adverse fetal outcome or 146 premature delivery was ≤ 10 days in 4 cases out of 5. 147 Fever was the only clinical sign which led to perform nasopharyngeal tests in mothers 1, 2, 3. 148 Mother 4 presented also with ageusia, and mother 5 with fever, myalgia and rhinopharyngitis. 149 Neonates' outcome 150 The 2 cases born prematurely by C-section were admitted and followed in a level III Neonatal Placental Pathology Findings during and after SARS-CoV-2 Infection: Features of Villitis and Malperfusion Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: A case series Vertical transmission of SARS-CoV-2 infection 421 and preterm birth Placental Pathology of COVID-19 with and without Fetal and 424 Neonatal Infection: Trophoblast Necrosis and Chronic Histiocytic Intervillositis as Risk 425 Factors for Transplacental Transmission of SARS-CoV-2 Placental Pathology Coxsackie Virus A16 Infection of Placenta with Massive Perivillous Fibrin Deposition Leading to Intrauterine Fetal Demise at 36 Weeks 449 Massive Perivillous Fibrin Deposition in Congenital Cytomegalovirus Infection: A Case 452 Massive Perivillous Fibrin Deposition Associated With Placental Syphilis: A Case Report -456 Extending the Spectrum of Massive Perivillous Fibrin Deposition 460 (Maternal Floor Infarction) Pre-eclampsia-like 464 syndrome induced by severe COVID-19: a prospective observational study Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia Sequential plasma angiogenic factors levels in 472 women with suspected preeclampsia Detection of SARS-CoV-2 in 491 placental but not fetal tissues in the second trimester SARS-CoV-2 494 placentitis: An uncommon complication of maternal COVID-19 Probable congenital SARS-CoV-2 infection 498 in a neonate born to a woman with active SARS-CoV-2 infection Preterm 501 delivery, maternal death, and vertical transmission in a pregnant woman with COVID-502 19 infection Excretion of SARS-CoV-2 in human 505 breast milk Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of 508 advanced COVID-19 pathology -EBioMedicine Cytokine storm in 512 COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment Coagulation abnormalities in 515 SARS-CoV-2 infection: overexpression tissue factor UK Obstetric Surveillance System SARS-CoV-2 Infection in 519 Characteristics and outcomes of pregnant women 520 admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population 521 based cohort study Autoantibodies against type I IFNs in 539 patients with life-threatening COVID-19 Mutations Strengthened SARS-CoV-2 Infectivity J o u r n a l P r e -p r o o f