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      Clinical‐pathological features in placentas of pregnancies with SARS‐CoV‐2 infection and adverse outcome: case series with and without congenital transmission


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          To correlate clinical outcomes to pathology in SARS‐CoV‐2 infected placentas in stillborn and live‐born infants presenting with fetal distress.


          Retrospective, observational.




          Five stillborn and nine live‐born infants from 13 pregnant women infected with SARS‐CoV‐2 seeking care at seven different maternity units in Sweden.


          Clinical outcomes and placental pathology were studied in 14 cases (one twin pregnancy) of maternal SARS‐CoV‐2 infection with impaired fetal outcome. Outcomes were correlated to placental pathology in order to investigate the impact of virus‐related pathology on the villous capillary endothelium, trophoblast and other cells.

          Main outcome measures

          Maternal and fetal clinical outcomes and placental pathology in stillborn and live‐born infants.


          Reduced fetal movements were reported (77%) and time from onset of maternal COVID‐19 symptoms to signs of fetal distress among live‐born infants was 6 (3–12) days and to diagnosis of stillbirth 11 (2–25) days. Two of the live‐born infants died during the postnatal period. Signs of fetal distress led to emergency caesarean section in all live‐born infants with umbilical cord blood gases and low Apgar scores confirming intrauterine hypoxia. Five stillborn and one live‐born neonate had confirmed congenital transmission. Massive perivillous fibrinoid deposition, intervillositis and trophoblast necrosis were associated with SARS‐CoV‐2 placental infection and congenital transmission.


          SARS‐CoV‐2 can cause rapid placental dysfunction with subsequent acute fetal hypoxia leading to intrauterine fetal compromise. Associated placental pathology included massive perivillous fibrinoid deposition, intervillositis and trophoblast degeneration.

          Tweetable abstract

          SARS‐CoV‐2 can cause rapid placental dysfunction and intrauterine fetal compromise.

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          Most cited references51

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          Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis

          Abstract Objective To determine the clinical manifestations, risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed coronavirus disease 2019 (covid-19). Design Living systematic review and meta-analysis. Data sources Medline, Embase, Cochrane database, WHO COVID-19 database, China National Knowledge Infrastructure (CNKI), and Wanfang databases from 1 December 2019 to 26 June 2020, along with preprint servers, social media, and reference lists. Study selection Cohort studies reporting the rates, clinical manifestations (symptoms, laboratory and radiological findings), risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed covid-19. Data extraction At least two researchers independently extracted the data and assessed study quality. Random effects meta-analysis was performed, with estimates pooled as odds ratios and proportions with 95% confidence intervals. All analyses will be updated regularly. Results 77 studies were included. Overall, 10% (95% confidence interval 7% to14%; 28 studies, 11 432 women) of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed covid-19. The most common clinical manifestations of covid-19 in pregnancy were fever (40%) and cough (39%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with covid-19 were less likely to report symptoms of fever (odds ratio 0.43, 95% confidence interval 0.22 to 0.85; I2=74%; 5 studies; 80 521 women) and myalgia (0.48, 0.45 to 0.51; I2=0%; 3 studies; 80 409 women) and were more likely to need admission to an intensive care unit (1.62, 1.33 to 1.96; I2=0%) and invasive ventilation (1.88, 1.36 to 2.60; I2=0%; 4 studies, 91 606 women). 73 pregnant women (0.1%, 26 studies, 11 580 women) with confirmed covid-19 died from any cause. Increased maternal age (1.78, 1.25 to 2.55; I2=9%; 4 studies; 1058 women), high body mass index (2.38, 1.67 to 3.39; I2=0%; 3 studies; 877 women), chronic hypertension (2.0, 1.14 to 3.48; I2=0%; 2 studies; 858 women), and pre-existing diabetes (2.51, 1.31 to 4.80; I2=12%; 2 studies; 858 women) were associated with severe covid-19 in pregnancy. Pre-existing maternal comorbidity was a risk factor for admission to an intensive care unit (4.21, 1.06 to 16.72; I2=0%; 2 studies; 320 women) and invasive ventilation (4.48, 1.40 to 14.37; I2=0%; 2 studies; 313 women). Spontaneous preterm birth rate was 6% (95% confidence interval 3% to 9%; I2=55%; 10 studies; 870 women) in women with covid-19. The odds of any preterm birth (3.01, 95% confidence interval 1.16 to 7.85; I2=1%; 2 studies; 339 women) was high in pregnant women with covid-19 compared with those without the disease. A quarter of all neonates born to mothers with covid-19 were admitted to the neonatal unit (25%) and were at increased risk of admission (odds ratio 3.13, 95% confidence interval 2.05 to 4.78, I2=not estimable; 1 study, 1121 neonates) than those born to mothers without covid-19. Conclusion Pregnant and recently pregnant women are less likely to manifest covid-19 related symptoms of fever and myalgia than non-pregnant women of reproductive age and are potentially more likely to need intensive care treatment for covid-19. Pre-existing comorbidities, high maternal age, and high body mass index seem to be risk factors for severe covid-19. Preterm birth rates are high in pregnant women with covid-19 than in pregnant women without the disease. Systematic review registration PROSPERO CRD42020178076. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
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            Transplacental transmission of SARS-CoV-2 infection

            SARS-CoV-2 outbreak is the first pandemic of the century. SARS-CoV-2 infection is transmitted through droplets; other transmission routes are hypothesized but not confirmed. So far, it is unclear whether and how SARS-CoV-2 can be transmitted from the mother to the fetus. We demonstrate the transplacental transmission of SARS-CoV-2 in a neonate born to a mother infected in the last trimester and presenting with neurological compromise. The transmission is confirmed by comprehensive virological and pathological investigations. In detail, SARS-CoV-2 causes: (1) maternal viremia, (2) placental infection demonstrated by immunohistochemistry and very high viral load; placental inflammation, as shown by histological examination and immunohistochemistry, and (3) neonatal viremia following placental infection. The neonate is studied clinically, through imaging, and followed up. The neonate presented with neurological manifestations, similar to those described in adult patients.
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              Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection : The INTERCOVID Multinational Cohort Study

              This cohort study assesses the association between COVID-19 and maternal and neonatal outcomes in pregnant women with COVID-19 diagnosis compared with concomitantly enrolled pregnant women without COVID-19 diagnosis. Question To what extent does COVID-19 in pregnancy alter the risks of adverse maternal and neonatal outcomes compared with pregnant individuals without COVID-19? Findings In this multinational cohort study of 2130 pregnant women in 18 countries, women with COVID-19 diagnosis were at increased risk of a composite maternal morbidity and mortality index. Newborns of women with COVID-19 diagnosis had significantly higher severe neonatal morbidity index and severe perinatal morbidity and mortality index compared with newborns of women without COVID-19 diagnosis. Meaning This study indicates a consistent association between pregnant individuals with COVID-19 diagnosis and higher rates of adverse outcomes, including maternal mortality, preeclampsia, and preterm birth compared with pregnant individuals without COVID-19 diagnosis. Importance Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. Exposures COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

                Author and article information

                John Wiley and Sons Inc. (Hoboken )
                22 April 2022
                22 April 2022
                [ 1 ] Obstetrics & Gynaecology, Institution of Clinical Sciences Lund Lund University Lund Sweden
                [ 2 ] Department of Obstetrics and Gynaecology Skåne University Hospital Lund Sweden
                [ 3 ] Clinical Genetics and Pathology, Laboratory Medicine Skåne University Hospital Lund Sweden
                [ 4 ] Division of Clinical Genetics, Department of Laboratory Medicine Lund University Lund Sweden
                [ 5 ] Department of Women's and Children's Health Karolinska Institute Stockholm Sweden
                [ 6 ] Department of Obstetrics and Gynaecology Karolinska University Hospital Stockholm Sweden
                [ 7 ] Department of Women's and Children's Health Uppsala University Uppsala Sweden
                [ 8 ] Perinatal and Cardiovascular Epidemiology Institution of Clinical Sciences Malmö, Lund University Lund Sweden
                [ 9 ] Department of Pathology Medical College of Georgia, Augusta University Augusta Georgia USA
                [ 10 ] Department of Obstetrics and Gynaecology, Helsingborg Hospital, Department of Clinical Science Helsingborg Lund University Lund Sweden
                [ 11 ] Department of Obstetrics and Gynaecology and Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
                [ 12 ] Department of Laboratory Medicine, Division of Pathology, Karolinska Institute and Department of Pathology Karolinska University Hospital Stockholm Sweden
                [ 13 ] Department of Obstetrics and Gynaecology Halland Hospital Varberg Sweden
                [ 14 ] Department of Obstetrics and Gynaecology Sahlgrenska Academy, University of Gothenburg Gothenburg Sweden
                [ 15 ] Region Västra Götaland, Sahlgrenska University Hospital Department of Obstetrics and Gynaecology Gothenburg Sweden
                Author notes
                [*] [* ] Correspondence

                Mehreen Zaigham, Department of Obstetrics & Gynaecology, Lund University and Skåne University Hospital, 205 01 Malmö, Sweden.

                Email: mehreen.zaigham@ 123456med.lu.se

                BJO17132 BJOG-21-1784.R1
                © 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 1, Tables: 2, Pages: 14, Words: 7247
                Funded by: South Hospital Region Project Grant
                Award ID: 2021‐2020‐0689
                Funded by: Swedish government and the county councils, the ALF‐agreement
                Award ID: YF0054
                Research Article
                Research Articles
                Custom metadata
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.6 mode:remove_FC converted:17.05.2022

                Obstetrics & Gynecology
                chronic histiocytic intervillositis,coronavirus,covid‐19,covid‐19 maternal‐fetal transmission,fetal distress,maternal floor infarction,placental endothelial cells,placental pathology,sars‐cov‐2,sars‐cov‐2 placental infection,vertical sars‐cov‐2 transmission,villous macrophages


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