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Figure.  Placental Histology
Placental Histology

A, Neutrophils and macrophages in the subchorial space indicating acute subchorionitis (hematoxylin-eosin ×20). B, Increased intervillous fibrin deposit and syncytial knots (hematoxylin-eosin ×10). C, Funisitis and umbilical cord vasculitis (hematoxylin-eosin ×20). D, Funisitis with neutrophil-specific staining (myeloperoxidase immunohistochemistry ×20).

Table.  SARS-CoV-2 RT-PCR Resultsa
SARS-CoV-2 RT-PCR Resultsa
1.
Chen  H, Guo  J, Wang  C,  et al.  Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.   Lancet. 2020;395(10226):809-815. doi:10.1016/S0140-6736(20)30360-3PubMedGoogle ScholarCrossref
2.
Zhu  H, Wang  L, Fang  C,  et al.  Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.   Transl Pediatr. 2020;9(1):51-60. doi:10.21037/tp.2020.02.06PubMedGoogle ScholarCrossref
3.
Liu  Y, Chen  H, Tang  K, Guo  Y.  Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy.   J Infect. 2020;S0163-4453(20)30109-2. doi:10.1016/j.jinf.2020.02.028PubMedGoogle Scholar
4.
Kimberlin  DW, Stagno  S.  Can SARS-CoV-2 infection be acquired in utero? more definitive evidence is needed.   JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4868PubMedGoogle Scholar
5.
Favre  G, Pomar  L, Musso  D, Baud  D.  2019-nCoV epidemic: what about pregnancies?   Lancet. 2020;395(10224):e40. doi:10.1016/S0140-6736(20)30311-1PubMedGoogle Scholar
6.
Wong  SF, Chow  KM, Leung  TN,  et al.  Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome.   Am J Obstet Gynecol. 2004;191(1):292-297. doi:10.1016/j.ajog.2003.11.019PubMedGoogle ScholarCrossref
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    1 Comment for this article
    EXPAND ALL
    Less Than Meets the Eye ?
    Yves Ville, MD | Obstetrics and Fetal Medicine and Bettina Bessière. Fetal pathology . Hôpital Necker Enfants Malades. University of Paris.
    This report is adequately provocative and finds its credibility in the care taken to perform the placental swab and biopsies. The viral RNA could only be amplified from the nasopharyngeal sample and the placenta.

    How would the virus reach the placenta before delivery while it could not be retrieved from the vagina, maternal blood, nor from any fetal sampling site ?

    One possibility is that the placenta could have been contaminated at delivery by maternal infected feces. Those were not tested, although symptomatic patients especially those with digestive symptoms as in this case excrete the virus
    in their stools.

    The authors did not mention if antibiotics had been administered prior to delivery. If so, this could have contributed to the negativity of the microbiological examination on the fetus and placenta.

    Placental histological changes are compatible with severe inflammatory changes and so is funisitis. This might illustrate the process for SARS-CoV-2 to cause perinatal morbidity. Large series of standardized placental histological examinations are needed.

    In addition, if the placenta can be damaged through a deregulated inflammatory process. Rupture of membranes might therefore have occurred primarily and be the cause for non-specific chorioamnionitis or alternatively chorioamnionitis could be the result of the inflammatory process caused by SARS-CoV-2 infection.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    April 30, 2020

    Second-Trimester Miscarriage in a Pregnant Woman With SARS-CoV-2 Infection

    Author Affiliations
    • 1Department Woman-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland
    • 2Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland
    • 3Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
    JAMA. Published online April 30, 2020. doi:10.1001/jama.2020.7233

    No data exist regarding the effect on fetuses of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first or second trimester of pregnancy, and data are limited regarding infections that occur during the third trimester. However, reports of newborns with fetal distress or requiring admission to the intensive care unit1,2 and a stillbirth after maternal coronavirus disease 2019 (COVID-19)3 in the third trimester suggest the possibility of COVID-19–induced placental pathology.

    We present a case of miscarriage during the second trimester in a pregnant woman with COVID-19.

    Methods

    A pregnant woman in her second trimester who had a miscarriage was evaluated at Lausanne University Hospital on March 20, 2020. Institutional review board approval and written informed consent were obtained. Information was obtained from medical records. Reverse transcriptase–polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 and cultures to detect bacterial pathogens and PCR for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, and Ureaplasma urealyticum were performed on samples from the mother, fetus, and placenta (Table). Placental histological examination and fetal autopsy were performed by 2 experienced perinatal pathologists (C.G. and E.D.). Hematoxylin-eosin, myeloperoxidase immunohistochemistry, Gram, and periodic acid–Schiff colorations were performed on the placenta.

    Results

    A 28-year-old obese, primigravida woman presented at 19 weeks’ gestation with fever (102.5 °F [39.2 °C]), myalgia, fatigue, mild pain with swallowing, diarrhea, and dry cough for 2 days. A nasopharyngeal swab was positive for SARS-CoV-2. She was given oral acetaminophen and discharged home.

    Two days later, she presented with severe uterine contractions, fever, and no improvement of her symptoms. Physical examination did not reveal any signs of pneumonia. Vaginal examination demonstrated bulging membranes through a 5-cm dilated cervix. Active fetal movements; fetal tachycardia (180/min); and normal fetal morphology, growth, and amniotic fluid were detected on ultrasound. Prophylactic amoxicillin–clavulanic acid and regional anesthesia were started. The patient wore a mask throughout her labor, as did 2 health care professionals who both tested negative for SARS-CoV-2. Amniotic fluid and vaginal swabs sampled during labor tested negative for SARS-CoV-2 and bacterial infection (Table).

    A stillborn infant was delivered vaginally after 10 hours of labor. Swabs from the axillae, mouth, meconium, and fetal blood obtained within minutes of birth tested negative for SARS-CoV-2 and bacterial infection. Fetal autopsy showed no malformations, and fetal lung, liver, and thymus biopsies were negative for SARS-CoV-2.

    Within minutes of placental expulsion, the fetal surface of the placenta was disinfected and incised with a sterile scalpel, and 2 swabs and biopsies (close to the umbilical cord and peripheral margin) were obtained. All were negative for bacterial infection but were positive for SARS-CoV-2. At 24 hours, the placenta remained positive for SARS-CoV-2. At 48 hours, maternal blood, urine, and vaginal swab were all negative for SARS-CoV-2, whereas a nasopharyngeal swab remained positive. Placental histology demonstrated mixed inflammatory infiltrates composed of neutrophils and monocytes in the subchorial space and unspecific increased intervillous fibrin deposition (Figure). Funisitis (inflammation of the umbilical cord connective tissue suggesting fetal inflammatory response) was also present. Gram and periodic acid–Schiff staining of the placenta, PCR, and culture did not identify any bacterial or fungal infections.

    Discussion

    This case of miscarriage during the second trimester of pregnancy in a woman with COVID-19 appears related to placental infection with SARS-CoV-2, supported by virological findings in the placenta. Contamination at the time of delivery, sampling, or laboratory evaluation is unlikely, as all other swabs were negative for SARS-CoV-2. No other cause of fetal demise was identified. There was no evidence of vertical transmission, but absence of the virus is not surprising given the stage of fetal development and short time of maternal infection. Whether SARS-CoV-2 crosses the placental barrier warrants further investigation.4

    Limitations include the single case and that other causes of miscarriage, such as spontaneous preterm birth, cervical insufficiency, or undetected systemic or local bacterial infection, cannot be ruled out.

    Infection of the maternal side of the placenta inducing acute or chronic placental insufficiency resulting in subsequent miscarriage or fetal growth restriction was observed in 40% of maternal infections with Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus.5,6 Additional study of pregnant women with COVID-19 is warranted to determine if SARS-CoV-2 can cause similar adverse outcomes.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: David Baud, MD, PhD, Materno-fetal and Obstetrics Research Unit, Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland (david.baud@chuv.ch).

    Accepted for Publication: April 20, 2020.

    Published Online: April 30, 2020. doi:10.1001/jama.2020.7233

    Author Contributions: Dr Baud had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Baud, Favre, Jaton, Pomar.

    Acquisition, analysis, or interpretation of data: Baud, Greub, Favre, Gengler, Dubruc, Pomar.

    Drafting of the manuscript: Baud, Favre, Jaton, Pomar.

    Critical revision of the manuscript for important intellectual content: Baud, Greub, Favre, Gengler, Dubruc, Pomar.

    Administrative, technical, or material support: All authors.

    Supervision: Baud, Greub.

    Conflict of Interest Disclosures: Dr Greub reported having ongoing research agreements with Resistell and Becton-Dickinson and being medical advisor for Resistell; he also reported being developer of a card game on microbes and funding JeuPro, a start-up company that distributes the game Krobs. No other disclosures were reported.

    References
    1.
    Chen  H, Guo  J, Wang  C,  et al.  Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.   Lancet. 2020;395(10226):809-815. doi:10.1016/S0140-6736(20)30360-3PubMedGoogle ScholarCrossref
    2.
    Zhu  H, Wang  L, Fang  C,  et al.  Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.   Transl Pediatr. 2020;9(1):51-60. doi:10.21037/tp.2020.02.06PubMedGoogle ScholarCrossref
    3.
    Liu  Y, Chen  H, Tang  K, Guo  Y.  Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy.   J Infect. 2020;S0163-4453(20)30109-2. doi:10.1016/j.jinf.2020.02.028PubMedGoogle Scholar
    4.
    Kimberlin  DW, Stagno  S.  Can SARS-CoV-2 infection be acquired in utero? more definitive evidence is needed.   JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4868PubMedGoogle Scholar
    5.
    Favre  G, Pomar  L, Musso  D, Baud  D.  2019-nCoV epidemic: what about pregnancies?   Lancet. 2020;395(10224):e40. doi:10.1016/S0140-6736(20)30311-1PubMedGoogle Scholar
    6.
    Wong  SF, Chow  KM, Leung  TN,  et al.  Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome.   Am J Obstet Gynecol. 2004;191(1):292-297. doi:10.1016/j.ajog.2003.11.019PubMedGoogle ScholarCrossref
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