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Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections

  • Author Footnotes
    ∗ NA and GR contributed equally and should be considered as co-first authors
    Noemi Alcover
    Footnotes
    ∗ NA and GR contributed equally and should be considered as co-first authors
    Affiliations
    Division of Obstetrics and Gynecology, “Antoine Béclère” Hospital, Paris Saclay University Hospitals, APHP (Clamart – France)
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  • Author Footnotes
    ∗ NA and GR contributed equally and should be considered as co-first authors
    Giulia Regiroli
    Footnotes
    ∗ NA and GR contributed equally and should be considered as co-first authors
    Affiliations
    Division of Pediatrics and Neonatal Critical Care, “Antoine Béclère” Hospital, Paris Saclay University Hospitals, APHP (Clamart – France)
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  • Alexandra Benachi
    Affiliations
    Division of Obstetrics and Gynecology, “Antoine Béclère” Hospital, Paris Saclay University Hospitals, APHP (Clamart – France)
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  • Christelle Vauloup-fellous
    Affiliations
    Division of Virology, “Paul Brousse” Hospital, Paris Saclay University Hospitals, APHP (Villejuif, France)
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  • Author Footnotes
    # AJV and DDL contributed equally and should be considered as co-last authors
    Alexandre J. Vivanti
    Footnotes
    # AJV and DDL contributed equally and should be considered as co-last authors
    Affiliations
    Division of Obstetrics and Gynecology, “Antoine Béclère” Hospital, Paris Saclay University Hospitals, APHP (Clamart – France)
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  • Author Footnotes
    # AJV and DDL contributed equally and should be considered as co-last authors
    Daniele De luca
    Correspondence
    Corresponding author: Prof. Daniele De Luca, Division of Pediatrics and Neonatal Critical Care Hôpital Antoine Béclère, 157 rue de la porte de Trivaux, 92140 Clamart, +33145474444.
    Footnotes
    # AJV and DDL contributed equally and should be considered as co-last authors
    Affiliations
    Division of Pediatrics and Neonatal Critical Care, “Antoine Béclère” Hospital, Paris Saclay University Hospitals, APHP (Clamart – France)
    Search for articles by this author
  • Author Footnotes
    # AJV and DDL contributed equally and should be considered as co-last authors
    ∗ NA and GR contributed equally and should be considered as co-first authors
Published:January 24, 2023DOI:https://doi.org/10.1016/j.ajog.2023.01.019
Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections
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      ABSTRACT

      Objective

      To describe the characteristics of fetal demises following SARS-CoV-2 infections and clarify if they are associated with clinical severity, placental lesions or malformations or due to actual fetal infections.

      Data Sources

      PubMed and Web of Science databases (searched between December 1, 2019 and April 30, 2022).

      Study eligibility criteria

      Cohort, cross-sectional and case-control studies, as well as case series or case reports describing stillbirths or late miscarriages (i.e. pregnancy loss occurring between 14 and 22 weeks, before and after the onset of labor, respectively) from mothers infected by SARS-CoV-2 during pregnancy (demonstrated by at least one positive real-time reverse transcription polymerase chain reaction on nasopharyngeal swabs, and/or placental infection with SARS-CoV-2). No language restrictions were applied; cases with other causes possibly explaining the fetal demise were excluded.

      Study appraisal and synthesis methods

      PRISMA and MOOSE guidelines were followed. Quality of case series/reports was evaluated with the specific Mayo Clinic Evidence-Based Practice Center tool. Maternal and clinical fetal data were collected as well as placental and fetal virology and histology findings. Data were summarized with descriptive statistics using World Health Organization criteria to classify disease severity and fetal-neonatal infections.

      Results

      Data from 184 mothers and 190 fetuses were analyzed. No clear link with maternal clinical severity or fetal malformation was evident. Approximately 78% of fetal demises occurred during the second and third trimester, ≈6 and 13 days after diagnosis of SARS-CoV-2 infection or the beginning of symptoms, respectively. Most (88%) placentas were positive for SARS-CoV-2 or presented the histological features of placentitis (massive fibrin deposition and chronic intervillositis) previously observed in transplacentally transmitted infections (≈85-91%). Eleven (5.8%) and 114 (60%) fetuses had a confirmed or possible in utero transmitted SARS-CoV-2 infection, respectively.

      Conclusions

      The synthesis of available data shows that fetal demises generally occur a few days after the infection with histological placental inflammatory lesions associated with transplacental SARS-CoV-2 transmission and eventually causing placental insufficiency.

      KEYWORDS

      Article info

      Publication history

      Accepted: January 17, 2023
      Received in revised form: January 7, 2023
      Received: November 17, 2022

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      The authors report no conflict of interest

      The study has no funding

      PROSPERO n. CRD42022365327

      CONDENSATION

      Fetal demise occurs mostly in the third trimester, shortly after the SARS-CoV-2 infection and with histological anomalies associated with transplacental transmission and placental insufficiency.

      AJOG AT A GLANCE

      A. Why was this study conducted? Because it was unknown if fetal demises (miscarriage or stillbirth) were associated with clinical severity, placental lesions or malformations and if they might be due to actual SARS-CoV-2 fetal infections.

      B. What are the key findings? Fetal demises generally occurred 6-13 days after the infection and diagnosed at or right after the delivery (between 14- and 39-weeks’ gestation), without link with maternal clinical severity and comorbidities or with congenital fetal malformations. Most placentas were SARS-CoV-2-positive or presented the histological anomalies previously observed in transplacentally transmitted infections and eventually causing placental insufficiency; ≈65% of the fetuses had a confirmed or possible in utero transmitted infection.

      C. What does this study add to what is already known? We synthesize the characteristics of fetal demises from women infected by SARS-CoV-2 and help understand the role of this infection in fetal demise.

      Identification

      DOI: https://doi.org/10.1016/j.ajog.2023.01.019

      Copyright

      © 2023 Elsevier Inc. All rights reserved.

      ScienceDirect

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