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Original research
Adverse maternal, fetal, and newborn outcomes among pregnant women with SARS-CoV-2 infection: an individual participant data meta-analysis
  1. Emily R Smith1,
  2. Erin Oakley1,
  3. Gargi Wable Grandner1,
  4. Kacey Ferguson1,
  5. Fouzia Farooq1,
  6. Yalda Afshar2,
  7. Mia Ahlberg3,
  8. Homa Ahmadzia4,
  9. Victor Akelo5,
  10. Grace Aldrovandi6,
  11. Beth A Tippett Barr5,
  12. Elisa Bevilacqua7,
  13. Justin S Brandt8,
  14. Nathalie Broutet9,
  15. Irene Fernández Buhigas10,
  16. Jorge Carrillo11,
  17. Rebecca Clifton12,
  18. Jeanne Conry13,
  19. Erich Cosmi14,
  20. Fatima Crispi15,
  21. Francesca Crovetto15,
  22. Camille Delgado-López16,
  23. Hema Divakar17,
  24. Amanda J Driscoll18,
  25. Guillaume Favre19,
  26. Valerie J Flaherman20,
  27. Chris Gale21,
  28. Maria M Gil10,
  29. Sami L Gottlieb9,
  30. Eduard Gratacós15,
  31. Olivia Hernandez22,
  32. Stephanie Jones23,
  33. Erkan Kalafat24,
  34. Sammy Khagayi25,
  35. Marian Knight26,
  36. Karen Kotloff27,
  37. Antonio Lanzone7,
  38. Kirsty Le Doare28,29,
  39. Christoph Lees30,
  40. Ethan Litman4,
  41. Erica M Lokken31,
  42. Valentina Laurita Longo32,
  43. Shabir A Madhi23,
  44. Laura A Magee33,
  45. Raigam Jafet Martinez-Portilla34,
  46. Elizabeth M McClure35,
  47. Tori D Metz36,
  48. Emily S Miller37,
  49. Deborah Money38,
  50. Sakita Moungmaithong39,
  51. Edward Mullins30,
  52. Jean B Nachega40,
  53. Marta C Nunes23,
  54. Dickens Onyango41,
  55. Alice Panchaud42,
  56. Liona C Poon39,
  57. Daniel Raiten43,
  58. Lesley Regan13,
  59. Gordon Rukundo28,
  60. Daljit Sahota39,
  61. Allie Sakowicz37,
  62. Jose Sanin-Blair44,
  63. Jonas Söderling3,
  64. Olof Stephansson3,
  65. Marleen Temmerman45,
  66. Anna Thorson9,
  67. Jorge E Tolosa46,
  68. Julia Townson47,
  69. Miguel Valencia-Prado48,
  70. Silvia Visentin14,
  71. Peter von Dadelszen49,
  72. Kristina Adams Waldorf31,
  73. Clare Whitehead50,
  74. Murat Yassa51,
  75. Jim M Tielsch1
  76. Perinatal COVID PMA Study Collaborators
    1. 1 Department of Global Health, The George Washington University Milken Institute School of Public Health, Washington, DC, USA
    2. 2 Division of Maternal Fetal Medicine, University of California Los Angeles, Los Angeles, California, USA
    3. 3 Department of Medicine, Solna, Clinical Epidemiology Division, Karolinska Institute, Stockholm, Sweden
    4. 4 Division of Maternal-Fetal Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
    5. 5 Office of the Director, US Centers for Disease Control and Prevention, Kisumu, Kenya
    6. 6 Department of Pediatrics, University of California Los Angeles, Los Angeles, California, USA
    7. 7 Department of Women and Child Health, Women Health Area, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy
    8. 8 Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
    9. 9 Department of Sexual and Reproductive Health and Research, World Health Organization, Geneve, Switzerland
    10. 10 Department of Obstetrics and Gynecology, Hospital Universitario de Torrejón, Madrid, Spain
    11. 11 Departamento de Obstetricia y Ginecologia, Universidad del Desarrollo Facultad de Medicina Clinica Alemana, Santiago, Chile
    12. 12 The Biostatistics Center, The George Washington University Milken Institute School of Public Health, Rockville, Maryland, USA
    13. 13 International Federation of Gynecology and Obstetrics, London, UK
    14. 14 Department of Women's and Children's Health, University of Padua, Padova, Italy
    15. 15 Department of Maternal-Fetal Medicine, BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Sant Joan de Déu and Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
    16. 16 Surveillance for Emerging Threats to Mothers and Babies, Puerto Rico Department of Health, San Juan, Puerto Rico
    17. 17 Asian Research and Training Institute for Skill Transfer (ARTIST), Bengaluru, India
    18. 18 Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA
    19. 19 Materno-Fetal and Obstetrics Research Unit, Department ‘Femme-Mère-Enfant’, Lausanne University Hospital, Lausanne, Switzerland
    20. 20 Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
    21. 21 Neonatal Medicine, School of Public Health, Imperial College London Faculty of Medicine, London, UK
    22. 22 Gynecology and Obstetrics, Felix Bulnes Hospital and RedSalud Clinic, Santiago, Chile
    23. 23 South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa
    24. 24 Department of Obstetrics and Gynecology, Koç University School of Medicine, Istanbul, Turkey
    25. 25 Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
    26. 26 Nuffield Department of Population Health, University of Oxford, Oxford, UK
    27. 27 Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA
    28. 28 Uganda Virus Institute and the London School of Hygiene & Tropical Medicine, Entebbe, Uganda
    29. 29 Pediatric Infectious Diseases Research Group, St George's University of London, London, UK
    30. 30 Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
    31. 31 Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, Washington, USA
    32. 32 Institute of Obstetrics and Gynecology Clinic, Catholic University of Sacred Heart, Rome, Italy
    33. 33 Department of Women and Children’s Health, School of Life Course and Population Sciences, King's College London, London, UK
    34. 34 Clinical Research Division, National Institute of Perinatology, Mexico City, Mexico
    35. 35 RTI International, Research Triangle Park, North Carolina, USA
    36. 36 Departments of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake, Utah, USA
    37. 37 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    38. 38 Department of Obstetrics and Gynecology, The University of British Columbia, Vancouver, British Columbia, Canada
    39. 39 Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    40. 40 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
    41. 41 Kisumu County Department of Health, Kisumu, Kenya
    42. 42 Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
    43. 43 Pediatric Growth and Nutrition Branch, National Institute of Health, Bethesda, Maryland, USA
    44. 44 Universidad Pontificia Bolivariana, Medellin, Antioquia, Colombia
    45. 45 Centre of Excellence in Women and Child Health, Aga Khan University, Nairobi, Kenya
    46. 46 Department of Obstetrics and Gynecology, St Luke's University Health Network, Bethlehem, Pennsylvania, USA
    47. 47 Centre for Trials Research, Cardiff University, Cardiff, UK
    48. 48 Children with Special Medical Needs Division, Puerto Rico Department of Health, San Juan, Puerto Rico
    49. 49 Department of Women and Children's Health, King's College London Faculty of Life Sciences and Medicine, London, UK
    50. 50 Department of Maternal-Fetal Medicine, The Royal Women's Hospital, University of Melbourne, Parkville, Victoria, Australia
    51. 51 Department of Obstetrics and Gynecology, Sancaktepe Sehit Prof Dr Ilhan Varank Training and Research Hospital, Istanbul, Turkey
    1. Correspondence to Dr Emily R Smith; emilysmith{at}gwu.edu

    Abstract

    Introduction Despite a growing body of research on the risks of SARS-CoV-2 infection during pregnancy, there is continued controversy given heterogeneity in the quality and design of published studies.

    Methods We screened ongoing studies in our sequential, prospective meta-analysis. We pooled individual participant data to estimate the absolute and relative risk (RR) of adverse outcomes among pregnant women with SARS-CoV-2 infection, compared with confirmed negative pregnancies. We evaluated the risk of bias using a modified Newcastle-Ottawa Scale.

    Results We screened 137 studies and included 12 studies in 12 countries involving 13 136 pregnant women.

    Pregnant women with SARS-CoV-2 infection—as compared with uninfected pregnant women—were at significantly increased risk of maternal mortality (10 studies; n=1490; RR 7.68, 95% CI 1.70 to 34.61); admission to intensive care unit (8 studies; n=6660; RR 3.81, 95% CI 2.03 to 7.17); receiving mechanical ventilation (7 studies; n=4887; RR 15.23, 95% CI 4.32 to 53.71); receiving any critical care (7 studies; n=4735; RR 5.48, 95% CI 2.57 to 11.72); and being diagnosed with pneumonia (6 studies; n=4573; RR 23.46, 95% CI 3.03 to 181.39) and thromboembolic disease (8 studies; n=5146; RR 5.50, 95% CI 1.12 to 27.12).

    Neonates born to women with SARS-CoV-2 infection were more likely to be admitted to a neonatal care unit after birth (7 studies; n=7637; RR 1.86, 95% CI 1.12 to 3.08); be born preterm (7 studies; n=6233; RR 1.71, 95% CI 1.28 to 2.29) or moderately preterm (7 studies; n=6071; RR 2.92, 95% CI 1.88 to 4.54); and to be born low birth weight (12 studies; n=11 930; RR 1.19, 95% CI 1.02 to 1.40). Infection was not linked to stillbirth. Studies were generally at low or moderate risk of bias.

    Conclusions This analysis indicates that SARS-CoV-2 infection at any time during pregnancy increases the risk of maternal death, severe maternal morbidities and neonatal morbidity, but not stillbirth or intrauterine growth restriction. As more data become available, we will update these findings per the published protocol.

    • COVID-19
    • Maternal health
    • Epidemiology

    Data availability statement

    No data are available. Individual patient data should be requested from the original or parent study investigators.

    https://creativecommons.org/licenses/by/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

    https://doi.org/10.1136/bmjgh-2022-009495

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      Data availability statement

      No data are available. Individual patient data should be requested from the original or parent study investigators.

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      Footnotes

      • Handling editor Seye Abimbola

      • Twitter @DrEmilyRSmith, @IreneFB80, @ConryJeanne, @ShabirMadh

      • Collaborators Perinatal COVID PMA Study Collaborators: AFRHealth Study (Nachega et al., 2021): Eduard Langenegger, MBChB, PhD, Department of Obstetrics and Gynecology, Tygerberg Teaching Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Nadia A. Sam-Agudu, MD, International Research Center of Excellence, Institute of Human Virology Nigeria, Abuja, Nigeria; Onesmus W. Gachuno, MBChB, Department of Obstetrics and Gynaecology, University of Nairobi, Nairobi, Kenya; Musa Sekikubo, MBChB, Department of Obstetrics and Gynaecology, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; Denis M. Mukwege, MD, PhD, Gynaecology and General Surgery, Panzi General Referral Hospital, Bukavu, and Université Evangelique en Afrique (UEA), Bukavu, Democratic Republic of the Congo.

        Adverse Pregnancy Outcomes Associated with COVID-19 Infection (ANCOV) Kenya Study (Akelo, Tippett Barr, et al., 2021): Richard Omore, ANCOV Kenya; Gregory Ouma, Kenya Medical Research Institute, Centre for Global Health Research; Clayton Onyango, Kenya Medical Research Institute, Centre for Global Health Research; Kephas Otieno, Kenya Medical Research Institute, Centre for Global Health Research; Zacchaeus Abaja Were, Kenya Medical Research Institute, Centre for Global Health Research; Joyce Were, Kenya Medical Research Institute, Centre for Global Health Research. Koc University Hospital (Kalafat 2020): Pinar Birol İlter, Kartal Dr. Lutfi Kirdar Hospital, Istanbul, Turkey. PREPARE Uganda (periCOVID) Study (Le Doare, et al., 2021): Robert Mboizi, PREPARE Uganda; Lauren Hookham, PREPARE Uganda. Rome Hospital Study (Bevilacqua, Laurita Longo, et al., 2020): Federica Meli, Department of Women's and Child Health Sciences and Public Health, IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy; Giulia Bonanni, Department of Women's and Child Health Sciences and Public Health, IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy; Federica Romanzi, Department of Women's and Child Health Sciences and Public Health, IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy; Eleonora Torcia, Department of Women's and Child Health Sciences and Public Health, IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy; Chiara di Ilio, Department of Women's and Child Health Sciences and Public Health, IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy. Rutgers Robert Wood Johnson Medical School (Brandt, et al., 2020): Cande V. Ananth, PhD, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Jennifer Hill, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Ajay Reddy, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Haylea Sweat Patrick, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. University of the Witwatersrand Study (Nunes et al., 2021): Vuyelwa Baba, University of the Witwatersrand, Johannesburg, South Africa; Mary Adam, University of the Witwatersrand, Johannesburg, South Africa; Philiswa Mlandu, University of the Witwatersrand, Johannesburg, South Africa; Yasmin Adam, University of the Witwatersrand, Johannesburg, South Africa; Renate Strehlau, University of the Witwatersrand, Johannesburg, South Africa.

      • Contributors Conceptualisation: ERS, EO, JT. Data curation: ERS, EO. Formal analysis: ERS, EO, GWG, KF, FF, GR, JS. Funding acquisition: ERS. Investigation: ERS, YA, MA, HA, VA, GA, BATB, OH, EB, JSB, NB, IFB, JCa, RC, JCo, EC, FCri, FCro, CD-L, HD, AJD, GF, VJF, CG, MMG, SLG, EG, SJ, EK, SK, MK, KK, AL, KLD, CL, EL, EML, VLL, LAM, RJM-P, EMM, TDM, ESM, DM, SM, EM, JBN, MCN, DO, AP, LCP, DR, GR, DS, AS, JS-B, JS, OS, MT, AT, JET, JT, MV-P, SV, PvD, KAW, CW, MY. Methodology: ERS, EO, FF, JT. Project administration: KF, EO, GWG. Supervision: ERS, JT. Visualisation: ERS, FF, EO. Writing—original draft preparation: ERS, GWG, EO, KF, JT. Writing—review and editing: all authors. ERS is responsible for the overall content.

      • Funding Funded by the Bill & Melinda Gates Foundation grant to ERS (INV-022057).

      • Competing interests CW declares a relationship with Ferring Pharmaceuticals COVID-19 Investigational Grant and NHMRC Fellowship (salary support). AP declares the following research grants to her institution: ‘H2020-Grant—Consortium member of Innovative medicine initiative call 13 topic 9 «ConcePTION», Efficacy and safety studies on Medicines EMA/2017/09/PE/11, Lot 4, WP 2 lead, Safety monitoring of COVID-19 vaccines in the EU—Reopening of competition no. 20 under a framework contract following procurement procedure EMA/2017/09/PE (Lot 3) (Euro 110,000), Federal Office of Public Health (207,000 CHF)’. EM declares a relationship with the National Institute for Health Research (project grant for PAN COVID study). DM declares a relationship with the Canadian Institutes of Health Research (payments to institution only), Public Health Agency of Canada (payments to institution only), BC Women’s Foundation (payments to institution only) and is a member of the COVID-19 Immunity Task Force sponsored by the Canadian government. TDM declares a relationship with Pfizer (site principal investigator for SARS-CoV-2 vaccination in pregnancy study, money paid to institution and member of Medical Advisory Board for SARS-CoV-2 vaccination in pregnancy study, money paid to TDM), NICHD (subcommittee chair for the NICHD Maternal-Fetal Medicine Units Network Gestational Research Assessments of COVID-19 (GRAVID) study) and Society for Maternal-Fetal Medicine (board member). EL declares a relationship with the US NIH (paid institution) and is an employee of AbbVie, but was employed at the University of Washington at the time of the study. KK declares a relationship with the Bill & Melinda Gates Foundation. VJF declares a relationship with the Bill & Melinda Gates Foundation (payments to institution), Yellow Chair Foundation (payments to institution), Robert Woods Johnson Foundation (payments to institution), CDC Foundation, California Health Care Foundation (payments to institution), Tara Health Foundation (payments to institution), UCSF Women’s Health Center of Excellence (payments to institution) and California Department of Health Care Services (payments made to institution). JS-B declares a relationship with the Ferring Pharmaceuticals, which gave a grant ($10 000) for the expenses of RECOGEST trial and is a part of the Columbian Federation of Perinatology. YA declares a relationship with the Bill & Melinda Gates Foundation (payments made to institution), CDC Foundation (payments made to institution), Robert Woods Johnson Foundation (payments made to institution) and UCLA Dean’s Office COVID-19 research (payments made to institution). RC declares a relationship with the NIH HD36801 (MFMU Network DCC). MCN declares a relationship with the BMGF (project grant made to institution), EDCTP, Sanofi, AstraZeneca, Pfizer (research grants made to institution), Sanofi Pasteur (payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events) and Sanofi Pasteur and Pfizer (payment for expert testimony). ESM declares a relationship with Pfizer (site principal investigator for phase 2/3 RCT of COVID vaccine during pregnancy). OS declares a relationship with the NordForsk Funding (Nordic research funding grant number: 105545), the Swedish Medical Products Agency (funding for reports on COVID-19 vaccines and pregnancy) and Karolinska Institutet (funding for COVID research and pregnancy: 2020-01567). EG declares a relationship with the Stavros Niarchos Foundation, Santander Foundation and ‘La Caixa’ Foundation (payments made to institution). SAM declares a relationship with BMGF (funded study in South Africa).

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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