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Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study

  • Papageorghiou, Aris T.1, 2, 3
  • Deruelle, Philippe4
  • Gunier, Robert B.5
  • Rauch, Stephen5
  • García-May, Perla K.6
  • Mhatre, Mohak7
  • Usman, Mustapha Ado8
  • Abd-Elsalam, Sherief9
  • Etuk, Saturday10
  • Simmons, Lavone E.11
  • Napolitano, Raffaele12, 13
  • Deantoni, Sonia1, 2, 14
  • Liu, Becky3
  • Prefumo, Federico15, 16
  • Savasi, Valeria17
  • do Vale, Marynéa Silva18
  • Baafi, Eric19
  • Zainab, Ghulam20
  • Nieto, Ricardo21
  • Maiz, Nerea22
  • And 37 more
  • 1 Nuffield Department of Women’s & Reproductive Health, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford, United Kingdom
  • 2 Oxford Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, United Kingdom
  • 3 Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
  • 4 Department of Obstetrics and Gynecology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  • 5 Center for Environmental Research and Community Health (CERCH), School of Public Health, University of California, Berkeley, CA
  • 6 Hospital Regional Lic. Adolfo López Mateos ISSSTE, Mexico City, Mexico
  • 7 Tufts Medical Center, Boston, MA
  • 8 Department of Obstetrics and Gynaecology, Muhammad Abdullahi Wase Teaching Hospital, Kano State, Nigeria
  • 9 Tropical Medicine and Infectious Diseases Department, Tanta University, Tanta, Egypt
  • 10 University of Calabar Teaching Hospital, Calabar, Nigeria
  • 11 Department of Obstetrics and Gynecology, University of Washington, Seattle, WA
  • 12 Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, United Kingdom
  • 13 Fetal Medicine Unit, University College London Hospitals NHS Foundation Trust, London, United Kingdom
  • 14 Neonatal Care Unit, Department of Public Health and Pediatrics, School of Medicine, University of Turin, Italy
  • 15 Division of Obstetrics and Gynecology, zienda Socio Sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy
  • 16 Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
  • 17 Department of BioMedical and Clinical Sciences, Ospedale Luigi Sacco University Hospital, University of Milan, Milan, Italy
  • 18 Universidade Federal do Maranhão, São Luís, Brazil
  • 19 Holy Family Hospital, Nkawkaw, Ghana
  • 20 Department of Obstetrics and Gynaecology, the Aga Khan University, Karachi, Pakistan
  • 21 Division Neonatología, Hospital Materno Infantil Ramón Sarda, Buenos Aires Argentina
  • 22 Obstetrics Department, Hospital Universitari Vall d’Hebron, Barcelona Hospital Campus, Barcelona, Spain
  • 23 Department of Obstetrics and Gynaecology, Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria
  • 24 Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico
  • 25 Department of Pediatrics, General Hospital Borka Taleski, Prilep, Republic of North Macedonia
  • 26 Department of Obstetrics and Gynaecology, Faculty of Clinical Sciences, College of Medical Sciences, Gombe State University, Gombe, Nigeria
  • 27 Obstetrics Department, Aragon Institute of Health Research, Hospital Clínico Universitario Lozano Blesa Zaragoza, Zaragoza, Spain
  • 28 Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
  • 29 Département de la Femme, de l’Enfant et de l’Adolescent, Hôpitaux Universitaires de Genève, Geneva, Switzerland
  • 30 Bayero University Kano, Nigeria
  • 31 Aminu Kano Teaching Hospital, Kano State, Nigeria
  • 32 Hospital de Moron, Moron, Provincia de Buenos Aires, Argentina
  • 33 Neonatal Special Care Unit, Regina Margherita Children Hospital, Città della Salute e della Scienza di Torino, Turin, Italy
  • 34 Department of Obstetrics and Gynecology Bordeaux University Hospital, Bordeaux, France
  • 35 Servicio de Neonatologia del Departamento Materno Infantil del Hospital Universitario Austral, Pilar, Provincia de Buenos Aires, Argentina
  • 36 Department of Obstetrics and Gynecology, the Jikei University School of Medicine, Tokyo, Japan
  • 37 Sanatorio Otamendi, Ciudad de Buenos Aires, Argentina
  • 38 Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
  • 39 Translational Health Science and Technology Institute, Faridabad, India
  • 40 Department of Woman, Child and Neonate, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
  • 41 Department of BioMedical and Clinical Sciences, Ospedale Vittore Buzzi Children’s Hospital, University of Milan, Milan, Italy
  • 42 Fr. Thomas Alan Rooney Memorial Hospital, Asankragwa, Ghana
  • 43 Department of Obstetrics and Gynecology, Medical Faculty, Universitas Airlangga, Surabaya, Indonesia
  • 44 Soetomo General Academic Hospital, Surabaya, Indonesia
  • 45 Universidad de Buenos Aires, Buenos Aires, Argentina
  • 46 Universidad de Moron, Moron, Argentina
  • 47 National Medical Research Center for Obstetrics, Gynecology & Perinatology, Moscow, Russia
  • 48 Department of Obstetrics and Gynecology, University of Illinois Hospital and Health Science System, Chicago, IL
  • 49 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Harvard Medical School, Boston, MA
  • 50 Division of Critical Care Medicine, Department of Anesthesia, Perioperative, and Pain Medicine, Harvard Medical School, Boston, MA
  • 51 Hôpital Universitaire Necker-Enfants Malades, AP-HP, Université de Paris, France
  • 52 Mainland Hospital Yaba, Lagos, Nigeria
  • 53 Maternal and Child Department, Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina
  • 54 Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  • 55 Department of Obstetrics and Gynaecology, IRCCS San Raffaele Hospital and University, Milan, Italy
  • 56 Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • 57 Center for Global Child Health, Hospital for Sick Children, Toronto, Canada
  • 58 Center of Excellence in Women & Child Health, The Aga Khan University, Karachi, Pakistana
Published Article
American Journal of Obstetrics and Gynecology
Published by Elsevier Inc.
Publication Date
Jun 26, 2021
DOI: 10.1016/j.ajog.2021.05.014
PMID: 34187688
PMCID: PMC8233533
PubMed Central
  • Original Research
  • Obstetrics


Background It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. Objective This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. Study Design This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. Results We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32–2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25–2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17–3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99–2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99–5.49) and 6.26 (95% confidence interval, 4.35–9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63–2.86; risk ratio, 2.53; 95% confidence interval, 1.44–4.45; and risk ratio, 2.84; 95% confidence interval, 1.67–4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32–2.35), 2.07 (95% confidence interval, 1.20–3.57), and 2.77 (95% confidence interval, 1.66–4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. Conclusion COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

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