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The link between COVID-19 and preeclampsia

  • Aris T. Papageorghiou
    Affiliations
    Fetal Medicine Unit, Department of Obstetrics and Gynaecology, Nuffield Department of Women’s & Reproductive Health, University of Oxford, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
    Oxford Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, United Kingdom
    St George's University Hospitals National Health Services Foundation Trust, London, United Kingdom
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  • Robert B. Gunier
    Affiliations
    Centre for Environmental Research and Community health, School of Public Health, University of California, Berkeley, CA
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  • José Villar
    Affiliations
    Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, United Kingdom
    Oxford Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, United Kingdom
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Published:September 05, 2021DOI:https://doi.org/10.1016/j.ajog.2021.08.047
      We thank the authors for their interest in our work.
      • Papageorghiou A.T.
      • Deruelle P.
      • Gunier R.B.
      • et al.
      Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.
      ,
      • Villar J.
      • Ariff S.
      • Gunier R.B.
      • et al.
      Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID Multinational Cohort Study.
      Boujenaha

      Boujenaha J. Preeclampsia, a risk factor to get infected with COVID or a selection bias? Am J Obstet Gynecol. https://doi.org/10.1016/j.ajog.2021.08.042. Accessed September 13, 2021.

      suggests that the association between COVID-19 and preeclampsia
      • Papageorghiou A.T.
      • Deruelle P.
      • Gunier R.B.
      • et al.
      Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.
      may be because of selection bias, as the nondiagnosed group included women without a negative test (Desseauve et al

      Desseauve D, Pomar L, Baud D. INTERCOVID prospective longitudinal study: preeclampsia and COVID-19. Am J Obstet Gynecol. https://doi.org/10.1016/j.ajog.2021.08.043. Available September 13, 2021.

      make the same point); we acknowledge that this group may have included a small number of unidentified, asymptomatic, and infected women. However, this is not a strong source of bias, because including infected women in the reference group would dilute, rather than strengthen, the observed association. Secondly, although it is possible that preeclamptic women admitted to the hospital were more likely to be diagnosed with COVID-19, the study design
      • Villar J.
      • Ariff S.
      • Gunier R.B.
      • et al.
      Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID Multinational Cohort Study.
      avoided such systematic bias by selecting 2 women immediately after a diagnosed woman at the same level of care, as the reference group. Thirdly, the study ended in February 2021 when vaccine use in pregnancy was still uncommon; the case numbers here would be largely unaffected. Finally, adjustment by study site as a covariate and using mixed-effects models with random slopes by site were conducted in the study, and the results were very similar (Table 2 in the original report).
      We have now undertaken further analyses that are restricted to undiagnosed women who had a negative polymerase chain reaction or antibody test result, reducing the total sample size to 1359 women. The association between COVID-19 diagnosis and preeclampsia (compared with Table 2 in the original report) had a similar but slightly reduced risk ratio (RR) of 1.71 (95% confidence interval [CI], 1.14–2.56) in the unadjusted and 1.52 (95% CI, 1.01–2.31) in the full model (adjusted for maternal age, previous parity, tobacco use during pregnancy, overweight status, and the history of diabetes, cardiac disease, hypertension, kidney disease, or adverse pregnancy outcomes). The associations with hypertensive disease in pregnancy and gestational hypertension (GH) (previously reported in Table 4) were similar, with a slightly increased RR for GH. The RRs for hypertensive disease in pregnancy and GH were 1.61 (95% CI, 1.21–2.13) and 1.80 (1.21–2.68), respectively, in the unadjusted model; and 1.47 (95% CI, 1.10–1.95) and 1.66 (95% CI, 1.11–2.47), respectively, in the adjusted model.
      We initiated a pragmatic, observational study within routine clinical care just a few days after the World Health Organization declared COVID-19 a global pandemic and long before universal testing became available. By carefully selecting women diagnosed with COVID-19 and a reference group, we obtained vitally important data, quickly. Strict quality control measures were implemented to ensure that the enrolment of women who were not diagnosed was unbiased; the data have been explored for possible selection bias using several strategies. The results remain largely unchanged, suggesting that the association between COVID-19 and preeclampsia is not because of confounding by common risk factors.

      References

        • Papageorghiou A.T.
        • Deruelle P.
        • Gunier R.B.
        • et al.
        Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.
        Am J Obstet Gynecol. 2021; 225: 289.e1-289.e17
        • Villar J.
        • Ariff S.
        • Gunier R.B.
        • et al.
        Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID Multinational Cohort Study.
        JAMA Pediatr. 2021; 175: 817-826
      1. Boujenaha J. Preeclampsia, a risk factor to get infected with COVID or a selection bias? Am J Obstet Gynecol. https://doi.org/10.1016/j.ajog.2021.08.042. Accessed September 13, 2021.

      2. Desseauve D, Pomar L, Baud D. INTERCOVID prospective longitudinal study: preeclampsia and COVID-19. Am J Obstet Gynecol. https://doi.org/10.1016/j.ajog.2021.08.043. Available September 13, 2021.

        • World Health Organization
        Timeline: WHO’s COVID-19 response.
        (Available at:) (Accessed March 11, 2020)

      Linked Article

      • Preeclampsiada risk factor to get infected with COVID-19 or a selection bias?
        American Journal of Obstetrics & GynecologyVol. 226Issue 1
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          In the recent report of the INTERCOVID study—a prospective international study—the authors observed an association between COVID-19 and preeclampsia.1 The hypothesis formulated for the observed association was that preeclampsia is a vascular condition that precedes infection by SARS-CoV-2, and it increases the risk of COVID-19. This underlying pathway is unclear and could reflect selection bias. Considering this issue, the selection of women might overestimate the association. Firstly, the controls should be identified as cases if they have developed the disease, and the probability of developing the disease should be consistent in both the groups.
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      • INTERCOVID prospective longitudinal study: preeclampsia and COVID-19
        American Journal of Obstetrics & GynecologyVol. 226Issue 1
        • Preview
          Based on the hypothesis of a pathologic relationship of SARS-CoV-2 and multifaceted endothelial damage,1 Papageorghiou et al2 reported a strong association between COVID-19 and preeclampsia from the INTERCOVID study. Although we appreciate the meticulous work that the authors did, to present adequate statistics to identify this association, we are concerned that there is a risk of misclassification in the control group that could lead to an overestimation of the effect.
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