SARS-CoV-2 infection in pregnant women and incidence of thromboembolic disease: an analysis of the Covid-19-Related Obstetric and Neonatal Outcome Study (CRONOS) in Germany

Archives of Gynecology and Obstetrics https://doi.org/10.1007/s00404-025-08007-5 RESEARCH SARS‑CoV‑2 infection in pregnant women and incidence of thromboembolic disease: an analysis of the Covid‑19‑Related Obstetric and Neonatal Outcome Study (CRONOS) in Germany Ulrich Pecks1 · Michael K. Bohlmann2 · Kristin Andresen3 · Johanna Büchel4 · Catharina Bartmann4 · Magdalena Sitter5 · Anastasia Tihon4 · Peter Kranke5 · Achim Wöckel4 · Regina Hollweck6 · Iris Dressler‑Steinbach7 · Susanne Gruessner8 · Teresa M. Gruber7 · Teresa Eichinger9 · Jula Manz10 · Ina M. Ruehl11 · Angela Lihs12 · Anna‑Lena Biermann13 · Lea M. Bauerfeind14 · Kathleen M. Oberste15 · Babett Ramsauer16 · Eveline Russe17 · Susanne Schrey‑Petersen18 · Filiz Markfeld Erol19 · Cahit Birdir20 · Lisa Kaup21 · Gregor Seliger22 · Christine Morfeld23 · Martin A. Berghaeuser24 · Manuela F. Richter25 · Peter Jakubowski26 · Birgit Linnemann27 · Werner Rath3 Received: 27 January 2025 / Accepted: 10 March 2025 © The Author(s) 2025 Abstract Purpose The aim of the present study was to quantify the rate of thromboembolic events (TE) in pregnant women with SARS-CoV-2 infection and to characterize risk factors to provide a basis for individualized recommendation on prophylactic measures. Methods CRONOS is a multicenter, prospective observational study conducted in Germany and Austria during the COVID19 pandemic. Pregnant women with confirmed SARS-CoV-2 infection were enrolled. Data on demographics, medical history, COVID-19-related aspects, and pregnancy and birth outcomes were collected. TE was particularly queried and used as the primary outcome. A combination of “TE,” “maternal or fetal death,” or “severe postpartum hemorrhage” was defined as a secondary endpoint. Risk analyses were performed using univariate and multivariable logistic regression models. Results Data from 8033 pregnant patients showed 40 TEs (0.5% incidence). TE rates were 10% in ICU patients, 0.2–0.4% in those with moderate-to-mild COVID-19, and < 0.1% in asymptomatic women. Pulmonary embolism occurred in 21 cases, deep vein thrombosis in 12, and 7 had atypical or arterial TE. Risk factors included advanced gestational age, COVID-19 symptoms, hospitalization or ICU admission, premature birth, cesarean section, delivery within 4 weeks of infection, higher weight gain, anemia, and chronic inflammatory bowel disease. COVID-19 vaccination reduced risk. The logistic risk model yielded an AUC of 0.87 (95% CI 0.81–0.94). Conclusion The TE rate in pregnant women is largely determined by the severity of the disease. In asymptomatic or mild cases, other factors outweigh TE risk, while severe COVID-19 requiring ICU admission poses a high TE risk despite prophylaxis. Keywords Stillbirth · Blood transfusion · Maternal death · Invasive ventilation · Heparin Extended author information available on the last page of the article Vol.:(0123456789) Archives of Gynecology and Obstetrics What does this study add to the clinical work This study highlights that the risk of thromboembolic events (TE) in pregnant women with SARSCoV-2 infecton is strongly linked to disease severity, with ICU admission posing the highest risk despite prophylaxis. It underscores the need for individualized risk stratification in clinical practice, considering factors like vaccination status, gestational age, and pre-existing conditions to guide anticoagulation therapy. than 8000 women with SARS-CoV-2 infection during pregnancy from 130 hospitals, aimed to collect data on maternal and perinatal morbidity and mortality [15, 16]. TE—among others—was considered an important research question not only for a better understanding of the disease, but also for evidence-based practices to protect maternal health and mitigate the negative consequences of TE associated with COVID-19 and pregnancy in future. The aim of this project was to determine the rate of TE in women affected by SARS-CoV-2 infection during their pregnancy and to correlate these data with disease severity, virus variants, immunization status and other risk factors. Materials and methods Introduction The coronavirus disease COVID-19, which is caused by the “severe acute respiratory syndrome coronavirus 2” (SARSCoV-2), primarily affects the respiratory system, leading to acute respiratory distress syndrome but is also considered a multi-organ disease. In this context, thromboembolic events (TE) have been considered a challenging problem [1, 2], particularly in pregnancy and puerperium [3, 4]. Pregnancy per se fulfills the criteria of Virchow’s triad, which is characterized by physiological hypercoagulability due to increased production of coagulation factors and a decrease in fibrinolytic activity, venous stasis and birth trauma. The absolute incidence of TE in pregnant women is estimated at 0.1% [5], and the daily risk is 5–10 times higher than in non-pregnant women [6, 7]. Systemic infections were considered additional transient risk factors for TE [8]. Particularly, patients with severe COVID-19 are at risk for thromboembolic complications through at least two different mechanisms: immunothrombogenic processes and severe illness with the need of hospitalization and treatment [9]. Immunothrombosis is a complex reciprocal process linking inflammation and coagulation [10, 11]. The main components of immunothrombosis are endothelial activation/dysfunction as a direct endothelial response to the virus, inflammation with activation of monocytes/macrophages, a massive increase in the production of proinflammatory cytokines (“cytokine storm”), activation of the coagulation cascade and finally hypoxia, which subsequently lead to micro- and macrovascular thrombosis [12–14]. Hospitalization-associated bedrest/immobilization additionally contributes to thromboembolic risk. In pregnancy, the risk of hospitalization and ICU admission for COVID-19 increases with ongoing gestational age [8, 9, 12–15]. As there was hardly any specific data available at the beginning of the pandemic, the “COVID-19-Related Obstetric and Neonatal Outcome Study” (CRONOS), a nationwide, multicenter, prospective observational study involving more CRONOS is a multicentric prospective observational study established by the German Society of Perinatal Medicine in April 2020 with the aim of offering a timely and factbased extension of the counseling of pregnant women. Women with confirmed SARS-CoV-2 infection at any time during pregnancy who were treated in one of the participating maternity clinics regardless of the indication were included. Ethics approval was obtained (University Hospital Schleswig–Holstein, Kiel, AZ: D 451/20) and supplemented by votes from the local ethics committees. Information on CRONOS is published on the website www.d gpm- online.org and in the German Register of Clinical Studies (DRKS00021208). Methods and parts of the study results have been published [15–20]. Data management For collecting data, a reporting form was developed using the cloud (...truncated)