Risk of Adverse Maternal and Fetal Outcomes Associated with COVID-19 Variants of Concern: A Sequential Prospective Meta-Analysis

Introduction The main objective of this study is to conduct an individual patient data meta-analysis with collaborators from various countries to identify SARS-CoV-2 variants of concern associated with adverse maternal and neonatal outcomes. Methods Eligible studies included registries and single- or multi-site cohort studies that recruited pregnant and recently postpartum women with confirmed COVID-19. Studies must have enrolled at least 25 women within a defined catchment area. Studies also had to have data that overlapped more than a single COVID-19 variant time period. We invited principal investigators already participating in an ongoing sequential, prospective meta-analysis of perinatal COVID-19. Investigators shared individual patient data (IPD) with the technical team for review and analysis. We examined 31 outcomes related to: i) COVID-19 severity (n=5); ii) maternal morbidities including adverse birth outcomes (n=14); iii) fetal and neonatal morbidity and mortality (n=5) and iv) adverse birth outcomes (n=8). SARS-CoV-2 strains that have been identified as variants of concern (VOC) by the WHO were analyzed using the publicly available strain frequency data by [Nextstrain.org][1] and strains were classified as dominant when they were more than half of sequences in a given geographic area. We applied a 2-stage IPD meta-analytic framework to generate pooled relative risks, with 95% CI for each dominant variant and outcome pair when there were one or more studies with available data. Results Our data show that the Delta wave, compared to Omicron, was associated with a higher risk of all adverse COVID-19 severity outcomes in pregnancy including risk of hospitalization [RR 4.02 (95% CI 1.10, 14.69), n=1 study], risk of ICU admissions [RR 2.59 (95% CI 1.26, 5.30, n=3 studies], risk of critical care admission [RR 2.52 (95% CI 1.25, 5.08, n=3 studies], risk of needing ventilation [RR 3.96 (95% CI 1.47, 10.71), n=3 studies] and risk of pneumonia [RR 6.73 (95% CI 2.17, 20.90), n=3 studies]. The majority of maternal morbidity and mortality indicators were not at increased risk during any of the COVID-19 variant waves except hemorrhage, any Cesarean section, intrapartum Cesarean section and maternal composite outcome, although data was limited. Risk of fetal and neonatal morbidity and mortality did not show significant increases in risks during any of the COVID-19 waves except stillbirth and perinatal death during the Delta wave ([RR 4.84 (95% CI 1.37, 17.05, n=3 studies], [RR 6.03 (95%CI 1.63, 22.34), n=3 studies], respectively) when compared to the Pre-alpha wave. Adverse birth outcomes including very low birthweight and very preterm birth also showed increased risks during the Delta wave compared to the Pre-alpha wave. Discussion During periods of Delta strain predominance, all COVID-19 severity outcomes were more severe among pregnant women, compared to periods when other COVID-19 strains predominated. In addition, there are limited data comparing the impact of different variants on pregnancy outcomes. This highlights the importance of ongoing genomic surveillance among special populations. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This study was funded by the Bill & Melinda Gates Foundation grant to Dr. Emily Smith (INV-022057). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Our study is a secondary analysis of the data from the perinatal COVID-19 sequential prospective meta-analysis study by Smith et al17 (protocol was registered with PROSPERO (ID: 188955; protocol # CRD42020188955)) and was determined to be exempt from IRB review at The George Washington University. Approval from each study site was granted as follows: Martinez-Portilla, 2021 (Mexico): Study protocol was approved by the General Hospital of Mexico (Dr Eduardo Liceaga), Mexico City, Mexico, under ethics committee number CE/23020. Bracero, Valencia, Delgado-Lopez, 2021 (Puerto Rico): Research was conducted through the COVID-19 surveillance system under the guidance of the Puerto Rico Department of Health; no IRB review needed. Favre, Panchaud, 2022 (Switzerland, France): Study was approved by both the Swiss Ethical Board (CER-VD-2020-00548) and the local ethics boards at each participating center. French data was registered with the French National Data Protection Commission (CNIL - authorization 2217464). Poon, 2021 (Hong Kong, China): Study was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee. Ethical approval was granted (CREC Ref. No. 2020.210). Bevilacqua, Laurita Longo, 2020 (Rome, Italy): Study was approved by the Universita Cattolica del Sacro Cuore (Approval number: No PROT.APROV.IST DIPUSVSP-24.02-217). Akelo, Tippett Barr, 2021 (Kenya): Study was approved by the Kenya Medical Research Institute (KEMRI) (SERU # 4166). Study was also cleared by the CDC in Kenya (CDC Project ID # 0900f3eb81c36d6c). Gil, Fernandez Buhigas, 2021 (Madrid, Spain): Study was approved by the Comite de Etica de la Investigacion con Medicamentos de los Hospitales Universitarios de Torrevieja y Elche-Vinaolopo, c/ Tonico Sansano Mora 14, 03293, Elche, Alicante, affiliated with Hospital Universitario del Vinalopo (Approval number: 2020.03; Date of approval: 17 June 2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: http://Nextstrain.org