Undetected SARS-CoV-2 transmission in a Malawian pregnancy cohort: A longitudinal serological surveillance study

1.BackgroundDespite COVID-19s global impact, surveillance remains challenging in resource-limited settings. This study investigated IgG to SARS-CoV-2 antigens in Malawian pregnant women participating in the REVAMP trial, where no COVID-19 clinical cases or positive SARS-CoV-2 tests were reported during the pandemic (April 2020 - September 2021). MethodsWe analysed serum samples collected from November 2018-September 2021 from 852 pregnant women at enrolment (second trimester) and delivery, measuring IgG against five SARS-CoV-2 antigens using a multiplex bead assay. IgG to Tetanus toxoid served as a positive control, and IgG to four seasonal coronavirus antigens and Influenza A were used for context. FindingsWomen recruited after the start of the pandemic were younger than those recruited before the emergence of COVID-19 (median age 19 vs 21 years) and more likely primigravid (60.1% vs 51.1%). IgG levels to SARS-CoV-2 antigens showed sharp increases of 18.5%-29.7% every 30 days during COVID waves 2 and 3. Overall seropositivity to SARS-CoV-2 antigens reached 39.3% during the pandemic; however, the 14.7% seropositivity detected pre-pandemic demonstrates the presence of cross-reactive antibody responses against other antigens in Malawi. Surprisingly, pregnancies within the pandemic showed improved outcomes, with longer gestations (mean difference: 0.6 weeks [95% CI: 0.2-0.9]) and higher birth weights (mean difference: 169.3g, [65.9-272.6]) when comparing to pregnancies occurring pre-pandemic. We found no evidence that SARS-CoV-2 IgG levels were associated with pregnancy outcomes. InterpretationsThis study demonstrates that serological surveillance of pregnancy cohorts reveals undetected SARS-CoV-2 exposure where traditional testing was limited. The improvement in pregnancy outcomes during the pandemic suggests community-level exposure did not offset the social impacts of the pandemic in this population. These findings highlight pregnancy cohorts as valuable sentinel populations for infectious disease surveillance, emphasising the importance of serosurveillance in resource-limited settings. FundingBill & Melinda Gates Foundation (INV-010612), National Health and Medical Research Council (GNT1158696 and GNT2009047). Research in contextEvidence before this study: The COVID-19 pandemic presented unique surveillance challenges in resource-limited settings where constrained testing capacity complicated efforts to track SARS-CoV-2 transmission. In Malawi, despite early public health measures, significant challenges in disease surveillance left the true extent of viral spread uncertain. We searched Pubmed, Medline and official statistics from the Malawi government for "pregnancy" and "COVID" or "SARS-CoV-2" and "antibody" or "serology" between November 2019 and February 2025. Official data suggested relatively low case numbers across the population compared to other regions; however, limited testing capacity, particularly in rural areas, made it difficult to ascertain actual infection rates. Serological studies across Africa revealed SARS-CoV-2 seroprevalence estimates ranging from 0-63%, with Malawian studies estimating 10-85% depending on the sampling strategy and population. Added value of this studyThis study leveraged samples from the REVAMP trial (November 2018-September 2021) to investigate undetected SARS-CoV-2 transmission in a Malawian pregnancy cohort where no clinical cases were reported. The trial provided reliable pre-pandemic baseline samples and consistent monitoring during the pandemic period. Despite the absence of reported symptoms and positive tests as part of the trial, population-level IgG to SARS-CoV-2 antigens increased during well-defined COVID periods. Increased inter-antigenic correlation during the COVID period supports true population transmission. Surprisingly, pandemic pregnancies showed improved outcomes, with longer gestations and higher birth weights, while SARS-CoV-2 IgG levels were not associated with pregnancy outcomes. Implications of all the available evidenceThis study provides evidence supporting pregnancy as a sensitive sentinel period for infectious disease surveillance. Our findings demonstrate that serological surveillance can reveal undetected SARS-CoV-2 transmission where traditional testing was limited. The high background seropositivity for SARS-CoV-2 antigens detected in Malawi warrants further research into its clinical significance. Improved pregnancy outcomes during the pandemic, despite serological evidence of transmission, suggest community-level exposure did not adversely affect pregnancy in this population during this period. This may be due to exposure levels below a significant threshold, where SARS-CoV-2s negative impacts are less significant than the improvements from reductions in other infections, or the infection impacts are outweighed by demographic shifts in the study population. These findings highlight pregnancy cohorts as valuable sentinel populations, emphasising the importance of serosurveillance in resource-limited settings where traditional surveillance methods may be inadequate.