Long COVID-19 in pregnancy: increased risk but modest incidence following mild Omicron infection in a boosted obstetric cohort during endemicity.

Background: Significant heterogeneity has been reported in estimates of long-term sequelae following SARS-CoV-2 infection in pregnant women, and most studies were conducted pre-Omicron and pre-dated vaccination rollout. Less severe COVID-19 attributed to milder Omicron may potentially attenuate risk of post-COVID-19 sequelae.

Objective: We sought to examine long-term risk of new-incident multi-systemic sequelae following SARS-CoV-2 Delta/Omicron infection in a population-based cohort of pregnant women, contrasted against a)test-negatives; b)infected non-pregnant women of childbearing age. We hypothesize that increased risk of long-term sequelae post-SARS-CoV-2 infection in pregnancy persists into COVID-19 endemicity.

Study Design: Retrospective population-based cohort study of all Singaporean pregnant women infected during Delta/Omicron-predominant transmission, and a) a contemporaneous test-negative pregnant group; b) infected non-pregnant women of child-bearing age, constructed using the national COVID-19 registry. Between-group-differences were adjusted for using inverse-propensity-weighting, and Cox-regression was utilized to estimate risks of new-incident post-acute diagnoses/symptoms reported in national healthcare-claims data, at 31-300 days post-infection RESULTS: 11,208 pregnant COVID-19 cases, 15,255 uninfected pregnant test-negatives, and 332,198 COVID-19 cases in non-pregnant women of child-bearing age were included. 72.1% (8079/11208) of pregnant COVID-19 cases were boosted, and 97.0% (10869/11208) were infected during Omicron-predominant transmission. Risk of any post-acute sequelae in pregnant COVID-19 cases was 1.6 times that of pregnant test-negatives (any post-acute diagnosis: adjusted-hazards-ratio, aHR=1.68[95%CI=1.24-2.26], p<0.001; any post-acute symptom: aHR=1.65[95%CI=1.23-2.22], p<0.001). The risk of long-COVID-19 was substantially increased with pregnancy; risk of any post-acute sequelae in pregnant COVID-19 cases was 13.4 times that observed amongst women of childbearing age infected outside of pregnancy (any post-acute diagnosis: aHR=13.39[95%CI=10.55-16.98], p<0.001; any post-acute symptom: aHR=21.82[95%CI=16.77-28.41], p<0.001). However, though risk was increased, absolute incidence was modest; <1% of pregnant COVID-19 cases reported any post-acute sequelae. In subgroup analyses, pregnant COVID-19 cases infected during the third trimester were at higher risk for post-acute sequelae. Risk of any post-acute sequelae in pregnant COVID-19 cases infected during the third trimester was 2-3 times that of pregnant test-negatives (any post-acute diagnosis: aHR=2.03[95%CI=1.32-3.15], p<0.001; any post-acute symptom: aHR=3.91[95%CI=2.25-6.80], p<0.001), whereas risk of post-acute sequelae was not significantly increased in pregnant COVID-19 cases infected before the third trimester, versus test-negatives. Risk of post-acute sequelae was not significantly different in pregnant COVID-19 cases boosted prior to infection, versus unboosted cases.

Conclusion: Increased risk of long-term multi-systemic sequelae 31-300 days post-COVID-19 was still observed in a highly-vaccinated population-based cohort of pregnant women predominantly infected with the mild Omicron SARS-CoV-2 variant, versus test-negatives and infected non-pregnant women of childbearing age. Women infected in the third trimester of pregnancy were at increased risk of post-acute sequelae. However, <1% reported post-acute sequelae following SARS-CoV-2 infection. The beneficial impact of vaccination might have attenuated overall risk of post-acute sequelae, given that 99% of pregnant women had completed primary vaccination; though prior receipt of an additional COVID-19 booster dose did not significantly attenuate risk of post-acute sequelae in pregnancy (versus unboosted individuals). Low prevalence of long-term sequelae following COVID-19 in a highly-vaccinated pregnant cohort highlights the importance of maternal COVID-19 vaccination; this is of significance given increasing vaccine hesitancy amongst pregnant women during COVID-19 endemicity.