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

Yong Yi Tan; Enoch Xue Heng Loy; Wei Zhi Tan; An Ting Tay; Jue Tao Lim; Calvin J Chiew; Mahesh Choolani; David Chien Lye; Kelvin Bryan Tan; Liang En Wee

doi:10.1016/j.ajog.2025.03.004

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

Am J Obstet Gynecol. 2025 Mar 10:S0002-9378(25)00147-4. doi: 10.1016/j.ajog.2025.03.004. Online ahead of print.

Authors

Affiliations

¹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
² National Centre for Infectious Diseases, Singapore.
³ Ministry of Health, Singapore.
⁴ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; National Centre for Infectious Diseases, Singapore.
⁵ National Centre for Infectious Diseases, Singapore; Ministry of Health, Singapore.
⁶ Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Obstetrics and Gynaecology, National University Centre for Women and Children, National University Health System, Singapore.
⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; National Centre for Infectious Diseases, Singapore; Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore.
⁸ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; National Centre for Infectious Diseases, Singapore; Ministry of Health, Singapore; Duke-National University of Singapore Graduate Medical School, National University of Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
⁹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; National Centre for Infectious Diseases, Singapore; Duke-National University of Singapore Graduate Medical School, National University of Singapore, Singapore; Department of Infectious Diseases, Singapore General Hospital, Singapore. Electronic address: ian.wee.l.e@singhealth.com.sg.

PMID: 40073919
DOI: 10.1016/j.ajog.2025.03.004

Abstract

Background: Substantial 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 attenuate the risk of post-COVID-19 sequelae.

Objective: This study aimed to examine the long-term risk of new-incident multisystemic sequelae after SARS-CoV-2 Delta/Omicron infection in a population-based cohort of infected pregnant women compared against test-negative pregnant women and SARS-CoV-2-infected non-pregnant women of childbearing age. In addition, this study hypothesized that an increased risk of long-term sequelae after SARS-CoV-2 infection in pregnancy persists into COVID-19 endemicity.

Study design: A retrospective population-based cohort study comprising all Singaporean pregnant women infected with SARS-CoV-2 during Delta-predominant/Omicron-predominant transmission, a contemporaneous test-negative pregnant group and a group of SARS-CoV-2-infected non-pregnant women of childbearing age. Groups were constructed using the national COVID-19 registry. Between-group differences were adjusted for using inverse propensity weighting, and Cox regression was used to estimate the risks of new-incident postacute diagnoses/symptoms reported in national healthcare claims data at 31 to 300 days after infection.

Results: Of note, 11,208 pregnant women with COVID-19, 15,255 test-negative pregnant women without infection, and 332,198 nonpregnant women of childbearing age with COVID-19 were included. In addition, 8079 of 11,208 pregnant women (72.1%) with COVID-19 were boosted, and 10,869 of 11,208 pregnant women (97.0%) were infected during Omicron-predominant transmission. The risk of any postacute sequelae in pregnant women with COVID-19 was 1.6 times that of test-negative pregnant women (any postacute diagnosis: adjusted hazards ratio, 1.68 [95% confidence interval, 1.24-2.26]; P<.001; any postacute symptom: adjusted hazards ratio, 1.65 [95% confidence interval, 1.23-2.22]; P<.001). The risk of long COVID-19 was substantially increased with pregnancy. The risk of any postacute sequelae in pregnant women with COVID-19 was 13.4 times that observed among women of childbearing age infected outside of pregnancy (any postacute diagnosis: adjusted hazards ratio, 13.39 [95% confidence interval, 10.55-16.98]; P<.001; any postacute symptom: adjusted hazards ratio, 21.82 [95% confidence interval, 16.77-28.41]; P<.001). However, although the risk was increased, absolute incidence was modest. Of note, <1% of pregnant women with COVID-19 reported any postacute sequelae. In subgroup analyses, pregnant women with COVID-19 infected during the third trimester of pregnancy were at higher risk of postacute sequelae. The risk of any postacute sequelae in pregnant women with COVID-19 infected during the third trimester of pregnancy was 2 to 3 times that of test-negative pregnant women (any postacute diagnosis: adjusted hazards ratio, 2.03 [95% confidence interval, 1.32-3.15]; P<.001; any postacute symptom: adjusted hazards ratio, 3.91 [95% confidence interval, 2.25-6.80]; P<.001), whereas the risk of postacute sequelae was not significantly increased in pregnant women with COVID-19 infected before the third trimester of pregnancy vs test-negative pregnant women. The risk of postacute sequelae was not significantly different between pregnant women with COVID-19 boosted before infection and those with COVID-19 unboosted before infection.

Conclusion: Increased risk of long-term multisystemic sequelae 31 to 300 days after 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 vs test-negative pregnant women and SARS-CoV-2-infected nonpregnant women of childbearing age. Women infected in the third trimester of pregnancy were at increased risk of postacute sequelae. However, <1% of pregnant women reported postacute sequelae after SARS-CoV-2 infection. The beneficial effect of vaccination might have attenuated the overall risk of postacute sequelae, given that 99% of pregnant women had completed primary vaccination. Previous receipt of an additional COVID-19 booster dose did not significantly attenuate the risk of postacute sequelae in pregnancy (vs unboosted individuals). The low prevalence of long-term sequelae after COVID-19 in a highly vaccinated pregnant cohort highlights the importance of maternal COVID-19 vaccination. This is of significance given increasing vaccine hesitancy among pregnant women during COVID-19 endemicity.

Keywords: COVID-19; Omicron; SARS-CoV-2; boosting; long COVID-19; postacute sequelae of SARS-CoV-2; pregnancy; vaccination.