Highlights
- Pregnancy confers a significantly increased risk of developing long COVID-19 multisystemic sequelae following SARS-CoV-2 infection, especially during Omicron-predominant periods.
- Despite increased relative risk, the absolute incidence of postacute sequelae in vaccinated pregnant women infected with predominantly mild Omicron variant remains modest (<1%).
- Infection during the third trimester correlates with heightened susceptibility to postacute sequelae compared to infections earlier in pregnancy.
- COVID-19 booster vaccination prior to SARS-CoV-2 infection did not significantly reduce the risk of postacute sequelae beyond primary vaccination in pregnancy.
Background
The COVID-19 pandemic has profoundly impacted maternal health globally. Previous studies on postacute sequelae of SARS-CoV-2 infection (commonly known as long COVID) in pregnancy demonstrated substantial variability in incidence, partly due to heterogeneous study designs, timing relative to virus variant predominance, and vaccination status. Early pandemic data largely predated the Omicron variant’s emergence and widespread vaccination rollout. Omicron’s association with less severe clinical manifestations raised the question of whether it might attenuate long-term post-COVID-19 risks for pregnant women, who physiologically experience immune and cardiopulmonary adaptations influencing disease susceptibility and progression. This review synthesizes recent high-quality epidemiologic and clinical evidence focusing on long COVID in pregnancy amidst evolving viral and immunization landscapes.
Key Content
Study Design and Cohort Characteristics
The seminal work by Tan et al. (2025) employed a retrospective population-based cohort design leveraging Singapore’s national COVID-19 registry and healthcare claims databases. The study encompassed 11,208 pregnant women with confirmed SARS-CoV-2 infection—72.1% boosted and 97% infected during Omicron predominance (late 2021 to 2023), contrasting them with 15,255 test-negative pregnant women and 332,198 infected nonpregnant women of childbearing age. Propensity score weighting adjusted for confounders; Cox regression modeled risks of new-incident multisystemic diagnoses and symptoms occurring between 31 and 300 days post-infection.
Incidence and Risk of Postacute Sequelae
The analysis notably found that pregnant women with COVID-19 had a 1.6-fold increased risk for any postacute sequelae compared with test-negative pregnant controls (adjusted hazard ratio [aHR] 1.68; 95% CI 1.24-2.26; P<.001). When compared to infected nonpregnant women of childbearing age, the risk elevation was markedly higher (aHR 13.39; 95% CI 10.55-16.98; P<.001), underscoring pregnancy as a significant modifier.
However, the absolute risk was modest: less than 1% of pregnant COVID-19 cases reported any postacute sequelae, suggesting that while pregnancy amplifies relative risk, population-level incidence remains low in this highly vaccinated cohort.
Trimester-Specific Risk Stratification
Subgroup analyses revealed a critical temporal risk gradient: infection occurring in the third trimester was associated with a 2- to 3-fold increased risk of postacute sequelae relative to test-negative pregnant women (diagnoses aHR 2.03; symptoms aHR 3.91; both P<.001). Infections before the third trimester did not significantly elevate risk, highlighting potential biological vulnerability linked to late pregnancy immunophysiology or placental-fetal interactions.
Impact of Vaccination Status
A vast majority (99%) of the pregnant cohort had completed primary COVID-19 vaccination, and 72.1% were boosted prior to infection. Intriguingly, additional booster dosing before infection did not significantly attenuate long COVID risk compared to unboosted pregnant women—indicating that primary vaccination likely confers substantial protection against severe and long-term sequelae, with diminishing incremental benefit from boosters regarding postacute complications in pregnancy.
Other Long COVID Features and Clinical Presentation
The spectrum of new-incident postacute sequelae was multisystemic, encompassing respiratory, cardiovascular, neurological, and general symptoms consistent with prior clinical descriptions of long COVID. The milder Omicron variant profile correlated with lower severe acute disease burden but did not fully eliminate risk of persistent symptoms.
Comparative Evidence from Earlier Pandemic Phases and Other Settings
Pre-Omicron, pre-vaccination studies frequently reported higher rates of long COVID in pregnancy, often exceeding 5-10%, typically in cohorts infected with more pathogenic variants and lacking immunization. Meta-analyses (e.g., Allotey et al., 2021; Flaherman et al., 2023) identified pregnancy as a risk factor for adverse COVID outcomes but yielded heterogeneous long COVID prevalence due to variable definitions and measurement windows.
Later evidence incorporating vaccination and Omicron shifted the risk paradigm. This study aligns with emerging population-based data from other regions, affirming that vaccination and milder variants mitigate but do not abolish long COVID risk in pregnancy.
Expert Commentary
The marked increase in long COVID risk attributable to pregnancy underscores complex immunologic and physiological adaptations that may predispose to persistent postviral sequelae. Immunomodulatory shifts in the third trimester—favoring anti-inflammatory states and altered cellular immunity—may influence viral persistence or dysregulated repair mechanisms.
Nonetheless, the low absolute incidence among a nearly universally vaccinated cohort suggests effective protective effects of primary immunization against severe and chronic complications. The absence of significant additional risk reduction from booster doses may reflect ceiling effects of immunity, or the predominant effect of variant milder phenotype.
Clinicians should remain vigilant in counseling pregnant patients regarding long COVID risk, especially in late pregnancy infections, and reinforce the importance of vaccination to minimize acute and chronic morbidity. Diagnostic vigilance for long COVID symptoms should integrate multidisciplinary approaches—considering cardiopulmonary, neurological, and mental health domains.
Limitations include the retrospective design, reliance on claims data subject to diagnostic coding bias, and limited granularity on symptom severity or functional impairments. Future prospective studies could elucidate mechanistic underpinnings and optimal management strategies.
Conclusion
The study by Tan et al. provides nuanced, population-level evidence that pregnancy remains a significant risk factor for long COVID despite the predominance of milder Omicron infections and high vaccination coverage. The incidence of postacute sequelae, although increased relative to controls, remains modest (<1%), emphasizing vaccination’s protective benefit and highlighting ongoing challenges posed by long COVID in obstetrics.
Infection during the third trimester presents a critical window for heightened risk, warranting targeted surveillance and supportive care. As SARS-CoV-2 transitions to endemicity, these insights should inform maternal health policies, vaccination campaigns, and clinical management to address emerging long-term sequelae in pregnancy.
References
- Tan YY, Loy EXH, Tan WZ, Tay AT, Lim JT, Chiew CJ, Choolani M, Lye DC, Tan KB, Wee LE. 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 Oct;233(4):323.e1-323.e12. doi: 10.1016/j.ajog.2025.03.004. PMID: 40073919.
- Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2021;370:m3320. doi:10.1136/bmj.m3320.
- Flaherman VJ, Afshar Y, Boscardin WJ, et al. Health Outcomes of Pregnant and Postpartum Women With SARS-CoV-2 Infection. JAMA. 2023;329(6):475–485. doi:10.1001/jama.2023.1175.
- Groß R, Zanoni M, Georgakopoulos-Soares I, et al. Risk of Long Covid in SARS-CoV-2 Infection During Pregnancy: A Systematic Review. BMJ Open. 2023;13(3):e067139. doi:10.1136/bmjopen-2022-067139.
- Centers for Disease Control and Prevention (CDC). Pregnancy Considerations for COVID-19 Vaccination. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html