Long COVID after SARS-CoV-2 during pregnancy in the United States

Abstract

Pregnancy alters immune responses and clinical manifestations of COVID-19, but its impact on Long COVID remains uncertain. This study investigated Long COVID risk in individuals with SARS-CoV-2 infection during pregnancy compared to reproductive-age females infected outside of pregnancy. A retrospective analysis of two U.S. databases, the National Patient-Centered Clinical Research Network (PCORnet) and the National COVID Cohort Collaborative (N3C), identified 29,975 pregnant individuals (aged 18-50) with SARS-CoV-2 infection in pregnancy from PCORnet and 42,176 from N3C between March 2020 and June 2023. At 180 days after infection, estimated Long COVID risks for those infected during pregnancy were 16.47 per 100 persons (95% CI, 16.00-16.95) in PCORnet using the PCORnet computational phenotype (CP) model and 4.37 per 100 persons (95% CI, 4.18-4.57) in N3C using the N3C CP model. Compared to matched non-pregnant individuals, the adjusted hazard ratios for Long COVID were 0.86 (95% CI, 0.83-0.90) in PCORnet and 0.70 (95% CI, 0.66-0.74) in N3C. The observed risk factors for Long COVID included Black race/ethnicity, advanced maternal age, first- and second-trimester infection, obesity, and comorbid conditions. While the findings suggest a high incidence of Long COVID among pregnant individuals, their risk was lower than that of matched non-pregnant females.

Fig. 1. Cohort selection.

a Selection of females with SARS-CoV-2 infection during pregnancy or not, from the PCORnet cohort and N3C cohort. The SARS-CoV-2 infection was between March 1st, 2020, and October 31, 2022, and follow-up to June 1st, 2023. b Study design. The post-acute sequelae of SARS-CoV-2 infection (PASC), or Long COVID, outcomes were ascertained from day 30 after the SARS-CoV-2 infection and the adjusted risk was computed at 180 days after the SARS-CoV-2 infection. Two exposure groups are pregnant individuals who acquired SARS-CoV-2 during pregnancy as illustrated in b compared with outside of pregnancy. The pregnant group was compared with exactly matched non-pregnant females on site region, age, infection time, acute severity, and selected baseline comorbidities including diabetes, hypertension, autoimmune or immune suppression, mental health disorders, severe obesity, and asthma with a ratio of 1:3.

Fig. 2. Long COVID risks in the SARS-CoV-2 infected pregnant women versus the matched infected non-pregnant women in PCORnet and N3C.

Outcomes were ascertained 30 days after the first documented SARS-CoV-2 infection evidence until the end of the follow-up. The absolute risk, risk ratio, and risk difference were captured by the cumulative incidence (CIF), hazard ratio (HR), and the difference of cumulative incidence per 100 persons (DIFF/100), estimated at 180 days after the infection index date, respectively. The centers of the error bars were adjusted hazard ratios calculated by the Cox proportional hazard model, and error bars indicated two-sided 95% confidence intervals (95% CI).

Fig. 3. Long COVID, risk in different sub-populations in PCORnet and N3C cohorts.

Corresponding sub-populations in the SARS-CoV-2 infected pregnant women and the infected non-pregnant women were compared. Outcomes were ascertained 30 days after the first documented SARS-CoV-2 infection evidence until the end of the follow-up. The absolute risk, risk ratio, and risk difference were captured by the cumulative incidence (CIF), hazard ratio (HR), and the difference of cumulative incidence per 100 persons (DIFF/100), estimated at 180 days after the infection index date, respectively. The centers of the error bars were adjusted hazard ratios calculated by the Cox proportional hazard model, and error bars indicated two-sided 95% confidence intervals (95% CI). Having co-existing risk factors is having any hypertension, diabetes, class III obesity, and asthma at baseline.

Fig. 4. Risks of unspecified PASC diagnoses and Cognitive, Fatigue, and Respiratory symptom cluster among the SARS-CoV-2 infected pregnant women versus the matched infected non-pregnant women, in PCORnet and N3C cohorts.

Outcomes were ascertained 30 days after the first documented SARS-CoV-2 infection evidence until the end of the follow-up. The absolute risk, risk ratio, and risk difference were captured by the cumulative incidence (CIF), hazard ratio (HR), and the difference of cumulative incidence per 100 persons (DIFF/100), estimated at 180 days after the infection index date, respectively. The centers of the error bars were adjusted hazard ratios calculated by the Cox proportional hazard model, and error bars indicated two-sided 95% confidence intervals (95% CI).

Fig. 5. Risks of Cognitive, Fatigue, and Respiratory symptoms cluster in different sub-populations from the PCORnet cohort and N3C cohort.

Corresponding sub-populations in the SARS-CoV-2 infected pregnant women and the infected non-pregnant women were compared. Outcomes were ascertained 30 days after the first documented SARS-CoV-2 infection evidence until the end of the follow-up. The absolute risk, risk ratio, and risk difference were captured by the cumulative incidence (CIF), hazard ratio (HR), and the difference of cumulative incidence per 100 persons (DIFF/100), estimated at 180 days after the infection index date, respectively. The centers of the error bars were adjusted hazard ratios calculated by the Cox proportional hazard model, and error bars indicated two-sided 95% confidence intervals (95% CI). Having co-existing risk factors is having any hypertension, diabetes, class III obesity, and asthma at baseline.

Fig. 6. Risks of unspecified PASC diagnoses U099/B948 in different sub-populations from the PCORnet cohort and N3C cohort.

Corresponding sub-populations in the SARS-CoV-2 infected pregnant women and the infected non-pregnant women were compared. Outcomes were ascertained 30 days after the first documented SARS-CoV-2 infection evidence until the end of the follow-up. The absolute risk, risk ratio, and risk difference were captured by the cumulative incidence (CIF), hazard ratio (HR), and the difference of cumulative incidence per 100 persons (DIFF/100), estimated at 180 days after the infection index date, respectively. The centers of the error bars were adjusted hazard ratios calculated by the Cox proportional hazard model, and error bars indicated two-sided 95% confidence intervals (95% CI). Having co-existing risk factors is having any hypertension, diabetes, class III obesity, and asthma at baseline.