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From the Journals

Pregnancy Linked to Lower Long COVID Risk

New research analyzing over 72,000 pregnant COVID-19 patients reveals they face a significantly reduced risk of developing long-term symptoms compared to nonpregnant women, with key risk factors identified across both cohorts.

Conexiant

In one of the largest retrospective cohort studies of its kind, researchers have found that individuals infected with SARS–CoV-2 during pregnancy have a lower risk of developing long COVID compared to nonpregnant reproductive-age individuals, according to a study.

The collaborative research, conducted as part of the National Institutes of Health (NIH) Researching COVID to Enhance Recovery initiative, included an analysis of electronic health records from 29 sites in the National Patient-Centered Clinical Research Networks (PCORnet) and 65 sites from the National COVID Cohort Collaborative (N3C).

"While the findings suggest a high incidence of long COVID among pregnant individuals, their risk was lower than that of matched non-pregnant individuals," first author Chengxi Zang, PhD, of Weill Medical College of Cornell University and the WCM Institute of AI for Digital Health, and colleagues wrote in Nature Communications.

Key Findings

The study identified 29,975 pregnant individuals with SARS–CoV-2 infection from PCORnet and 42,176 from N3C between March 2020 and June 2023. At 180 days after infection, the estimated long COVID risk for those infected during pregnancy were 16.47 per 100 persons (95% confidence interval [CI] = 16.00–16.95) in PCORnet and 4.37 per 100 persons (95% CI = 4.18–4.57) in N3C.

Compared to matched nonpregnant individuals, pregnant individuals had lower adjusted hazard ratios for long COVID: 0.86 (95% CI = 0.83–0.90) in PCORnet and 0.70 (95% CI = 0.66–0.74) in N3C. This translated to a risk reduction of 2.41 events per 100 persons (95% CI = 1.85–2.96) in PCORnet and 1.84 events per 100 persons (95% CI = 1.60–2.08) in N3C.

Risk Factors Identified

The study found several subgroups among pregnant individuals with higher long COVID risk:

  • Self-reported Black individuals compared to White individuals

  • Individuals with advanced maternal age (≥ 35 years) compared to those aged < 35 years

  • Those infected during the first two trimesters compared to the third trimester

  • Those infected during the Delta and Omicron periods of the pandemic compared to earlier variants

  • Individuals with obesity compared to those who were overweight or of normal weight

  • Those with baseline chronic medical conditions compared to those without.

Vaccination status did not appear to affect absolute long COVID risk in the pregnant population.

Multiple Definitions of Long COVID

To strengthen confidence in their findings, the researchers used multiple long COVID definitions across both datasets:

  • A PCORnet rule-based definition including 15 incident conditions across multi-organ systems

  • An N3C machine-learning phenotype for long COVID

  • Unspecified PASC (Post-Acute Sequelae of SARS–CoV-2) diagnostic codes U09.9/B94.8

  • A subcluster of cognitive, fatigue, and respiratory conditions.

All definitions showed consistent results, with pregnant individuals experiencing lower long COVID risk than matched nonpregnant individuals.

Sensitivity Analyses and Limitations

Sensitivity analyses consistently showed a lower risk of long COVID in pregnant individuals across different definitions and subpopulations. The authors acknowledged limitations of the study, including potential residual confounding, variability in electronic health record data, and the need for external cohort validation. Vaccination data were sparse and might not fully represent the impact of vaccination on long COVID risk in pregnancy.

Implications for Immune Response

The researchers suggested that the altered immune and inflammatory environment during pregnancy may contribute to the observed lower risk of long COVID. Pregnancy reflects a period of physiologic immune tolerance to accommodate fetal development, which may influence immune responses to SARS–CoV-2 infection. Further research is needed to explore immune mechanisms underlying the observed differences.

This study provides important clinical evidence for counseling pregnant patients about long COVID risk following SARS–CoV-2 infection and suggests future directions for research into immune mechanisms potentially protecting pregnant individuals from long COVID, concluded authors.

The authors declared no competing interests.