Despite heightened obstetric risks, pregnant women may face a lower chance of developing Long COVID—findings that challenge assumptions and call for deeper insight into the immune landscape of pregnancy.

Study: Long COVID after SARS-CoV-2 during pregnancy in the United States. Image Credit: Natalia Deriabina / Shutterstock

In a recent study published in the journal Nature Communications, researchers conducted a retrospective analysis to investigate the risk of Long COVID in pregnant women who acquired SARS-CoV-2 infections during their pregnancy, compared to matched, non-pregnant women with SARS-CoV-2 infections. Their study cohort comprised individuals from the PCORnet (n = 492,325) and N3C (n = 1,019,180) health networks, with 29,975 and 42,176 individuals, respectively, who were pregnant when they acquired the SARS-CoV-2 infection.

Study findings revealed that pregnant women with SARS-CoV-2 infections were less likely to develop Long COVID (adjusted Hazard Ratio [aHR] = 0.86 for PCORnet and 0.70 for N3C) than their non-pregnant, matched counterparts (in terms of age, region, infection, and comorbidities). These results were consistent across two different Long COVID definitions—rule-based computational phenotypes for PCORnet and machine learning models for N3C. Additional sensitivity analyses using ICD-10 codes and symptom clusters (fatigue, cognitive, and respiratory symptoms) confirmed the consistency of these results across definitions. The findings raise the hypothesis that immunological changes during pregnancy may contribute to a lower observed risk of Long COVID, though the study design does not establish causality, and warrant further investigation into the pathophysiology of Long COVID in pregnant women.

Background

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), which caused coronavirus disease of 2019 (COVID-19), remains one of the worst pandemics in human history, infecting more than 775 million individuals and claiming more than 7 million lives since its discovery in late 2019. Many of the ~770 million survivors of the disease experienced persistent, exacerbated, or even novel COVID-19 symptoms, which remained for months and, in some cases, years following recovery from the initial infections, a condition termed “post-acute sequelae of SARS-CoV-2 infection (PASC)”, or colloquially ‘Long COVID.’

Given its relative novelty, Long COVID remains an understudied yet rapidly expanding field of scientific research. Unfortunately, almost all knowledge in the field has been developed using adult, non-pregnant populations, with no literature on the risk of Long COVID in pregnant, SARS-CoV-2-infected individuals. In contrast, research has hitherto revealed that SARS-CoV-2 infections during pregnancy can substantially increase adverse pregnancy outcomes, including obstetric complications and mortality risk.

Since Long COVID is a debilitating condition and may impact a mother’s ability to take care of their offspring, understanding the risk of developing the condition following a SARS-CoV-2 infection during pregnancy can help prepare expectant mothers and their families for the challenges of infant caregiving in the months and years following parturition.

About the study

The present study aims to address existing gaps in the literature by evaluating the risk of Long COVID in pregnant women who contract SARS-CoV-2 infections during pregnancy and comparing them with matched SARS-CoV-2 patients who are not pregnant. It further aims to inform clinicians, caregivers, and expectant mothers about the relative risks of Long COVID associated with specific subpopulations, such as particular ethnic groups, specific SARS-CoV-2 strains, body mass index (BMI), vaccination status, and the trimester of SARS-CoV-2 infection.

Study data was obtained from within the United States (US) National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) initiative. RECOVER comprises electronic health records (EHRs) from two multisite cohorts – the National Patient-Centered Clinical Research Networks (PCORnet) and the National COVID Cohort Collaborative (N3C). These cohorts included 492,325 (29,975 pregnant) and 1,019,180 (42,176 pregnant) eligible reproductive-age females, respectively, with clinically validated SARS-CoV-2 infections between March 2020 and October 2022, and follow-up data extending to June 2023.

“…covariates included age at infection, self-reported race/ethnicity, national-level Area Deprivation Index (ADI), healthcare utilization, time of infection, the most recent body mass index (BMI), smoking status, ICU or ventilation in acute infection, COVID-19 vaccine status, and a range of baseline health comorbidities.”

For the present study, each pregnant SARS-CoV-2 patient was compared with three closest matched non-pregnant patients (ratio 1:3) based on region, age, infection time, infection severity (including ICU admission or mechanical ventilation), and comorbidity profile. Each dataset was evaluated and adjusted Hazard Ratios (aHRs; Cox survival model) generated using a different methodology – a rule-based Long COVID Computational Phenotype (CP) method for the PCORnet dataset, and a machine learning CP algorithm (PASC Machine Learning 2.0) for the N3C dataset. In addition, two alternative definitions—ICD-10 codes for unspecified PASC diagnoses (U09.9/B94.8) and symptom clusters involving fatigue, cognitive, and respiratory complaints—were applied in sensitivity analyses to confirm findings.

Study findings

One hundred eighty days of follow-up revealed that Long COVID risk was significantly lower for pregnant women than their non-pregnant counterparts (aHR PCORnet = 0.86, aHR N3C = 0.70), corresponding to 16.47 versus 18.88 events per 100 (PCORnet; risk reduction = 2.41 per 100) and 4.37 versus 6.21 events per 100 (N3C; risk reduction = 1.84 per 100).

Subpopulation-specific analyses revealed that pregnant Black women and those of advanced maternal age (35 years or older) were at higher Long COVID risk than their White and younger counterparts. Women infected during the first and second trimesters had higher Long COVID risk than those infected in the third trimester, particularly in the N3C cohort. However, in the PCORnet cohort, the increased risk associated with first-trimester infection was not statistically significant. Surprisingly, vaccination status did not affect the risk of Long COVID. However, the study noted that vaccination data were missing for more than 82% of pregnant individuals, limiting the ability to draw firm conclusions about vaccination’s impact. Patients infected during the Delta and Omicron COVID-19 periods had higher Long COVID risk than earlier SARS-CoV-2 strains.

“Our findings remain consistent across various SARS-CoV-2 identification methods, cohort selection criteria, and a modified rule-based Long COVID phenotype method.”

The authors also acknowledged that increased healthcare utilization among pregnant individuals, particularly during the first and second trimesters, may have contributed to higher ascertainment of Long COVID symptoms, potentially introducing detection bias in observational analyses.

Conclusions

The present study suggests that pregnancy or, more specifically, the inflammatory and immunological changes accompanying gestation may modulate the risk of Long COVID development. This lower relative risk is particularly notable given that SARS-CoV-2 infections are associated with worse obstetric outcomes. These findings highlight the need for future investigations into the pathophysiology of Long COVID in women infected with SARS-CoV-2 during the course of their pregnancy, including studies focused on gestational age and racial or ethnic disparities.