A new Kenyan preprint research paper posted to the medRxiv* server provides more evidence that the coronavirus disease 2019 (COVID-19) likely causes a more serious phenotype to arise in pregnant women.
Study: Correlation between Pregnancy Status and Severe Corona-Virus Disease Characterized by Cytokine Storm: Systematic Review and Meta-Analysis. Image Credit: Krakenimages.com / Shutterstock.com
As the pandemic began to sweep over the world at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for COVID-19, was recognized to cause an erratic pattern of clinical severity. Although SARS-CoV-2 mostly causes asymptomatic disease, in a significant minority of cases, it results in severe or life-threatening illness.
High-risk groups include elderly people and individuals with underlying health conditions such as heart disease, diabetes, chronic respiratory disease, and cancer. Pregnancy has also been thought to put women at an increased risk of adverse outcomes following infection by SARS-CoV-2. The critical illness associated with COVID-19 has largely been attributed to the cytokine storm that arises during the immune system’s response to the infection.
Earlier studies suggest that pregnancy may put women at an increased risk of developing respiratory distress with COVID-19. Other poor outcomes include a higher risk of preterm delivery, Cesarean delivery, and a greater need for mechanical ventilation.
What were the study findings?
In the current study, the researchers reviewed 17 previous reports that included over 840,000 women, of which included approximately 46,000 pregnant women with COVID-19. The remaining test subjects were non-pregnant women with COVID-19.
In their review, the researchers found that severe COVID-19, which was defined by the presence of a cytokine storm, was more likely in pregnancy. Furthermore, pregnant women were found to be more likely to experience adverse outcomes of COVID-19 as compared to nonpregnant women. To this end, about 14% of pregnant women with COVID-19 had unregulated high cytokine levels as compared to 3% of non-pregnant women. Thus, the odds of severe disease with high cytokine levels were 2.5 times higher in the former group.
Among multi-center studies, no single study contributed to the high degree of heterogeneity that was previously described, which signaled to the authors that these studies were of lower quality. When lower quality studies were removed from the analysis, the strength of association between severe COVID-19 with cytokine storm and pregnancy increased. As a result, the odds of severity were 7.4 times higher in this cohort, while the heterogeneity was much lower, thus increasing the reliability of the result.
Further subdividing the participants into subgroups by the number of centers involved in each study, the authors found that this did not reduce the heterogeneity of the studies. However, when selected studies were removed from the single-center group, the results improved substantially with very low heterogeneity.
In this homogeneous group, the odds of severe COVID-19 with cytokine storm were approximately four times higher in pregnant women.
Excluding studies with high heterogeneity
These findings are similar to those of earlier studies showing that pregnancy increases the risk of severe COVID-19 following SARS-CoV-2 infection. This adds strength to the observed association, thereby indicating the need for validating and exploring this conclusion further in the future.
Some researchers did, however, conclude that pregnancy carries no additional risk of severity in COVID-19 patients. Several meta-analyses came to this conclusion; however, many ignored the possibility of publication bias and heterogeneity.
The current study took care to evaluate these factors to arrive at a more reliable association of severe COVID-19 with cytokine storm and pregnancy, with low heterogeneity among single-center studies, and the overall group.
It appears that pregnancy may predispose patients to higher rates of inflammation that are similar to the cytokine storm seen in severe COVID-19, while also promoting the progression of the disease. The World Health Organization (WHO) has also arrived at the same conclusion, stating that “pregnant women are at a higher risk of developing severe COVID-19 related symptoms and possible mortality.”
Notably, the severity of COVID-19 appears to worsen during the later stages of pregnancy.
How does this agree with earlier research?
An earlier study also indicated a 25% case fatality rate from respiratory viruses in pregnancy, with 50% of the patients requiring intensive care unit admission and a third on mechanical ventilation.
In the case of SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) is the host cell receptor for the virus. The enhanced expression and activity of ACE2 in pregnancy may play a major role in regulating blood flow and blood pressure within the uteroplacental unit. This increase in ACE2 activity and expression may subsequently worsen the infectiousness of SARS-CoV-2 and the risk of severe COVID-19.
The cytokine storm may be partly responsible for the life-threatening course of COVID-19 in many pregnancies. This response is a dysregulated form of the normal inflammatory response to a pathogen, triggered by abnormally activated monocytes as part of the monocyte activation syndrome (MAS).
Therefore, pregnancy, coupled with high levels of inflammatory cytokines, presents a unified risk factor for severe COVID-19, presenting with acute respiratory distress and multi-organ dysfunction. The cytokines that have been found to rise during this cytokine storm include interleukin (IL)-1, IL-2, IL-6, IL-8, IL-17, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α.
Among these, significantly increased levels of IFN-γ, luteinizing hormone (LH), and prolactin is associated with recurrent pregnancy losses, which may imply that pregnant women are not only at risk for severe COVID-19 but also for miscarriage and preterm delivery. Further investigation is required to confirm this association.
Since most studies included in this analysis were retrospective, and the severity criteria were based on different parameters in different studies, it will be necessary to explore these conclusions in greater detail.
“Being pregnant is clearly associated with experiencing a severe COVID-19 characterized by a cytokine storm. The SARS-COV-2 epidemic should serve as an impetus for [research on] pregnant women diagnosed with COVID-19, and map out salient risk factors associated with its severity.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.