SARS-CoV-2 infection during pregnancy may cause preeclampsia

SARS-CoV-2 infection during pregnancy was associated with higher odds of preeclampsia, and this relationship may be causal, according to a study published by the American Journal of Obstetrics and Gynecology.

Agustin Conde-Agudelo, MD, MPH, PhD, and Roberto Romero, MD, DMedSci, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, selected 28 studies that assessed the relationship between SARS-CoV-2 infection during pregnancy and preeclampsia between Dec. 1, 2019, and May 31, 2021, for their systematic review. The studies involved 790,954 pregnant women, of whom 15,524 were diagnosed with SARS-CoV-2 infection.

Fourteen of these studies were prospective cohort studies, 12 were retrospective cohort studies and two were cross-sectional. Four studies specifically evaluated the association between SARS-CoV-2 infection during pregnancy and preeclampsia. The other 24 compared maternal and perinatal outcomes between pregnant women who did and did not have SARS-CoV-2 infection, including preeclampsia risks.

Based on the 26 studies with unadjusted ORs, women with SARS-CoV-2 infection were significantly more likely to develop preeclampsia compared with those without the infection (7% vs. 4.8%; pooled OR = 1.62; 95% CI, 1.45-1.82; P < .00001).

After a meta-analysis of adjusted ORs, Conde-Agudelo and Romero again found that SARS-CoV-2 infection during pregnancy was associated with a significant increase in the odds of preeclampsia (pooled OR = 1.58; 95% CI, 1.39-1.8; P < .0001).

Additionally, the researchers found a statistically significant increase in the odds of preeclampsia with severe features (OR = 1.76; 95% CI, 1.18-2.63); eclampsia (OR = 1.97; 95% CI, 1.01-3.84); and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (OR = 2.1; 95% CI, 1.48-2.97).

Conde-Agudelo and Romero further found that while asymptomatic and symptomatic SARS-CoV-2 infections both significantly increased the odds of preeclampsia, the odds were higher among patients with symptomatic illness (OR = 2.11; 95% CI, 1.59-2.81) than among those with asymptomatic illness (OR = 1.59; 95% CI, 1.21-2.1).

Overall, pregnant women with SARS-CoV-2 infection faced a 62% greater risk of developing preeclampsia than those without SARS-CoV-2 infection, and the researchers explained why this relationship may be causal.

Conde-Agudelo and Romero noted the dose-gradient response effect as women with symptomatic SARS-CoV-2 infections faced greater risks for preeclampsia than those with asymptomatic infections.

Also, the researchers found evidence of a meaningful temporal relationship between SARS-CoV-2 infection and preeclampsia, with a 3.79-week interval between SARS-CoV-2 infection diagnosis and preeclampsia diagnosis.

The virus binds with cell membrane angiotensin-converting enzyme 2 (ACE2) receptors, an important component of the renin-angiotensin system (RAS), the researchers said. The RAS regulates placental function, but this binding then downregulates it, possibly influencing preeclampsia’s pathophysiology, Conde-Agudelo and Romero said.

SARS-CoV-2 proteins also interact with proteins that are involved in vital placenta functions, the researchers said, possibly leading to interactions that could be involved in the development of preeclampsia, such as trophoblast invasion, migration, proliferation and differentiation processes.

Furthermore, SARS-CoV-2 infection upregulates sFlt-1 and endoglin, vasoconstrictive peptides, nitric oxide modulators and prothrombotic-related molecules, potentially impacting molecular pathways related to preeclampsia’s pathogenesis including angiogenesis, hypoxia, inflammatory signaling, thrombin/platelet activation and vasoactive peptide imbalance.

Conde-Agudelo and Romero called their rigorous methodology for systematic review and meta-analysis of observational studies the main strength of their study. They also cited the relatively large number of studies they used involving global populations and additional unpublished data.

However, only one of the studies reported on the temporality of the association between SARS-CoV-2 infection during pregnancy and preeclampsia. Also, only half of the studies controlled for potential confounding factors.

There was evidence of funnel plot asymmetry as well, indicating possible publication bias, although the researchers said that “the potential impact of publication bias is probably trivial.” There was also a small number of studies reporting on the relationship between SARS-CoV-2 infection and preeclampsia based on the infection’s severity.

In the meanwhile, Conde-Agudelo and Romero advise health care professionals to be aware of this increased risk so they can plan close monitoring and adopt early effective interventions to reduce risks to mothers and their fetuses and neonates.