New evidence strongly suggests that COVID-19 disease causes an increased risk of preeclampsia and preterm birth in those who have an infection while pregnant, according to a retrospective observational study published in the American Journal of Obstetrics and Gynecology. Though the study was observational, its primary finding was a dose-response relationship between the severity of COVID-19 disease and the likelihood of preeclampsia or preterm birth, fulfilling a key criterion for establishing causality in an association.
“The fact that 43% (13/30) of the cases of preeclampsia diagnosed after SARS-Cov-2 infection were preterm preeclampsia (< 37 weeks) suggests that COVID-19 may be a cause for medically indicated preterm birth that contributes to the excess preterm birth delivery rate previously reported,” wrote Jonathan Lai, MD, of the Fetal Medicine Research Institute of King’s College Hospital, London, and colleagues. The study also found an increased likelihood of COVID-19 disease in those who had preeclampsia before their infection. “Whether preeclampsia can predispose COVID-19 some cases, or that the two conditions may co-occur because they share similar risk factors requires further investigation,” the authors wrote.
It’s also unclear whether the increased risk of pre-eclampsia is contributing to the higher preterm birth risk, according to Linda Eckert, MD, a professor of Ob.Gyn. at The University of Washington who specializes in maternal immunization.
“COVID is linked to preeclampsia in this study, and COVID is linked to preterm birth,” Dr. Eckert said in an interview. “The question of whether preeclampsia leading to preterm birth is also linked to infection is not possible to tease out in this study as all the factors are likely interrelated. There is a relationship between COVID and preterm birth absent preeclampsia.”
The researchers retrospectively examined data from 1,223 pregnant women who tested positive for SARS-CoV-2 between February 2020 and March 2021 at any of 14 National Health Service maternity hospitals in the United Kingdom. The researchers compared the severity of disease among the women with their risk of preeclampsia as a primary outcome, followed by the outcomes of preterm birth and gestational age at delivery.
COVID-19 infections were classified as asymptomatic, mild illness (lacking shortness of breath, dyspnea, or abnormal chest imaging), moderate illness (evidence of lower respiratory disease but an oxygen saturation of at least 94%), and severe illness (requiring “high dependency or intensive care secondary to respiratory impairment/failure or multiorgan dysfunction”).
The researchers adjusted their analysis of preeclampsia to account for prior risk of preeclampsia based on maternal characteristics and medical history. Analysis of preterm birth risk included adjustment for maternal age, weight, height, race, method of conception, chronic hypertension, smoking, and diabetes.
Preeclampsia occurred in 4.2% of the women, and 17.6% of the women had a preterm birth. In addition, 1.3% of the cohort had a miscarriage, and there were 10 (0.81%) fetal deaths. Since 21 cases of preeclampsia occurred before the women tested positive, the researchers removed those cases from the analysis. Among the remaining 30 cases, 13 women had preterm preeclampsia and 17 had term preeclampsia.
When the researchers compared the study population’s risk of preeclampsia with that of a separate population with similar risk factors, they found a dose-response increased risk in those with COVID-19 infections. While 1.9% of asymptomatic patients had preeclampsia, incidence was 2.2% in patients with mild disease, 5.7% in those with moderate disease, and 11.1% in those with severe disease. Women with severe COVID-19 tended to be older and to have a higher body mass index.
After adjustments, women were nearly five times more likely to develop preeclampsia if they had severe COVID-19 compared to women with asymptomatic infection (adjusted relative risk [aRR] = 4.9). Those with moderate or severe disease had triple the risk of preeclampsia compared to those with mild or asymptomatic infection (aRR = 3.3).
To investigate whether having preeclampsia predisposes women to develop COVID-19 disease, the researchers compared the women who had preeclampsia before their infection with women in the study who never developed preeclampsia. Although they found a trend toward higher risk of moderate or severe COVID-19 following preeclampsia, the association was not significant before or after adjustment.
The researchers also found a dose-response relationship in risk of preterm birth. While 11.7% of asymptomatic patients had preterm birth, the incidence was 12.8% in those with mild COVID-19, 29.9% in those with moderate disease, and 69.4% in those with severe disease. Women with severe disease were more than five times more likely to have a preterm birth than were women with an asymptomatic infection (aRR = 5.64), and the risk of preterm birth was 2.5 times greater in women with moderate disease (aRR = 2.47).
“Moreover, there was a dose-response relationship between gestational age at delivery and the severity of SARS-CoV-2 infection,” the authors reported. Mean gestational age at delivery was 38.7 weeks in asymptomatic women compared to 37.5 weeks for those with moderate disease and 33 weeks in those with severe disease (P < .001).
”The more severe the infection with SARS-CoV-2, the greater the risk of preeclampsia and preterm birth,” the authors wrote. “SARS-CoV-2 infection can lead to endothelial dysfunction, intravascular inflammation, proteinuria, activation of thrombin, and hypertension, which are all features of preeclampsia. Therefore, a causal relationship must be considered.”
A dose-response association is only one criterion for causality, however, so it’s still premature to say definitively that a causal relationship exists, Dr. Eckert said.
“More investigation in different populations across different ethnicities is needed before causality can be confidently assured,” she said.
Anthony Sciscione, DO, director of maternal-fetal medicine and the ob.gyn. residency at ChristianaCare in Delaware, agreed that the precise relationship between the two remains unresolved.
”We don’t know what causes preeclampsia,” but “we strongly suspect it has to do with a placental dysfunction, or endothelial dysfunction, and it’s really clear that women who get COVID have a much higher risk of preeclampsia,” Dr. Sciscione said in an interview. It’s possible that no real relationship exists between the two (or that greater surveillance of women with COVID-19 is picking up the relationship) but it’s more likely that one of two other situations is happening, Dr. Sciscione said. Either COVID-19 involves a syndrome that looks like preeclampsia in pregnant women, or the disease “leads to the cascade that causes preeclampsia,” he said.
One clear clinical implication of these findings is that “women who have severe COVID early in pregnancy may need to be watched more closely for signs of developing preeclampsia” and that “women with severe COVID are more likely to have preterm births,” Dr. Eckert said. “This absolutely lends support to the need for pregnant individuals to receive a COVID vaccine.”
Dr. Sciscione said his experience counseling pregnant patients about the vaccine has made it clear that patients generally want to do what’s safest for their babies and may feel uneasiness about the safety of the vaccine. “The truth is, now there’s mounting evidence that there are fetal effects, not just maternal effects” from COVID-19 disease. He added that preterm birth is associated with a variety of long-term adverse outcomes, such as cerebral palsy and learning disabilities.
“At this time it’s critically important that women be offered and get the vaccine because we know that people that are vaccinated don’t get as sick,” Dr. Sciscione said.
The research was funded by the Fetal Medicine Foundation and the National Institutes of Health. The authors and Dr. Eckert have no disclosures. Dr. Sciscione is the associate editor of the American Journal of Obstetrics and Gynecology, where the study appeared.