We found that SARs-CoV-2 infection in pregnancy is associated with significantly higher incidence of HDP. After controlling for other variables, patients with SARs-CoV-2 infections were nearly 4 times more likely to have a diagnosis of HDP compared to patients without a history of SARs-CoV-2 infection in pregnancy. SARs-CoV-2 infection was the third highest contributor to HDP diagnoses, only behind previous history of preeclampsia and comorbid chronic hypertension (Fig. 1). Overall, 31.4% of patients with a COVID-19 during their pregnancy developed a HDP, compared to 13.3% of controls. Our results are consistent with the available literature18, 24. While one meta-analysis9 did not demonstrate this association, the studies included had heterogenous designs, different primary outcomes, and most lacked a control group. The one study within the meta-analysis with matched controls found a higher incidence of preeclampsia in pregnant patients with COVID-19 (7.7% vs. 4.3%, OR 1.84, CI 1.00-3.36) .
Rosenbloom and Raghuraman (2021) found that a COVID-19 diagnosis conferred an approximate 2-fold risk of HDP (hazard ratio (HD) 1.93; CI 1.13–3.31) . This was especially true if COVID-19 was diagnosed prior to 32 weeks’ gestation, with the HR of 2.17 (CI 1.11–4.24). This is consistent with our findings. Madden et al (2021) found overall rates of gestational hypertension of 9.0% and 3.6% (p < 0.001), preeclampsia without severe features of 3.6% and 1.4% (p = 0.034), and preeclampsia with severe features 5.4% and 3.6% (p = 0.12) for patients with and without COVID-19, respectively . They did not report an aggregate risk, however, and they did not control for other variables.
Metz et al. (2021) found that for patients with COVID-19, HDP was the most common indication among preterm births. In contrast to our study, they found a relative risk of 1.61 (95% CI 1.18–2.20) for severe COVID-19, with rates of HDP increasing with the severity of COVID-19 manifestation . However, the impact of confounders was not ascertained. In our study, patients with a positive SARs-CoV-2 test and those who were asymptomatic had the highest likelihood of developing HDP. This is an important finding as patients with positive screening test may be at a higher risk of developing HDP, even if asymptomatic. While COVID-19 conferred a significant increased likelihood of having a diagnosis of HDP in our study, a diagnosis of chronic hypertension and having preeclampsia in a previous pregnancy conferred the greatest risk for HDP. However, COVID-19 remained a significant risk factor for HDP after controlling for these confounders.
Patients with COVID-19 were more likely to have lower absolute lymphocyte count and elevated CRP and uric acid. There was a trend toward a higher ferritin level. However, it should be noted that laboratory values were not analyzed as a predictor of HDP in our study given the relatively small proportion of control patients with inflammatory markers and the lack of a standard COVID-19 laboratory order-set across institutions. However, these results are consistent with the inflammatory state associated with COVID-19. Inflammation has been shown to play a significant role in the pathogenesis of HDP [26–28]. Furthermore, HDP has been associated with alterations in proinflammatory cytokines [26–27, 29]. The inflammatory response is a central clinical characteristic of SARs-CoV infection, with well-established extrapulmonary systemic hyperinflammation secondary to a proinflammatory state driven by the release of host cytokines [30–34]. Thus, it is likely that the acute inflammatory state, even if subclinical, may provoke or exacerbate HDP.
It has been reported that COVID-19 modulates angiotensin-converting enzyme 2 (ACE-2) within the placenta, which may provide one component in the pathogenesis of HDP in pregnancies complicated by SARs-CoV-2 infection . ACE-2 has been shown to be heavily expressed in the placenta, including cells involved in decidualization, trophoblast invasion, vascular remodeling, and placental blood flow . ACE2 is upregulated in pregnancy, and alterations in the levels of angiotensin II (vasoconstrictor) and angiotensin-(1–7) (vasodilator) caused by SARs-CoV-2 can lead to vasoconstriction, inflammation and pro-coagulopathic effects seen in HDP20. Furthermore, Mendoza et al (2020) showed abnormalities in angiogenic factors related to COVID-19 infection that resulted in increased risk of a preeclampsia-like syndrome . Finally, it has been shown that placentas of women infected with SARs-CoV-2 have higher rates of decidual arteriopathy when compared to controls . Together, these reports provide compelling evidence for the pathogenesis behind the observed increased risk of HDP in pregnant patients with COVID-19.
The timing of SARs-CoV-2 infection appears to be important. Early infection (before 32 weeks’ gestation) was associated with a significantly increased risk of HDP compared to negative controls. Infections occurring after 32 weeks’ gestation showed a trend toward increased risk of HDP, however was not statistically significant. Our study was not powered for this outcome and it is likely that a larger sample would have generated a significant increased risk for late SARs-CoV-2 infection compared to COVID-19 negative controls. When comparing only COVID-19 positive pregnancies, early infection conferred a significantly higher risk for HDP than late infection. This observation is consistent with the inflammatory explanation of increased HDP risk in COVID-19. Through modulation of angiogenic factors and inflammatory cytokines, it is likely that COVID-19 exerts maximal impact on placental physiology at earlier gestations, enabling these physiologic changes to manifest as HDP over time.
Our study has several strengths. Most studies to date that have reported increased risk of HDP associated with COVID-19 have lacked a control group. Our study incorporated a control group of unaffected patients. We compared COVID-19 cases to 3 controls that delivered in temporal proximity to the index case, thus eliminating inherent temporal biases as a result of fluctuations in the prevalence of COVID-19 cases. Furthermore, a large control group allowed us to conduct detailed statistical analyses to elucidate an association between SARs-CoV-2 infections and HDP. Other studies to date have lacked a larger control group.
The main limitation of this study is the retrospective design. With any retrospective study, there is potential misclassification based on nonreported or incorrectly recorded ICD-10 codes.
Additionally, given the scarcity of SARs-CoV-2 diagnostic tests early in the study period, approximately one-third of patients did not have a diagnostic test. This increases the potential for misclassification (e.g. including an asymptomatic COVID-19 positive case in the control group). However, we believe that this would potentially decrease the strength of association of COVID-19 and HDP, therefore the association found in this study may be an underestimate. There is also the possibility that patients could have tested positive at an outside institution during their pregnancy but did not disclose their positive test. Additionally, our study was underpowered for analysis of important subcategories, such as the effects of inflammatory markers on HDP within COVID-19 positive cases. It is recognized that there are overlapping signs (e.g. transaminitis) and symptoms (e.g headache) associated with COVID-19 and HDP. Accordingly, clinicians should take these overlapping features into account when making clinical decisions regarding HDP in COVID-19 positive pregnant patients.