COVID-19 illness during pregnancy has been associated with adverse maternal and pregnancy outcomes [1]. Due to the increased risk of severe illness and complications, including stillbirth, from SARS-CoV-2 infection during pregnancy, COVID-19 vaccines were recommended for all pregnant women [2]. Pregnant women were not included in randomized clinical trials of COVID-19 vaccines. To monitor vaccine safety during pregnancy nationally, the Centers for Disease Control and Prevention (CDC) established the COVID-19 Vaccine Pregnancy Registry (C19VPR) in January 2021 [3].

Affecting nearly 16% of U.S. women at delivery [4], hypertensive disorders of pregnancy (HDP) encompass a spectrum of diagnoses varying in severity and implications, including prepregnancy (chronic) hypertension, gestational hypertension, preeclampsia, and eclampsia. HDP are an important public health concern due to their association with maternal and fetal/neonatal morbidity and mortality [5], and represent an important outcome to monitor in vaccine safety surveillance. Among published studies investigating the risk of HDP following COVID-19 vaccination, three were conducted in the United States. Two large, retrospective studies using electronic health record (EHR) data found no differences in clinical subcategories of HDP (gestational hypertension, preeclampsia, or eclampsia) between pregnant women who had received ≥1 dose of an mRNA COVID-19 vaccine during pregnancy compared to propensity-score-matched unvaccinated pregnant women [6,7]. Neither study examined HDP as a composite indicator. A smaller retrospective study, also using EHR data, found no association between HDP and receipt of a primary series mRNA COVID-19 vaccine; however, most participants received a first dose during the third trimester [8]. Meta-analyses including these and Israeli studies reported no association between COVID-19 vaccination and HDP [9–11]. However, several studies in the meta-analyses did not control for confounders such as demographic, clinical, lifestyle, or geographic factors [8,12–14]; few included participants who were vaccinated early in pregnancy [7,15–17].

To monitor for risk of HDP following receipt of ≥1 COVID-19 vaccine dose during or just prior to pregnancy, we compared the proportion of C19VPR participants who self-reported HDP after vaccination with a matched cohort unvaccinated during pregnancy. We also assessed whether any associations were modified by vaccine manufacturer, timing of vaccination during pregnancy, or COVID-19 illness in pregnancy. As a secondary objective, we evaluated risk of HDP among a subset of matched pairs with data on COVID-19 illness during pregnancy.

Of the 8030 C19VPR participants eligible for the study, 8024 (99.9%) were matched to a PRAMS participant on age, race and ethnicity, and gestational age at delivery (Fig. 1). Six C19VPR participants were unable to be matched due to few PRAMS participants identifying as NH-Native Hawaiian or Pacific Islander or NH-American Indian and Alaska Native; unmatched participants were not included in analyses.

There were significant differences (p-values <0.0001) in the distributions of HDP, BMI, and diabetes by vaccination status (Table 1). Compared to PRAMS participants, more C19VPR participants had self-reported HDP (15.0% vs 12.0%) and normal weight (55.9% vs 43.9%); fewer were underweight (BMI ≤18.5 kg/m²; 2.1% vs 3.7%), overweight (BMI 25.0–29.9 kg/m²; 24.4% vs 26.4%), or obese (BMI ≥ 30 kg/m²; 17.6% vs 26.1%). Fewer C19VPR participants reported diabetes during pregnancy compared to PRAMS participants (9.4% vs 11.5%). C19VPR participants delivered their infants predominately in 2021 (98.9%) whereas PRAMS participants delivered in 2019 (17.4%), 2020 (54.5%), and 2021 (28.1%). Fig. 2 displays the onset of the COVID-19 pandemic, timing of availability of vaccines, and month of delivery for C19VPR and PRAMS participants. Among matched pairs, PRAMS pregnancies ended an average of 11.4 calendar months (standard deviation 8.9) before C19VPR pregnancies. Among C19VPR participants, 3.4% reported COVID-19 illness during pregnancy compared to 2.9% of PRAMS participants; however, status was unknown for 49.7% of PRAMS participants, as not all states in 2020 and 2021 collected this data. Among C19VPR participants, 60.4%, 37.3%, and 2.3% reported Pfizer-BioNTech, Moderna, and Janssen, respectively, as the manufacturer of their first COVID-19 vaccine dose. About half (51.9%) of C19VPR participants received their first registry-eligible dose prior to 20 weeks’ gestation; median gestational age of first vaccination within this group was 11.1 weeks. C19VPR participants resided in all 50 states, the District of Columbia, and the U.S. Virgin Islands; PRAMS participants resided in the District of Columbia, Puerto Rico, and all states except California, Idaho, Indiana, Nevada, Ohio, South Carolina, Texas, and Vermont (data not shown).

HDP was associated with each of the covariates listed in Table 2. HDP generally increased with age, with 18.4% of those aged 40+ years reporting HDP. HDP was highest among participants identifying as NH-Black (19.5%) and lowest among NH-Asian (7.5%). HDP was highest among participants with obesity class I (BMI 30–34.9 kg/m²), II (BMI 35.0–39.9 kg/m²), and III (BMI ≥40.0 kg/m²) (20.5%, 26.7%, 32.3%, respectively), diabetes (20.8%), and COVID-19 illness during pregnancy (16.4%). HDP substantially increased with year of delivery; 9.3% of participants who delivered in 2019 reported HDP compared to 14.6% of those who delivered in 2021 (Table 2). This pattern was similar among both C19VPR and PRAMS participants (Supplemental Fig. 2).

In this matched cohort study, we compared self-reported HDP diagnoses among pregnancy registry participants who received a COVID-19 vaccine just prior to or during pregnancy to those of a matched, unvaccinated cohort. We found a 24% higher risk of reporting HDP, defined as high blood pressure that started during this pregnancy or pre-eclampsia, in the registry cohort. Risk did not differ by vaccine manufacturer or gestational age at time of vaccination. Among the matched pairs with COVID-19 illness during pregnancy data available, we also observed a 28% increase in the risk of HDP among participants reporting COVID-19 illness in pregnancy compared with those reporting no COVID-19 illness in pregnancy.

Most previous studies have not reported statistically significant risks of HDP among women who received the COVID-19 vaccine during pregnancy compared to pregnant women who did not receive the COVID-19 vaccine [6–17,28,29]; however, point estimates in several studies were elevated. [7,9,10,14,29] For example, the Vaccine Safety Datalink evaluated 39,201 pregnant women (21.8% vaccinated) across eight integrated healthcare centers in the United States. Odds of gestational hypertension or preeclampsia were 1.08 (95%CI: 0.96, 1.22) and 1.10 (95%CI: 0.97, 1.24), respectively, among women who received the COVID-19 vaccine in pregnancy compared to those who did not [7]. Similarly, in the International INTERCOVID-2022 prospective cohort study, the risk ratio of HDP among 1478 women receiving their first COVID-19 vaccine during pregnancy compared to 1420 unvaccinated pregnant women was 1.30 (95%CI: 0.94, 1.80) [29]. Two studies reported a statistically significant increase (p-values <0.05) in the risk of HDP associated with periconceptional vaccination. [30,31] In a study of 3911 women undergoing assisted reproduction in China, those who received an inactivated COVID-19 vaccine before embryo transfer had a higher HDP risk (RR: 1.45, 95%CI: 1.10, 1.92), while women vaccinated with a recombinant COVID-19 vaccine prior to embryo transfer did not. [31] In a study of 80,253 pregnancies in Ontario, Canada, those receiving any COVID-19 vaccine in the periconceptional period or in the first trimester had a slightly higher risk of HDP (adjusted hazard ratio: 1.10, 95%CI: 1.03, 1.17) compared to unvaccinated pregnancies [30]. Therefore, our study is not the first to identify a higher risk of HDP among COVID-19-vaccinated pregnant women. However, specific types of COVID-19 vaccines received, the time interval between receipt of vaccination and pregnancy, and the ability to account for potential confounding differed by study.

Several methodological differences between our study and previous studies may contribute to the modestly different findings. First, C19VPR included participants vaccinated prior to pregnancy and in the first trimester, whereas the majority of previous studies included mostly women vaccinated in the second and third trimesters [6,8,12–14,28]. Although we found no statistically significant difference in risk by timing of vaccination, earlier vaccination allowed more time for hypertension to develop and opportunities to be diagnosed with vaccination occurring earlier in pregnancy. Second, most of the previously published studies were conducted outside the United States among populations differing in demographics, access to healthcare, and stressors experienced during the pandemic. Such differences may affect underlying risk or diagnosis of HDP. Third, the three prior U.S.-based studies [6–8] relied on electronic medical records to ascertain HDP diagnosis, whereas we used self-reported data, which may be subject to higher rates of misclassification. Fourth, the question asked of participants in this study (whether they had high blood pressure that started during pregnancy or pre-eclampsia) did not allow us to differentiate participants’ HDP diagnoses by severity. In contrast, other studies have examined clinical subcategories of HDP to assess associations based on diagnostic severity. For example, Vesco et al. analyzed gestational hypertension (less severe) separately from the combined outcome of pre-eclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome (more severe) [7]. While a large sample size increased our sensitivity to detect any association between COVID-19 vaccination and any HDP, our results may have more limited clinical implications because worse pregnancy outcomes (e.g., maternal seizure or stroke, preterm birth) are correlated with HDP severity. C19VPR data have not shown an association between COVID-19 vaccination during pregnancy and an increased risk of adverse outcomes that are often associated with severe HDP, including preterm birth or perinatal mortality (Madni et al., under review), which suggests the severity of HDP in this cohort may have been relatively low. Finally, the American College of Obstetricians and Gynecologists classifies hypertension diagnosed prior to 20 weeks’ gestation as chronic hypertension [32]. We included C19VPR participants with hypertension diagnosed after vaccination, even if diagnosed prior to 20 weeks, as it was consistent with our study objective. Furthermore, the timing of hypertension diagnosis was not available in PRAMS. Thus, we could not exclude those diagnosed with hypertension prior to 20 weeks. In contrast, other studies of COVID-19 vaccination either excluded all participants with hypertension diagnosed prior to 20 weeks’ gestation, categorized them as chronic hypertension even if identified after early vaccination, or only included participants with chronic hypertension who were diagnosed with superimposed preeclampsia, eclampsia, or HELLP syndrome [6–8,30]. If COVID-19 vaccination is associated with HDP, it is possible that exclusion of participants vaccinated early in pregnancy with subsequent hypertension onset prior to 20 weeks in these other studies could have underestimated the risk of HDP.

The etiology of HDP is complex and likely multifactorial given the heterogeneity of the disease [33]. There are at least two biological mechanisms that have been proposed that may support the observations in our study. First, the SARS-CoV-2 virus spike protein binds to the angiotensinogen-converting enzyme-2 (ACE2) receptors on host cells, including endothelial and placental cells. As a result, ACE2 receptors are downregulated, disrupting the renin-angiotensin system (RAS) that maintains blood pressure homeostasis, potentially leading to increased blood pressure [34,35]. Because COVID-19 mRNA vaccines encode the SARS-CoV-2 virus spike protein, elevations in blood pressure following vaccination may occur through the same proposed pathway [36,37]. Second, vaccines activate the release of pro-inflammatory cytokines as part of the body’s immune response; the level of inflammation varies by the recipient’s genetic background and previous level of immunity [38]. It is possible that elevations in blood pressure are due to an exaggerated systemic inflammatory response [39]. Imbalances between immune response and inflammation early in pregnancy may alter placental vascularity, leading to reduced blood flow through the placenta and to the fetus, contributing to the development of HDP [40,41]. Among non-pregnant populations, increased blood pressure following COVID-19 vaccination has been observed to affect fewer than 5% of vaccinees and generally was transient, with duration up to several weeks [42,43]. Whether increased blood pressure after vaccination during pregnancy would be sustained or substantial enough to lead to a diagnosis of HDP is unclear. The complexity of the pathophysiology of HDP and the lack of an association between the timing of vaccine receipt and HDP diagnosis in our study make interpretation challenging. However, given the association of HDP with adverse pregnancy outcomes as well as the relationship between HDP and increased cardiovascular risk later in life, the possible short- and long-term physiologic effects of COVID-19 vaccination on blood pressure merit further investigation, particularly in populations no longer immunologically naïve [44,45].

This study had the ability to validate self-report of HDP by C19VPR participants but is also subject to multiple limitations. All data are self-reported and subject to misclassification. We found high absolute agreement (87%) between self-report of HDP by C19VPR participants and medical record documentation. Compared with two validation studies of HDP conducted in three PRAMS jurisdictions [46,47], our sensitivity estimate (80%) fell within the reported ranges (66.7% in Maryland, 76.7% in New York City, and 85.1% in Vermont), while our specificity estimate (91%) was slightly lower than those reported in New York City (96.1%) and Vermont (93.7%). Participants were asked about HDP using similar questions in C19VPR and PRAMS surveys to reduce potential differential misclassification. However, an important limitation of our study is that nearly half of C19VPR participants reported working in healthcare [3]. During the pandemic, stress was notably high among healthcare personnel [48]. This high proportion of healthcare workers likely introduced unmeasured differences in education level between C19VPR and PRAMS participants. In addition, healthcare workers may differ from non-healthcare workers in health-seeking behaviors or willingness to report adverse health effects, potentially introducing reporting bias that may overestimate HDP risk given a good sensitivity and slightly lower specificity.

Exposure status (i.e., vaccinated vs. unvaccinated) and date of vaccination was likely correct for C19VPR participants as vaccination status was reported to V-safe and subsequently confirmed during enrollment into the C19VPR. Nearly 75% of PRAMS participants were pregnant prior to the availability of COVID-19 vaccines. Among the remaining 25% of PRAMS unvaccinated participants, it is possible that some may have been vaccinated prior to pregnancy or vaccine status was misreported, biasing results toward the null.

All pregnancies in the C19VPR started after mid-March 2020, when COVID-19 was declared a pandemic, whereas about one-third of PRAMS participants had already delivered prior to the pandemic. Being pregnant during the COVID-19 pandemic may have increased the risk for HDP [49,50], contributing to the higher incidence of HDP observed among C19VPR participants. The pandemic was associated with a wide array of disruptions and stressors that differed by location and changed over time (e.g., shutdowns, virus burden) [51–53] The pandemic altered access to healthcare and clinical practice, including for example, blood pressure surveillance. Increased medical scrutiny may have led to more diagnoses, while reduced in-person care may have led to underdiagnosis. If reporting accuracy differed over time, this could bias relative risk estimates in unpredictable directions. Similarly, over the six-month eligibility window, the availability of the COVID-19 vaccine by manufacturer varied during the study period, and the choice of manufacturer differed periodically by localities. Analyses assessing effect modification by vaccine manufacturer or gestational age at vaccination may reflect temporal or contextual differences rather than biological effects.

Furthermore, rates of HDP have been increasing annually for decades [4,54]. Data from the U.S. National Vital Statistics System show an average annual increase in HDP of 3.6% each year from 1989 through 2020 [21]. We observed increases in HDP over time with a higher percentage of participants reporting HDP in 2021 and 2022 compared to 2019 and 2020. Because PRAMS participants delivered on average 11 months earlier than C19VPR participants, some of the difference in HDP risk may be attributable to temporal trends. C19VPR and PRAMS also differ by participant recruitment methods, the modes of data collection, and timing of survey completion relative to the end of pregnancy, which may have contributed to reporting and recall biases affecting relative risk estimates in unpredictable directions.

Other limitations of our analyses include the inability to adjust for potential confounding factors such as alcohol use, smoking, use of assisted reproductive technologies, medical history, gestational weight gain, socioeconomic status, and urban residence, to name a few, as these data were not collected by both C19VPR and PRAMS. A substantial majority (93%) of C19VPR participants reported urban residence [3], which has been associated with HDP [54]. Similarly, we had limited ability to examine the influence of COVID-19 illness in pregnancy, as not all PRAMS jurisdictions collected this data; illness may also be under-reported and those who chose to provide data on illness history may differ from those who chose to leave the question unanswered (i.e., missing data not random). While the overall study population was large, results from some stratified models had wide CIs because of relatively smaller sample sizes. For those diagnosed with HDP, the time interval between vaccination and HDP onset could not be meaningfully evaluated because the onset date of HDP, often initially asymptomatic, is directly related to opportunities for routine blood pressure screening during prenatal visits, which typically occur in the course of a standardized gestational age-based appointment schedule. Therefore, it is possible that some C19VPR participants with undiagnosed HDP prior to vaccination were included in analyses, which would overestimate HDP risk. Our study findings may have limited generalizability. Our study population consisted of nulliparous pregnant women who were predominantly NH-White, older than the U.S. average age at delivery, and likely SARS-CoV-2-infection-naïve at the time of vaccination. The current U.S. population is no longer immunologically naïve; previous COVID-19 illness, COVID-19 vaccination, or both are common [55]. The vaccines received by C19VPR participants were the first available COVID-19 vaccines based on the native SARS-CoV-2 virus rather than subsequent circulating variants.

Our findings suggest that early in the pandemic, relative risk of HDP was similar among women who experienced COVID-19 illness during pregnancy and women who enrolled in V-safe and received a COVID-19 vaccine during, or just prior to, pregnancy. Previous studies have documented small, but not statistically significant (p-values >0.05), increased risk of HDP following COVID-19 vaccination. In contrast, an increased risk of HDP associated with SARS-CoV-2 infection has been well-documented and of a larger magnitude [23,56]. A 2022 meta-analysis of 26 studies showed that SARS-CoV-2 infection during pregnancy was associated with higher odds of developing preeclampsia (62%), preeclampsia with severe features (76%), eclampsia (97%), and HELLP (110%); a dose-response was also noted, with more severe COVID-19 symptoms related to higher odds of more severe HDP [56]. One prospective, population-based cohort study following over 312,000 pregnancies reported no association with SARS-CoV-2 infection at any time during pregnancy and HDP after 20 weeks’ gestation. [57]

During the COVID-19 pandemic, vaccination was recommended at any time during pregnancy because of the demonstrated increased risks of severe illness and pregnancy complications in unvaccinated pregnant women with COVID-19 [1]. One important consideration after the pandemic is that many studies evaluating risks of SARS-CoV-2 infection or COVID-19 vaccination were conducted among populations that were largely immunologically naïve to SARS-CoV-2. In 2025, women of childbearing age have varying degrees of vaccine- and infection-induced immunity. Therefore, findings from the early period of the COVID-19 pandemic are of uncertain significance for pregnant women in the post-pandemic era.

We found an increased risk of HDP after COVID-19 vaccination in the C19VPR cohort; however, our findings are subject to multiple limitations. These findings do not represent causal associations. Updated risk estimates of HDP associated with SARS-CoV-2 infection and continued safety monitoring of COVID-19 vaccines, are needed to update risk-benefit comparisons and inform decision-making. Vaccine studies that include data on the timing of vaccine receipt, the time interval between vaccination and initial HDP diagnosis, and COVID-19 illness and timing during pregnancy would provide important additional insights.