Objective
To examine the relationship between SARS-CoV-2 infection during pregnancy and the risk for preeclampsia.
Data Sources
MEDLINE, Embase, POPLINE, CINAHL, LILACS, and the World Health Organization COVID-19, Chinese, and preprint databases (all from December 1, 2019, to May 31, 2021). Google Scholar, bibliographies, and conference proceedings were also searched.
Study Eligibility Criteria
Observational studies that assessed the association between SARS-CoV-2 infection during pregnancy and preeclampsia and that reported unadjusted and/or adjusted risk estimates and 95% confidence intervals or data to calculate them.
Study Appraisal and Synthesis Methods
The primary outcome was preeclampsia. Secondary outcomes included preeclampsia with severe features, preeclampsia without severe features, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Two reviewers independently reviewed studies for inclusion, assessed their risk of bias, and extracted data. Pooled unadjusted and adjusted odds ratios with 95% confidence intervals, and 95% prediction interval were calculated. Heterogeneity was quantified using the І 2 statistic, for which І 2 ≥30% indicated substantial heterogeneity. Subgroup and sensitivity analyses were performed to test the robustness of the overall findings.
Results
A total of 28 studies comprising 790,954 pregnant women, among which 15,524 were diagnosed with SARS-CoV-2 infection, met the inclusion criteria. The meta-analysis of unadjusted odds ratios showed that the odds of developing preeclampsia were significantly higher among pregnant women with SARS-CoV-2 infection than among those without SARS-CoV-2 infection (7.0% vs 4.8%; pooled odds ratio, 1.62; 95% confidence interval, 1.45–1.82; P <.00001; І 2 =17%; 26 studies; 95% prediction interval of the odds ratio, 1.28–2.05). The meta-analysis of adjusted odds ratios also showed that SARS-CoV-2 infection during pregnancy was associated with a significant increase in the odds of preeclampsia (pooled odds ratio, 1.58; 95% confidence interval, 1.39–1.80; P <.0001; І 2 =0%; 11 studies). There was a statistically significant increase in the odds of preeclampsia with severe features (odds ratio, 1.76; 95% confidence interval, 1.18–2.63; І 2 =58%; 7 studies), eclampsia (odds ratio, 1.97; 95% confidence interval, 1.01–3.84; І 2 =0%, 3 studies), and HELLP syndrome (odds ratio, 2.10; 95% confidence interval, 1.48–2.97; 1 study) among pregnant women with SARS-CoV-2 infection when compared to those without the infection. Overall, the direction and magnitude of the effect of SARS-CoV-2 infection during pregnancy on preeclampsia was consistent across most prespecified subgroup and sensitivity analyses. Both asymptomatic and symptomatic SARS-CoV-2 infections significantly increased the odds of developing preeclampsial; however, it was higher among patients with symptomatic illness (odds ratio, 2.11; 95% confidence interval, 1.59–2.81) than among those with asymptomatic illness (odds ratio, 1.59; 95% confidence interval, 1.21–2.10).
Conclusion
SARS-CoV-2 during pregnancy is associated with higher odds of preeclampsia.
Introduction
Preeclampsia, a multisystem syndrome that complicates about 5% of pregnancies, is one of the leading causes of maternal mortality worldwide, accounting for approximately 14% of all maternal deaths. , In 2018, preeclampsia was responsible for 5.3% of maternal deaths in the United States. Preeclampsia is also associated with an increased risk for maternal morbidity and perinatal morbidity and mortality worldwide, mainly in low- and middle-income countries. In addition, women with preeclampsia are at a greater risk for developing cardiovascular disease later in life. , Although the etiology of preeclampsia remains unclear, it is currently believed that abnormal placentation leading to later placental malperfusion and dysfunction, syncytiotrophoblast stress, oxidative stress, imbalances in circulating placental angiogenic factors, perturbation of the renin-angiotensin system (RAS), placental senescence, inflammation, endothelial dysfunction, and immune abnormalities influenced by maternal genetics, epigenetics, lifestyle, and environmental factors are involved in the pathophysiology of this disorder.
Why was this study conducted?
Current evidence indicates that urinary tract infections and periodontal disease during pregnancy are associated with an increased risk for preeclampsia. We performed a systematic review and meta-analysis to assess whether SARS-CoV-2 infection during pregnancy also increases the risk for preeclampsia.
Key findings
Pregnant women with a SARS-CoV-2 infection had significantly increased odds of developing preeclampsia when compared to those without the infection (pooled odds ratio, 1.62; 95% confidence interval, 1.45-1.82). Moreover, SARS-CoV-2 infection during pregnancy was associated with increased odds of developing preeclampsia with severe features, eclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome. Both asymptomatic and symptomatic SARS-CoV-2 infections significantly increased the risk for preeclampsia.
What does this add to what is known?
Pregnant women with a SARS-CoV-2 infection are more likely to develop preeclampsia. Healthcare professionals should be aware of this association and closely monitor pregnant women with SARS-CoV-2 infection for early detection of preeclampsia.
In 2008, our group published a systematic review and meta-analysis that demonstrated that urinary tract infection and periodontal disease during pregnancy were associated with a significantly increased risk of preeclampsia. Similar findings were reported in more recent meta-analyses. Several studies have assessed the relationship between viral infections during pregnancy, such as those caused by HIV, , human papillomavirus, , cytomegalovirus, hepatitis B virus, herpes simplex virus, , Epstein-Barr virus, and influenza A (H1N1), and the risk for preeclampsia. The results of these studies have been conflicting. The mechanisms that have been proposed to explain the association between infection during pregnancy and preeclampsia include (1) direct effects of the infectious agents on trophoblast function and the arterial wall, including endothelial injury or dysfunction; (2) acute atherosis; (3) local inflammation that might cause relative uteroplacental ischemia; and (4) indirect effects through exaggerated maternal systemic inflammatory response.
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was first reported in China in December 2019. Individuals of all ages are at risk for infection and severe disease. Current evidence suggests that pregnancy does not increase susceptibility to SARS-CoV-2 infection, but it appears to worsen the clinical course of COVID-19 when compared to nonpregnant females of the same age. , Overall, pregnant women with COVID-19 were at higher risk for intensive care unit (ICU) admission, invasive mechanical ventilation use, need for extra corporeal membrane oxygenation, and maternal death than nonpregnant women with COVID-19.
Three meta-analyses have compared the risk for adverse maternal and perinatal outcomes between pregnant women with and without SARS-CoV-2 infection. , , Results from these studies indicate that pregnant women with SARS-CoV-2 infection have a significant increase in the risk for maternal death, admission to the ICU, preterm birth, and stillbirth when compared to those without SARS-CoV-2 infection. Moreover, infants born to mothers with SARS-CoV-2 infection were more likely to be admitted to the neonatal ICU than those born to mothers without the disease. The relationship between SARS-CoV-2 infection during pregnancy and the risk for preeclampsia has received less attention. This topic is relevant for public health and clinical practice. Hence, we performed a systematic review with the primary aim of compiling and critically assessing the existing evidence about the relationship between SARS-CoV-2 infection during pregnancy and the risk for preeclampsia by using formal methods of systematic review and meta-analytic techniques.
Material and Methods
This systematic review was conducted in accordance with a prospectively registered protocol (PROSPERO number CRD42021239092) and reported in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analyses of observational studies. Both authors independently reviewed studies for inclusion, assessed their risk of bias, and extracted data. Disagreements were resolved through consensus.
Literature search
To identify potentially eligible studies, we searched MEDLINE, Embase, CINAHL, LILACS, the World Health Organization COVID-19 database, China National Knowledge Infrastructure, Wanfang, and preprint databases such as medRxiv, bioRxiv, and search.bioPreprint (all from December 1, 2019, to May 31, 2021). Our search terms included a combination of keywords and text words related to SARS-CoV-2 (“SARS-CoV-2,” “COVID-19,” “2019-nCoV,” “nCov-2019,” “SARS-CoV-19,” “coronavirus,” “betacoronavirus,” and “severe acute respiratory syndrome”), preeclampsia (“preeclampsia,” “eclampsia,” “gestosis, EPH,” “pregnancy toxemia,” “pregnancy-induced hypertension,” “hypertensive disorders of pregnancy,” “gestational hypertension,” “pregnancy-associated hypertension,” and “pregnancy hypertension”), and pregnancy (“pregnancy,” “gestation,” and “gravidity”). Google Scholar, proceedings of congresses on obstetrics, maternal-fetal medicine, pediatrics, and neonatology, reference lists of identified studies, previously published systematic reviews, and review articles were also searched. No language restrictions were applied.
Study selection
We included observational studies that assessed the relationship between SARS-CoV-2 infection during pregnancy and preeclampsia and reported unadjusted and/or adjusted odds ratio (OR) or relative risk (RR) estimates and 95% confidence intervals (CIs) or data to calculate these values. The exposed group were pregnant women with a current or previous diagnosis of SARS-CoV-2 infection at any stage of gestation, which was based on a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result or positive antigen test result in a sample collected from the upper respiratory tract, or a positive result for anti–SARS-CoV-2 antibodies in serum. The unexposed group were pregnant women with a negative RT-PCR or antigen test result in a sample collected from the upper respiratory tract or a negative serum antibody test result, or those who were pregnant and delivered before the pandemic. Given that no routine diagnostic testing for SARS-CoV-2 infection was available at the beginning of the pandemic, we included studies in which pregnant women were assigned to exposed or unexposed groups based on the presence or absence of clinical signs or symptoms and/or computed tomography or radiography images of the chest.
Studies were excluded from the review if they (1) were case series or reports, editorials, comments, reviews, or letters without original data; (2) examined only the relationship between SARS-CoV-2 infection and gestational hypertension (new onset hypertension at ≥20 weeks of gestation in the absence of proteinuria or new signs of end-organ dysfunction); or (3) did not report risk estimates or CIs and sufficient information to calculate these values could not be retrieved. Studies published only as abstracts were excluded if information on methodological issues and results were not clearly reported. If a study included women with preeclampsia and gestational hypertension, it was not considered for inclusion in the review unless the data for women with preeclampsia were extractable or obtainable separately. For multiple or duplicate publications of the same dataset, we included only the most recent or complete study and supplemented it if additional information appeared in other publications.
Outcome measures
The primary outcome was preeclampsia, defined as hypertension (at or after 20 weeks of gestation in a previously normotensive woman, or that precedes pregnancy or is present before 20 weeks of gestation in a woman with preexisting chronic hypertension) accompanied by one or more of the following features at or after 20 weeks of gestation: proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, neurologic complications, , or fetal growth restriction. Secondary outcomes included preeclampsia with severe features, preeclampsia without severe features, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome.
Risk of bias assessment
The risk of bias in each included study was assessed by the judgement of 6 domains that were deemed by the authors to be important for the quality of observational studies evaluating the association between SARS-CoV-2 infection during pregnancy and preeclampsia. Each domain was judged as a “low,” “high,” or “unclear” risk of bias. The domains that were evaluated and how they were interpreted were as follows:
- 1.
Selection of participants – “low risk of bias”: women, both with and without SARS-CoV-2 infection, were recruited from the same population and during the same time period; “high risk of bias”: women, both with and without SARS-CoV-2 infection, were not recruited from the same population or during the same time period.
- 2.
Inclusion in the exposed cohort – “low risk of bias”: ≥90% of included women had a positive RT-PCR or antigen test result or tested positive for the presence of serum SARS-CoV-2 antibodies; “high risk of bias”: <90% of included women had a positive RT-PCR or antigen test result or tested positive for serum SARS-CoV-2 antibodies.
- 3.
Inclusion in the non-exposed cohort – “low risk of bias”: ≥90% of included women had a negative RT-PCR or antigen test result or tested negative for the presence of serum SARS-CoV-2 antibodies, or women were drawn from a historical control group who delivered before the beginning of the COVID-19 pandemic; “high risk of bias”: <90% of included women had a negative RT-PCR or antigen test result or tested negative for serum SARS-CoV-2 antibodies.
- 4.
Loss to follow-up or exclusions – “low risk of bias”: losses to follow-up or nonvalid exclusions <10%; “high risk of bias”: losses to follow-up or nonvalid exclusions ≥10%.
- 5.
Control for confounding factors – “low risk of bias”: the study controlled for potential confounding factors related to both SARS-CoV-2 infection and preeclampsia; “high risk of bias”: the study did not control for potential confounding factors related to both SARS-CoV-2 infection and preeclampsia.
- 6.
Temporality between the exposure and outcome – “low risk of bias”: the study reported the time elapsed between SARS-CoV-2 infection diagnosis and preeclampsia diagnosis; “high risk of bias”: the study did not report the time elapsed between SARS-CoV-2 infection diagnosis and preeclampsia diagnosis.
If there was insufficient information available to make a judgment about the bias of a domain, the domain was scored as having an “unclear risk of bias.”
Data extraction
Data were extracted by using a standardized data collection form. The following information was extracted from each study: first author’s name, date of publication, geographic location of the study, study design, inclusion and exclusion criteria, characteristics of the study population, sample size, case definition, tests used for diagnosing SARS-CoV-2 infection, gestational age at diagnosis of SARS-CoV-2 infection, severity of SARS-CoV-2 infection, criteria used to include women in the unexposed group, mean or median time elapsed between SARS-CoV-2 infection diagnosis and preeclampsia diagnosis, definition and severity of preeclampsia, confounding factors controlled for by matching or adjustment, report of dose-response gradient, and unadjusted and/or adjusted RRs or ORs with 95% CIs. The corresponding authors of primary studies were contacted to obtain additional information on methods used and/or unpublished relevant data.
Statistical analysis
The exposure (independent) variable was the presence or absence of a current or previous SARS-CoV-2 infection, and the outcome (dependent) variable was the presence or absence of preeclampsia. We estimated pooled unadjusted and adjusted ORs with 95% CIs as the measure of the association between SARS-CoV-2 infection during pregnancy and preeclampsia. The basic data used in the unadjusted analyses consisted of a series of 2×2 tables defined by the dichotomous SARS-CoV-2 infection/non–SARS-CoV-2 infection and preeclampsia/nonpreeclampsia for each study. The results from individual studies were then combined to produce the pooled unadjusted OR with 95% CI by using a random-effects model. This analysis model was chosen because of the high likelihood of between-study variance in observational studies. We also calculated the pooled adjusted OR with 95% CI by only taking into consideration studies that provided an adjusted estimate, either using appropriate methods of analysis or through matching of variables in the study design. The data needed from each study were the estimated adjusted effect (either the adjusted RR or the adjusted OR, the latter being a good approximation of the adjusted RR if the prevalence of the disease is low) and its estimated standard error (often obtained indirectly from the CI reported in the study).
The heterogeneity of the results among studies was evaluated by visually inspecting forest plots and by estimating the quantity І 2 . A significant level of heterogeneity was defined as І 2 ≥30%. Subgroup analyses were performed to test the robustness of the overall findings and to explore potential sources of heterogeneity. We also addressed heterogeneity by calculating the 95% prediction interval for the pooled unadjusted OR, which gives an estimate of the point at which the true effects are to be expected for 95% of similar studies that might be conducted in the future. Prespecified subgroup analyses were carried out according to the severity of SARS-CoV-2 infection (asymptomatic illness vs symptomatic illness), study design (retrospective cohort vs prospective cohort vs cross-sectional), study of the association (as primary aim vs as secondary aim), control for confounding factors (yes vs no), geographic location (North America vs Europe vs Asia vs Latin America vs Multiregion), sample size (<200 vs 200–999 vs 1000–5000 vs >5000), test used for diagnosing SARS-CoV-2 infection (RT-PCR vs RT-PCR or antigens vs antibodies in serum vs mixed or unclear), and timing of the diagnosis of SARS-CoV-2 infection (at any time during pregnancy vs at admission for delivery).
The impact of the risk of bias on the results was examined by performing a sensitivity analysis that included only studies with a low risk of bias in at least 5 of the 6 domains evaluated. We assessed publication and related biases visually by examining the symmetry of the funnel plots and statistically by measuring the degree of asymmetry with the Egger and Begg-Mazumdar tests, with P <.10 indicating significant asymmetry. In the presence of funnel plot asymmetry, we assessed the potential impact of publication bias on the overall effect size obtained in the meta-analysis by using the “Trim and Fill” method developed by Duval and Tweedie. ,
Statistical analyses were performed by using Review Manager (RevMan, version 5.4.1, The Cochrane Collaboration, London, United Kingdom) and StatsDirect (version 3.3.5; StatsDirect Ltd, Merseyside, United Kingdom).
Results
Selection, characteristics, and risk of bias of studies
Figure 1 shows the process of the literature search and selection of studies. The searches produced 3659 records of which 107 were considered relevant. Of these, 79 were excluded, the main reason being a lack of data on the relationship between SARS-CoV-2 infection and preeclampsia. A total of 28 studies (14 prospective cohort, 12 retrospective cohort, and 2 cross-sectional) including 790,954 pregnant women, among which 15,524 were diagnosed with SARS-CoV-2 infection, met the inclusion criteria. Four studies were specifically designed to evaluate the association between SARS-CoV-2 infection during pregnancy and preeclampsia. , , , The remaining 24 studies compared the maternal and perinatal outcomes for pregnant women with and those without SARS-CoV-2 infection and reported on the risk of preeclampsia. The corresponding authors of 8 studies supplied additional data. , , , , ,
The main characteristics of the studies included in the systematic review are presented in Table 1 . A total of 14 studies were conducted in North American countries (13 in the United States and 1 in Canada), 6 in European countries, 5 in Asian countries, and 2 in Latin America. The remaining study was performed across 18 countries. The sample size ranged from 24 to 406,446 (median, 907). Two cross-sectional studies, 1 from the United States and 1 from the United Kingdom, included a total of 748,526 pregnant women. , An RT-PCR test was used to diagnose SARS-CoV-2 infection in 18 studies, an RT-PCR or antigen test was used in 3 studies, and a serum antibody test was used in 3 studies. In the remaining 4 studies, SARS-CoV-2 infection was diagnosed based on laboratory tests and/or clinical signs and symptoms of COVID-19 and/or chest imaging suggestive of the disease. Among the 22 studies that reported on the severity of SARS-CoV-2 infection, 16 had a higher proportion of patients with asymptomatic illness, 5 had a higher proportion of patients with symptomatic illness, and 1 had the same proportion of patients with asymptomatic and symptomatic illness. Fifteen studies included women among whom SARS-CoV-2 infection was diagnosed at any time during pregnancy and 13 studies included women among whom SARS-CoV-2 infection was diagnosed at admission for delivery. Most patients were diagnosed with SARS-CoV-2 infection during the third trimester. In 25 studies, women with and without SARS-CoV-2 infection were recruited from the same population and during the same time period. In the remaining 3 studies, the comparison group without SARS-CoV-2 infection were pregnant women who delivered before the beginning of the COVID-19 pandemic.
| First author, y (country) | Design (sample size) | Group with SARS-CoV-2 infection | Timing of the diagnosis of SARS-CoV-2 infection | Group without SARS-CoV-2 infection | Adjustment for confounders or matching of variables | Outcome |
|---|---|---|---|---|---|---|
| Ahlberg, 2020 (Sweden) | Retrospective cohort (759) | n=155; women with a positive RT-PCR test result (98%) or positive for antibodies against SARS-CoV-2 (2%); 65% asymptomatic and 35% symptomatic | Admission for delivery (91%) and antepartum period (9%); ∼90% during the third trimester | n=604; women in labor with a negative RT-PCR test result (100%) | Maternal age, parity, body mass index, country of birth, living with partner, and prepregnancy comorbidity | Preeclampsia |
| Yang, 2020 (China) | Retrospective cohort (11,078) | n=65; women with a positive RT-PCR test result (100%) | “During late pregnancy” | n=11,013; women with a negative RT-PCR test result (57%) or without signs or symptoms of COVID-19 (43%) | Maternal age, occupation, education, gravidity, parity, gestational hypertension, preeclampsia, gestational diabetes mellitus, and premature rupture of membranes | Preeclampsia |
| Prabhu, 2020 (United States) | Prospective cohort (675) | n=70; women with a positive RT-PCR test result (100%); 79% asymptomatic and 21% symptomatic | Admission for delivery (100%); median gestational age, 39.0 wk | n=605; women admitted for delivery with a negative RT-PCR test result (100%) | No | Preeclampsia |
| Grechukhina, 2020 (United States) | Retrospective cohort (8768) | n=77; women with a positive RT-PCR test result (100%); 53% asymptomatic and 47% symptomatic | Admission for delivery (67%), antepartum period (24%), and postpartum period (9%); most during the third trimester | n=8691; prepandemic (2018–2019) control group of pregnant women | No | Preeclampsia |
| Adhikari, 2020 (United States) | Retrospective cohort (3280) | n=245; women with a positive RT-PCR test result (100%); 39% asymptomatic, 56% with mild or moderate illness and 5% with severe or critical illness | Admission for delivery (68%), antepartum period (30%), and unclear (2%); 93% during the third trimester and 7% during the second trimester | n=3035; women with a negative RT-PCR test result (100%) | No | Preeclampsia with severe features |
| Pirjani, 2020 (Iran) | Prospective cohort (199) | n=66; women with a positive RT-PCR test result, or signs or symptoms of COVID-19 plus a chest CT scan suggestive of the disease; 100% symptomatic | During the second (24%) and third (74%) trimester; mean gestational age, 32.6 wk | n=133; healthy women without signs or symptoms of COVID-19 (100%) | Maternal age, body mass index, previous delivery type, gestational age, previous pregnancy problems, and preexisting medical problems | Preeclampsia |
| Wang, 2020 (United States) | Retrospective cohort (813) | n=53; women with a positive RT-PCR or antigen test result (100%); 85% with asymptomatic or mild illness and 15% with moderate, severe, or critical illness | Admission to the hospital (100%); mean gestational age, 38.1 wk | n=760; women with a negative RT-PCR or antigen test result, or without signs or symptoms of COVID-19 | No | Preeclampsia with severe features |
| Egerup, 2021 (Denmark) | Prospective cohort (1313) | n=28; women with a positive result for anti–SARS-CoV-2 IgM or IgG antibodies in serum (100%); no woman had a positive RT-PCR test result; 50% asymptomatic and 50% symptomatic | Admission for delivery (100%); median gestational age, 40.1 wk | n=1285; women with a negative result for anti–SARS-CoV-2 IgM and IgG antibodies in serum (100%); one woman had a positive RT-PCR test result | No | Preeclampsia |
| Hcini, 2021 (French Guiana) | Prospective cohort (507) | n=137; women with a positive RT-PCR test result (100%); 63% asymptomatic, 33% with mild illness, and 4% with severe illness | Admission for delivery (100%); most during the third trimester | n=370; women admitted for delivery with a negative RT-PCR test result (100%) | “Unbalanced maternal characteristics” | Preeclampsia |
| Mahajan, 2021 (India) | Retrospective cohort (73) | n=10; women with multiple gestation and a positive RT-PCR test result (100%); 80% asymptomatic and 20% symptomatic | During the second (25%) and third (75%) trimesters; median gestational age, 34.5 wk | n=63; prepandemic (2019–2020) control group of pregnant women with multiple gestation | No | Preeclampsia and eclampsia |
| Madden, 2021 (United States) | Retrospective cohort (1715) | n=167; women with a positive RT-PCR test result (100%) | Admission to the hospital (100%) | n=1548; women with a negative RT-PCR test result (100%) | No | Preeclampsia, preeclampsia with severe features, and preeclampsia without severe features |
| Colon-Aponte, 2021 (United States) | Prospective cohort (24) | n=12; women with a positive RT-PCR test result (100%) | Admission for delivery (100%); mean gestational age, 39.0 wk | n=12; women with a negative RT-PCR test result (100%) | No | Preeclampsia |
| Yazihan, 2021 (Turkey) | Prospective cohort (187) | n=95; women with a positive RT-PCR test result (100%); 74% with mild illness, 24% with moderate illness, and 2% with severe illness | During the first (34%), second (34%) and third (33%) trimesters | n=92; healthy women without signs or symptoms of COVID-19 | No | Preeclampsia |
| Brandt, 2021 (United States) | Prospective cohort (183) | n=61; women with a positive RT-PCR test result (100%); 89% with asymptomatic or mild illness, and 11% with severe or critical illness | Mean gestational age, 38.8 wk for women with asymptomatic or mild illness and 33.6 wk for those with severe or critical illness | n=122; women with a negative RT-PCR test result or those without signs or symptoms of COVID-19 | Maternal age, obesity, maternal race, and comorbid medical problems (chronic hypertension, diabetes mellitus, renal disease, asthma, immunocompromised state, and anemia) | Preeclampsia |
| Cardona-Pérez, 2021 (Mexico) | Retrospective cohort (231) | n=67; women with a positive RT-PCR test result (100%); 86% asymptomatic and 14% symptomatic | Admission for delivery (100%); <28 wk, 10%; 28–36 wk, 24%, ≥37 wk, 66% | n=164; women with a negative RT-PCR test result (100%) | Maternal age, body mass index, preexisting comorbidities, and gestational age at admission | Preeclampsia |
| Steffen, 2021 (United States) | Prospective cohort (1000) | n=61; women with a positive result for anti–SARS-CoV-2 IgG antibodies in serum (84%) or RT-PCR test (5%) or both tests (11%); 51% asymptomatic and 49% symptomatic | Admission for delivery (100%); median gestational age, 39.0 wk | n=939; women with a negative result for anti–SARS-CoV-2 IgG antibodies in serum or RT-PCR test (100%) | No | Preeclampsia, preeclampsia with severe features, preeclampsia without severe features, and eclampsia |
| Jering, 2021 (United States) | Cross-sectional (406,446) | n=6380; women giving birth with a diagnosis of COVID-19 at discharge (ICD-10 code U07.1). Diagnostic criteria for SARS-CoV-2 infection were not reported | At birth; 98% in the third trimester | n=400,066; women giving birth without a diagnosis of COVID-19 at discharge (ICD-10 code U07.1) | Adjusted for propensity score, which included the following covariates: maternal age, race and ethnicity, geographic region, urban population, teaching hospital, discharge month, trimester of pregnancy, obesity, smoking, hypertension, gestational hypertension, diabetes, gestational diabetes, kidney disease, pulmonary disease | Preeclampsia, eclampsia, and HELLP syndrome |
| Vousden, 2021 (United Kingdom) | Prospective cohort (1842) | n=1148; women with a positive RT-PCR test result within 7 days of admission to hospital (99%) or chest imaging suggestive of COVID-19 (1%); 37% asymptomatic and 63% symptomatic | <22 wk, 7%; 22–27 wk, 7%; ≥28 wk, 86% | n=694; prepandemic (2017–2018) control group of pregnant women | Maternal age, ethnicity, body mass index, any relevant previous medical problem, cigarette smoking | Preeclampsia |
| Abedzadeh-Kalahroudi, 2021 (Iran) | Prospective cohort (149) | n=55; women with a positive RT-PCR test result, signs or symptoms of COVID-19, or laboratory tests and a chest CT scan suggestive of the disease; >90% symptomatic | During the first (7%), second (14%), and third (79%) trimesters; mean gestational age, 31.9 wk | n=94; healthy women without clinical signs or symptoms of COVID-19 (100%) | No | Preeclampsia |
| Crovetto, 2021 (Spain) | Prospective cohort (1304) | n=176; women with a positive result for anti–SARS-CoV-2 IgG or IgM or IgA antibodies in serum (∼99%) and/or RT-PCR test; 60% asymptomatic and 40% symptomatic | Admission for delivery (100%); 24–42 wk | n=1128; women with a negative result for anti–SARS-CoV-2 IgG and IgM or IgA antibodies in serum or negative RT-PCR test (100%) | No | Preeclampsia |
| Rosenbloom, 2021 (United States) | Retrospective cohort (249) | n=83; women with a positive RT-PCR or antigen test result (100%); 58% asymptomatic and 42% symptomatic | Any time during pregnancy | n=166; women with a negative RT-PCR test result (100%) | Race, parity | Preeclampsia, preeclampsia with severe features, and preeclampsia without severe features |
| Trahan, 2021 (Canada) | Retrospective cohort (270) | n=45; women with a positive RT-PCR test result (100%); 27% asymptomatic and 73% symptomatic | Any time during pregnancy; 98% in the third trimester | n=225; women with a negative RT-PCR test result (100%) | No | Preeclampsia |
| Soto-Torres, 2021 (United States) | Retrospective cohort (209) | n=106; women with a positive RT-PCR or antigen test result (100%); 54% asymptomatic and 46% symptomatic (28% with mild illness and 18% with severe illness) | Any time during pregnancy; median gestational age, 32.9 wk (range, 10.9–40.4 wk); | n=103; women with a negative RT-PCR or antigen test result (100%) | Maternal age, body mass index, parity, gestational age | Preeclampsia |
| Katz, 2021 (United States) | Prospective cohort (1454) | n=490; women with a positive RT-PCR test result within 14 d of delivery (100%); 64% asymptomatic and 36% symptomatic | Within 14 d of delivery; most in the third trimester | n=964; women with a negative RT-PCR test result (84%) or without signs or symptoms of COVID-19 (16%) | Maternal age, race, ethnicity, body mass index, and maternal comorbidities (including diabetes, preexisting hypertension, cardiac, pulmonary, or autoimmune disease) | Preeclampsia |
| Chornock, 2021 (United States) | Retrospective cohort (1008) | n=73; women with a positive RT-PCR test result (100%); 84% asymptomatic and 16% symptomatic | Admission for delivery (99.2%) and antepartum period (0.8%); mean gestational age, 40.1 wk | n=935; women with a negative RT-PCR test result at admission for delivery (100%) | Race, body mass index, aspirin use, and chronic hypertension | Preeclampsia, preeclampsia with severe features, and preeclampsia without severe features |
| Cruz Melguizo, 2021 (Spain) | Prospective cohort (2954) | n=1347; women with a positive RT-PCR test result (100%); 51% asymptomatic and 49% symptomatic (35% with mild or moderate illness and 14% with severe or critical illness) | Any time during pregnancy; most in the third trimester | n=1607; women with a negative RT-PCR test result at admission for delivery (100%) | No | Preeclampsia, preeclampsia with severe features, and preeclampsia without severe features |
| Gurol-Urganci, 2021 (United Kingdom) | Cross-sectional (342,080) | n=3527; women with a positive RT-PCR test result (100%) | At the time of birth (100%) | n=338,553; women without laboratory-confirmed SARS-CoV-2 infection (ICD-10 code U07.1) | Maternal age, ethnicity, parity, preexisting diabetes, preexisting hypertension, and socioeconomic deprivation | Preeclampsia |
| Papageorghiou, 2021 (Multicountry) a | Prospective cohort (2184) | n=725; women with a positive RT-PCR test result (92.7%), clinical signs or symptoms of COVID-19 (6.8%), or chest imaging suggestive of COVID-19 (0.6%); 40% asymptomatic and 60% symptomatic | ≤26 wk, 5%; >26 wk, 95%; median gestational age, 37.6 wk (IQR 34.3–39.1); 71% of women were diagnosed <10 d before giving birth | n=1459; women with a negative RT-PCR or antigen test result (50%) or women without signs or symptoms of COVID-19 (50%) | Maternal age, parity, cigarette smoking, overweight or obesity, history of diabetes, cardiac disease, hypertension, or renal disease, and history of adverse pregnancy outcomes | Preeclampsia |
a Includes cases from Argentina, Brazil, Egypt, France, Ghana, India, Indonesia, Italy, Japan, Mexico, Nigeria, North Macedonia, Pakistan, Russia, Spain, Switzerland, the United Kingdom, and the United States.
A total of 14 studies controlled for potential confounding factors related to both SARS-CoV-2 infection and preeclampsia. Most of them adjusted their results for maternal age, body mass index, preexisting comorbidities, and race or ethnicity. Twenty-six studies provided data on the relationship between SARS-CoV-2 infection and preeclampsia (with and without severe features), 7 on the relationship with preeclampsia with severe features, 5 on the relationship with preeclampsia without severe features, 3 on the relationship with eclampsia, and 1 on the relationship with HELLP syndrome.
The risk of bias in each included study is shown in Supplemental Figure 1 . No study was judged to be at low risk of bias for all 6 domains. Six studies were deemed to be at low risk of bias for 5 domains and 13 were judged to be at low risk of bias for 4 domains. The remaining 9 studies were judged to be at low risk of bias for ≤3 domains. The most common shortcomings were the failure to report temporality of the association between SARS-CoV-2 infection and preeclampsia and the lack of adjustment for confounding factors.
Association between SARS-CoV-2 infection during pregnancy and preeclampsia
A total of 26 studies, , , comprising 786,861 women, reported on the association between SARS-CoV-2 infection during pregnancy and the risk of preeclampsia (with and without severe features). All but 1 study found that the frequency of preeclampsia was higher among pregnant women with a diagnosis of SARS-CoV-2 infection than among those without a diagnosis of SARS-CoV-2 infection. The meta-analysis of unadjusted ORs showed that the odds of developing preeclampsia were significantly higher among pregnant women with SARS-CoV-2 infection than among those without SARS-CoV-2 infection (7.0% vs 4.8%; pooled unadjusted OR, 1.62; 95% CI, 1.45–1.82; P <.00001; 95% prediction interval of the OR, 1.28–2.05) ( Figure 2 ).
