Professor, Chair, and Associate Dean of Research, College of Public Health, Division of Epidemiology, The Ohio State University, Columbus
SYNOPSIS: A meta-analysis of 28 observational studies found that having SARS-CoV-2 infection during pregnancy was associated with a 58% increase in the adjusted odds of having preeclampsia compared to those without SARS-CoV-2 infection during pregnancy.
SOURCE: Conde-Agudelo A, Romero R. SARS-CoV-2 infection during pregnancy and risk of preeclampsia: A systematic review and meta-analysis. Am J Obstet Gynecol 2021; Jul 21:S0002-9378(21)00795-X. doi: 10.1016/j.ajog.2021.07.009. [Online ahead of print].
Preeclampsia, which occurs in 2% to 8% of pregnancies globally, is an important cause of maternal mortality as well as a risk factor for later heart disease and stroke. Genetic, epigenetic, environmental, and behavioral factors have been implicated in the development of preeclampsia. Researchers also have long hypothesized that viral infections (e.g., human immunodeficiency virus, human papillomavirus, cytomegalovirus, hepatitis B virus, and herpes simplex virus) during pregnancy could cause preeclampsia. In light of this, Conde-Agudelo and Romero carried out a systematic review and meta-analysis to evaluate whether infection with SARS-CoV-2 during pregnancy increases the risk of developing preeclampsia. They conducted a comprehensive search of databases for all reports of studies on this topic, regardless of publication status or language used, that were available from Dec. 1, 2019, to May 31, 2021. They found 28 eligible studies: 14 prospective cohort studies, 12 retrospective cohort studies, and two cross-sectional studies. The 28 studies included 790,954 pregnant women, 2% of whom (n = 15,524) were diagnosed with SARS-CoV-2. The studies were conducted in numerous countries. The sample sizes ranged from 24 to 406,446 pregnant women.
To be eligible for inclusion, the primary study had to include data on women with and without a diagnosis of SARS-CoV-2 infection during pregnancy, data on preeclampsia status, and either an odds ratio (OR) or a relative risk (RR) for the association between SARS-CoV-2 and preeclampsia and its associated 95% confidence interval (CI) or the data that would allow these estimates to be calculated. The authors used a tight clinical definition of preeclampsia. In contrast, because of the widespread lack of diagnostic tests at the beginning of the pandemic, they accepted a range of methods for defining SARS-CoV-2, including those that relied on clinical signs/symptoms or chest images suggestive of the disease as well as laboratory diagnoses from reverse transcriptase-polymerase chain reaction (RT-PCR), antigen, or serum antibody tests.
By pooling data from 26 studies, they found that 7.0% of pregnant women with SARS-CoV-2 during pregnancy had preeclampsia compared to 4.8% of those without SARS-CoV-2. Using a random effects model, the summary odds of preeclampsia for those with SARS-CoV-2 was 1.62 times (95% CI, 1.45-1.82) that of those without SARS-CoV-2. They repeated this analysis after restricting to the 11 studies that accounted for confounders of the association between SARS-CoV-2 and preeclampsia. These confounders typically included maternal age, body mass index, preexisting comorbidities, and race/ethnicity. The summary OR from the adjusted analysis (1.58; 95% CI, 1.39-1.80) was similar to the unadjusted summary estimate.
The authors also evaluated three secondary outcomes instead of preeclampsia and found each to be statistically significantly associated with SARS-CoV-2 during pregnancy. That is, SARS-CoV-2 during pregnancy was associated with higher odds of preeclampsia with severe features (summary OR, 1.76; 95% CI, 1.18-2.63); eclampsia (summary OR, 1.97; 95% CI, 1.01-3.84); and hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome (summary OR, 2.10; 95% CI, 1.48-2.97). Finally, they conducted several subgroup analyses and sensitivity analyses to explore further the relationship between SARS-CoV-2 and preeclampsia and to assess how robust the study findings were to the choice of analytic methods. These analyses suggested a possible dose effect with higher odds among those with symptomatic illness (summary OR, 2.11; 95% CI, 1.59-2.81) than the odds among those with asymptomatic illness (summary OR, 1.59; 95% CI, 1.21-2.10). Only six of the 28 studies were judged to be at low risk of bias for at least five of the six domains of bias evaluated. When the authors restricted the analysis to these six studies, they found a similar summary OR for the association between SARS-CoV-2 infection during pregnancy and preeclampsia (1.74; 95% CI, 1.35-2.23).
COMMENTARY
This systematic review and meta-analysis by Conde-Agudelo and Romero builds on a growing body of evidence that warns of increased health risks from SARS-CoV-2 during pregnancy. Previous research has indicated that SARS-CoV-2 infection during pregnancy poses greater risks relative to SARS-CoV-2 infection outside of pregnancy and that, among pregnant women, those with SARS-CoV-2 infection face higher risks of maternal mortality and adverse birth outcomes, including preterm birth and stillbirth, compared to those without this infection. The present article adds to this literature by synthesizing the available evidence on the association between SARS-CoV-2 during pregnancy and an increased risk of preeclampsia. Although the pooled effect estimate (adjusted summary OR, 1.58; 95% CI, 1.39-1.80) is statistically significant, the strength of this association could be considered weak.1 However, even a weak association can be important on a population level.
Despite the careful work and strong methods used by the authors, their meta-analysis combines evidence that came solely from observational studies. Consequently, the data cannot establish a causal relationship between SARS-CoV-2 and preeclampsia. Because pregnant women were not (and ethically could not be) randomly assigned to SARS-CoV-2 infection, controlling for confounders was critical. Otherwise, for example, the same risk factors that put a woman at higher risk of SARS-CoV-2 infection also could have put her at higher risk of preeclampsia. In this case, an apparent effect of SARS-CoV-2 on preeclampsia could be spurious. The authors addressed this concern by calculating a separate summary measure from the studies that accounted for confounders. The results from this adjusted analysis remained statistically significant, which helps support the interpretation that a true association between SARS-CoV-2 and preeclampsia exists. However, residual confounders could remain if the investigators of the primary studies did not account adequately for all confounding. Note that despite the large, pooled sample size of 790,954 pregnant women, most of the pooled sample (95%) came from only two cross-sectional studies, which were conducted in the United States or the United Kingdom. Although the investigators of these two studies adjusted for potential confounders, they used administrative records (hospital billing records) as their data source. Because administrative data are not collected for research purposes, often they have misclassification and missing data and may fail to collect the full range of relevant measures. Arguably, the limitations of using administrative data might be insurmountable.2
The analysis had numerous strengths. Notably, the association between SARS-CoV-2 during pregnancy and preeclampsia remained statistically significant in most subgroup and sensitivity analyses, indicating that the findings were robust. Because the pooled analyses had no, or little, evidence of heterogeneity between studies according to I2, the studies were appropriate to combine in meta-analysis. The consistency of the individual study findings supports the interpretation that SARS-CoV-2 infection during pregnancy is linked to preeclampsia. Furthermore, possible biological mechanisms by which SARS-CoV-2 during pregnancy could cause preeclampsia have been proposed.3 Given the strength of this evidence, healthcare providers should recommend that preconception and pregnant people complete the recommended vaccination against COVID-19 and implement protective measures to protect themselves against exposure (e.g., wearing masks in public indoors). The Centers for Disease Control and Prevention recommends vaccination against COVID-19 for people at least 12 years of age, including pregnant women.4 Healthcare providers should counsel pregnant women about their risks, including the increased risk of preeclampsia, from SARS-CoV-2 infection (including from asymptomatic infection), during pregnancy. Providers should remain aware of the increased risk of preeclampsia among pregnant women with SARS-CoV-2 infection to ensure the early detection and treatment of preeclampsia if needed.
REFERENCES
- Rosenthal JA. Qualitative descriptors of strength of association and effect size. J Soc Serv Res 1996;21:37-59.
- Grimes DA. Epidemiologic research using administrative databases: Garbage in, garbage out. Obstet Gynecol 2010;116:1018-1019.
- Conde-Agudelo A, Romero R. Mechanisms that may underlie a causal association between SARS-CoV-2 infection and preeclampsia. Am J Obstet Gynecol 2021; Sep 13. [In press].
- Zauche LH, Wallace B, Smoots AN, et al. Receipt of mRNA COVID-19 vaccines preconception and during pregnancy and risk of self-reported spontaneous abortions, CDC v-safe COVID-19 Vaccine Pregnancy Registry 2020-21. Res Sq 2021; Aug 9:rs.3.rs-798175. doi: 10.21203/rs.3.rs-798175/v1. [Preprint].
A meta-analysis of 28 observational studies found that having SARS-CoV-2 infection during pregnancy was associated with a 58% increase in the adjusted odds of having preeclampsia compared to those without SARS-CoV-2 infection during pregnancy.
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