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Introduction
Pregnancy can lead to physiological changes that increase a woman's susceptibility to infections [1]. There is a well-established link between pregnancy and an increased vulnerability to respiratory infections, which results in higher rates of morbidity and mortality [2]. Similar to infections with Zika virus and dengue virus during pregnancy, placental infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with chronic inflammatory disorders such as lymphohistiocytic villitis, chronic histiocytic intervillositis, and chronic deciduitis [3,4]. Since the discovery of SARS-CoV-2 in the placentas of pregnant individuals with coronavirus disease 2019 (COVID-19), there has been a heightened focus on the study of placental physiology. The virus invades cells by binding its spike protein to the angiotensin-converting enzyme-2 receptor, found in various placental locations including perivascular cells, stromal cells of the decidua, placental and fetal arteries, and cytotrophoblasts [5,6].
Ultrasound data have shown histopathological abnormalities in over 80% of placentas from fetuses displaying clinical signs of infection. Women with SARS-CoV-2 who exhibit mild symptoms have shown increased presence of fibrin, calcifications, vascular ectasia, avascular villi, and thrombi in larger fetal arteries. Additionally, findings include subchorionic fibrin deposition and chorangiosis, as documented in earlier studies [7-9]. These abnormalities can result in the loss of trophoblast cells, significant fibrin accumulation, and reduced nutrient flow between the mother and fetus [10,11]. Norman et al. (2021) [12] identified a clear association between SARS-CoV-2 infection in pregnant mothers and an increase in neonatal mortality. Boettcher and Metz (2023) [13] reported that pregnant women infected with SARS-CoV-2 face a significantly higher risk of developing various health issues, including composite morbidity, pre-eclampsia, premature birth, and the need for neonatal intensive care unit admissions. Furthermore, multiple clinical studies have detected SARS-CoV-2 in human placentas, noting its adverse effects on fetal circulation through the placenta and on placental features. Infection results in increased venous lakes and placental thickness, as well as enhanced blood flow through the umbilical veins, all of which can impede fetal growth [14-16].
However, the specific effects of SARS-CoV-2 on the fetal-placental unit in pregnant women remain unclear. While several studies have reported negative outcomes, others have found no significant impact. To evaluate the effects of SARS-CoV-2 infection on Doppler ultrasound and placental findings in pregnant women, a comprehensive systematic review and meta-analysis was conducted. This review included recent case-control studies that met specific inclusion and exclusion criteria [17-26].
This study aims to assess the impact of SARS-CoV-2 infection on Doppler ultrasound and placental characteristics in pregnant women through a comprehensive systematic review and meta-analysis of recent case-control studies.
Materials and Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [27] and Assessing the Methodological Quality of Systematic Reviews (AMSTAR) [28] procedures were followed to carry out this analysis within the specified parameters.
Study Design
To determine whether SARS-CoV-2 infection in pregnant women affects Doppler ultrasonography and placental outcomes, a systematic review and meta-analysis of ten case-control studies spanning from 2020 to 2023 was conducted.
Search Strategy
This meta-analysis was conducted after a thorough search across multiple databases, including Embase, PubMed, Scopus, and the Cochrane Library. The study covered the period from 2020 to 2023 and employed specific search terms, including "Doppler ultrasound" OR "placental findings" OR "pregnancy" OR "SARS-CoV-2 infection" OR "umbilical vein" OR "ultrasound" OR "placenta" OR "placental thickness" OR "perinatal death" OR "preterm delivery" OR "high-risk pregnancy" OR "placental abnormalities" OR "umbilical cord lesions" OR "Placental damage" OR "fetal biometry" OR "placental venous lakes" OR "umbilical vein blood flow" OR "UVBF" OR "case-control study" OR "systematic review" OR "meta-analysis." In accordance with the population, intervention, comparison, outcomes, and study design (PICOS) framework [29], keywords were identified and evaluated for concordance in both the Embase and Medline databases (Table 1). In the Scopus search, the aforementioned keywords were input into the Title (ti)-Abstract (abs)-Keyword (keyword) field. The search criteria "placental findings," "Doppler ultrasound of pregnant women," and "SARS-CoV-2 infection" were utilized in Cochrane. The application of the PICO structure facilitated the establishment of precise selection criteria. "P" referred to SARS-CoV-2 infected pregnant women, "I" represented the impact of SARS-CoV-2 infection on placental and Doppler ultrasound parameters, "C" referred to a control group of pregnant women, and "O" comprised the principal clinical outcomes, which included changes in placental characteristics such as placental thickness, placental venous lakes, the cerebroplacental ratio (CPR), and Doppler parameters, including fetoplacental circulation. The research design (S) was restricted to case-control studies. The inclusion criteria specified that only English-language publications would be considered. To identify relevant papers, two researchers independently peer-reviewed the entire collection of pertinent scientific literature.
Inclusion and Exclusion Criteria
The current study included studies that compared the placental and Doppler ultrasound results of pregnant women infected with SARS-CoV-2 to those of a control group. Inclusion criteria were as follows: (1) studies involving SARS-CoV-2–positive expectant mothers; (2) investigations focused on the properties of the placenta in these mothers; (3) research examining Doppler ultrasound parameters in pregnant women; and (4) use of case-control studies as the research design. The review encompassed studies from the years 2020 to 2023. Selection was based on the availability of complete texts and sufficient data for constructing a 2×2 table. The primary outcomes measured in this meta-analysis were changes in Doppler ultrasound parameters and placental characteristics between the intervention and control groups. Bibliographic references that were outdated, anecdotal, or based solely on expert opinions were excluded from the analysis. Additionally, studies relying on animal experiments, those lacking access to primary data and essential information, as well as qualitative research, non-research articles, and papers not written in English, were also excluded. Studies involving pregnant women co-infected with SARS-CoV-2 and acquired immune deficiency syndrome or other systemic infections were not considered. Two researchers independently gathered demographic profiles and event data containing relevant elements from the included trials.
Assessment of the Risk of Bias of the Included Studies
The researchers employed a standardized questionnaire to assess potential biases in the studies being reviewed. They applied a Cochrane Collaboration technique, as outlined in the Cochrane Handbook (version 5.3), to evaluate bias [30]. The assessment tool included five components: randomization bias, intervention deviations bias, absence of outcome data bias, outcome evaluation bias, and selection bias in reporting outcomes. Two reviewers independently assessed the studies to identify any potential biases. In cases of disagreement, a third reviewer served as an arbitrator to resolve the issues. Ultimately, the potential biases were categorized as "uncertain risk," "high risk," or "low risk." To evaluate publication bias, a funnel plot was used, and the statistical significance of this bias was confirmed using the Begg test [31] and MedCalc software [32].
Statistical Analysis
RevMan 5.3 [33] was used to evaluate and analyze the effects of various continuous and dichotomous outcomes. The use of this management software enhanced the efficiency of organizing, extracting, and discarding superfluous references. Forest plots were generated in all studies to assess the impact of outcome drivers. The DerSimonian-Laird method was used to calculate the odds ratio (OR) by analyzing event data in a 2×2 table. The relationship between the OR and a 95% confidence interval (CI) was used to evaluate binary outcomes. Heterogeneity was estimated using statistical methods, including the chi-square test with an accompanying P-value, and the I2 test. Since the studies were conducted under diverse conditions, a random effects model was applied. To evaluate the test accuracy of all included studies, a hierarchical summary receiver operating characteristic (HSROC) plot [34] was constructed.
Results
Results of Database Search
An inclusive electronic search across multiple databases yielded 217 articles that met the specified inclusion-exclusion criteria outlined in the PICOS framework. Of these, 85 articles were excluded due to duplication and issues with titles and abstracts. Following further screening, 132 records were assessed for eligibility. However, after applying the predetermined inclusion and exclusion criteria, 122 studies were deemed ineligible and subsequently excluded. The primary reasons for exclusion included non-compliance with the inclusion criteria, insufficient data for constructing 2×2 tables, and a lack of significant outcome measures. Ten case-control studies, conducted between 2020 and 2023 and meeting specific inclusion criteria, were included in this review and meta-analysis, as illustrated in Fig. 1. This analysis encompasses research involving 1,210 pregnant women across various age groups. Table 2 summarizes the key features of the articles used in this meta-analysis. The table includes details such as the writer's ID, the year and name of the journal in which the study was published, the study design, the aim of the case-control study, the total number of participants, the number of individuals in the case group, participants in the control group, gestational age at diagnosis, primary parameters evaluated, and main findings. Subsequently, the data from these events was used to conduct the meta-analysis.
Evaluation of Risk of Bias of the Included Studies
Table 3 presents the risk of biased evaluation outcomes for the studies involved, based on the predefined questionnaire. The summary plot for risk of bias, shown in Fig. 2, along with the traffic light plot for assessing bias in Fig. 3, indicates a low risk of bias in this study. Of the 10 case-control studies analyzed, eight were found to have a low risk of bias. However, the study by Soto-Sanchez et al. [22] was identified as having a moderate risk of bias due to deviations from the intended intervention. Additionally, the study by Erdem and Kulahcioglu [19] demonstrated a significant risk related to missing outcome data.
Findings from the Statistical Analysis
The current meta-analysis included 10 case-control studies involving a total of 1,210 pregnant women. Statistical analysis focused on the primary outcome of the investigation, yielding the following results (summarized in Table 4).
Risk of placental abnormalities in SARS-CoV-2 infected pregnant women
To estimate the risk of placental anomalies in SARS-CoV-2–infected expecting women, the OR was calculated using event data retrieved from the included studies, as shown in Fig. 4. Pregnant women infected with SARS-CoV-2 were at a higher risk of developing placental anomalies than pregnant women who had not contracted SARS-CoV-2, with an OR of 2.62 (95% CI, 1.66 to 4.13). The statistical analysis yielded a τ2 value of 0.23 (χ2=20.00, df=5, Z=4.14, I2=75%, P<0.001) (Fig. 4A). Moreover, there was a minimal probability of publication bias, as indicated by the symmetrical funnel plots in Fig. 4B with a P-value of 0.238 from the Begg test, which was above the specified significance threshold of 0.05 and therefore was statistically insignificant.
Risk of anomalous Doppler characteristics in SARS-CoV-2-infected pregnant women
The risk of anomalous Doppler parameters in SARS-CoV-2-infected pregnant women was evaluated by calculating the OR utilizing the event data from the studies included, as depicted in Fig. 5. Pregnant women infected with SARS-CoV-2 were at a higher risk of having abnormal Doppler parameters than those in the control group, with an OR of 1.95 (95% CI, 1.16 to 3.27). The statistical investigation yielded a τ2 value of 0.46 (χ2=45.24, df=7, Z=2.53, I2=85%, P=0.012) (Fig. 5A). Moreover, there was a nominal chance of publication bias, as shown by the symmetrical funnel plots in Fig. 5B and the statistically irrelevant P-value from the Begg test (P=0.211), exceeding the preset significance limit of 0.05.
Subgroup analysis
A subgroup analysis was conducted to assess the risk associated with specific placental and Doppler ultrasound characteristics. These included abnormal CPR, changes in fetoplacental circulation, increased placental thickness, and the presence of placental venous lakes, as shown in Fig. 6.
Risk of abnormal cerebroplacental ratio
Pregnant women who contracted SARS-CoV-2 were more prone to having an abnormal CPR compared to the individuals in the control group, with an OR of 2.68 (95% CI, 1.52 to 4.75). The statistical analysis resulted in a τ2 value of 0.42 (χ2=32.22, df=5, Z=3.39, I2=84%, P<0.001) (Fig. 6A).
Risk of alteration in fetoplacental circulation
Pregnant women with SARS-CoV-2 were more prone to having an altered fetoplacental circulation than those in the control group, with an OR of 1.56 (95% CI, 1.07 to 2.28). The statistical analysis resulted in a τ2 value of 0.10 (χ2=8.74, df=4, Z=2.30, I2=54%, p=0.023) (Fig. 6B).
Risk of increased placental thickness and placental venous lakes
SARS-CoV-2–infected pregnant women were more prone to having an augmented placental thickness and placental venous lakes than those in the control group, with an OR of 1.85 (95% CI, 1.25 to 2.72). The statistical analysis resulted in a τ2 value of 0.18 (χ2=18.63, df=6, Z=3.09, I2=68%, P=0.002) (Fig. 6C).
HSROC plot for test accuracy of involved studies
The test accuracy of all the involved case-control studies was calculated using an HSROC plot, as displayed in Fig. 7. The image clearly shows that the test accuracy of all the studies included was high, as indicated by the data points being clustered in the upper left corner where sensitivity and specificity values were close to 1.
Discussion
The placenta undergoes changes due to various viral infections. Adverse outcomes for newborns and persistent inflammatory states of the placenta are also associated with SARS-CoV-2. Recent studies on pregnancies infected with SARS-CoV-2 have noted numerous pathological changes in the placenta, including vascular and inflammatory alterations, placental permeation, thrombo-embolic complications, necrosis, and ischemia. These changes also feature markers of maternal vascular malperfusion, such as increased fibrin deposition, villous agglutination, intervillous thrombi, atherosis, increased syncytial knotting, and histologic alterations in placentas [35,36]. In a prospective case-control study, Kienast et al. (2023) [37] found that pregnant women were at a higher risk of hospitalization or intensive care unit admission when infected with SARS-CoV-2 compared to non-pregnant women. Additionally, the study revealed that the overall perinatal mortality rate is higher in pregnant women with SARS-CoV-2 infection compared to a group of non-pregnant individuals. Furthermore, SARS-CoV-2 infections during pregnancy can lead to placental lesions caused by vascular events, which can be effectively visualized using prenatal MRI. In their observational study, Pacu et al. (2022) [38] reported that microvasculopathy, primarily characterized by signs of maternal malperfusion, was frequently observed in the placentas of patients who tested positive for SARS-CoV-2. Although numerous studies have documented placental and Doppler ultrasonography results in pregnancies complicated by COVID-19 [39,40], the specific impact of SARS-CoV-2 infection on placental findings and Doppler ultrasound parameters remains unclear. Therefore, this study comprehensively reviewed and meta-analyzed a total of 10 case-control studies comparing the Doppler ultrasound parameters and placental features of pregnant women infected with SARS-CoV-2 to a control group. The key findings of the research are briefly described below.
Anuk et al. [17] conducted a case-control study comparing the fetal Doppler characteristics of 30 pregnant women who had recovered from COVID-19 with those of 40 healthy pregnant women. Doppler ultrasonography was used to assess the umbilical artery (UA), middle cerebral artery (MCA), and uterine artery (UtA) between 23 and 40 weeks of gestation. Additionally, the CPR was calculated based on gestational age. The study found that the case group exhibited significantly higher pulsatility and resistance indices for UA and UtA compared to the control group (P<0.05). Multivariable logistic regression analysis indicated a strong association between the mean pulsatility and resistance indices of the UtA and the disease (OR, >1,000; 95% CI, 9.77 to >1,000; P=0.009 and OR, P=0.001; 95% CI, 0.000 to 0.944; P=0.049). These findings suggest that uterine artery Doppler indices during the third trimester may have clinical significance for pregnant women who have recovered from COVID-19. Ayhan et al. [18] conducted a case-control study to evaluate fetal Doppler measures in pregnant women with COVID-19 infection. The study included 97 age-matched pregnant women in the control group and 54 pregnant women diagnosed with COVID-19 between weeks 28 and 39. Infection was confirmed using positive results from real-time polymerase chain reaction (RT-PCR). Doppler parameters assessed included the cerebral-placental-uterine ratio, ductus venosus, and uterine artery (right and left) for both groups. The study concluded that mild and moderate COVID-19 patients did not seem to experience adverse effects on fetoplacental circulation during the acute phase of the disease, as the demographic characteristics of the two groups were similar and fetal Doppler measurements did not show significant differences.
Erdem and Kulahcioglu [19] conducted a case-control study to examine the outcomes of Doppler ultrasonography in pregnant women diagnosed with COVID-19 who exhibited symptoms. The study involved 40 hospitalized pregnant women with COVID-19 and 30 healthy pregnant women (group 2). Records of birth histories and maternal characteristics were maintained. Several parameters used to assess blood flow between the fetus and mother, including the UA pulsatility index (PI), UA resistive index (RI), MCA PI, MCA RI, mean UtA PI, mean UtA RI, and CPR, showed statistically significant differences between the two groups. Hospitalized pregnant women with COVID-19 demonstrated compromised blood flow between the fetus and mother, as indicated by all measured parameters. Additionally, compared to healthy counterparts, their birth weights and biophysical profile (BPP) scores were significantly lower. Fetal and maternal vascular malperfusion, particularly decidual arteriopathy, has been noted in the placental pathologies of SARS-CoV-2–infected pregnant women. To assess the impact of SARS-CoV-2 infection during pregnancy on fetal Doppler ultrasound parameters, Ozer et al. [20] carried out a case-control study. The study included 71 pregnant women without COVID-19 and eighty-one pregnant women with mild to moderate infection. These women underwent ultrasound examinations, which included Doppler and embryonic biometry, between 34 and 37 weeks of gestation. Demographically, there was no significant difference between the COVID-19–infected and uninfected pregnant women. No statistically significant differences were observed in fetal Doppler parameters, including the systolic/diastolic ratio (S/D), left and right UtA PI, MCA PI, and PI. Additionally, neither UA S/D nor PI showed variations. These findings indicate that mild to moderate COVID-19 infection does not affect fetal well-being or alter Doppler ultrasound parameters during pregnancy.
In their case-control study, Rizzo et al. [21] investigated the impact of SARS-CoV-2 infection on cardiac function and fetal umbilical vein flow. The study included 54 consecutive pregnancies affected by SARS-CoV-2 and compared them with 108 pregnancies that were not impacted by the infection. The comparison focused on umbilical vein blood flow adjusted for fetal abdominal circumference (UVBF/AC), atrial area (AA), and ventricular sphericity indices (SI). The interquartile range of gestational age at the time of illness was 26.2 to 34.1 years, with a median age of 30.2 years. The UVBF/AC levels showed no significant differences between the pregnancies affected by SARS-CoV-2 and those unaffected. Similarly, there were no significant differences in the left and right AA (left 1.30 vs. 1.28, P=0.221; right 1.33 vs. 1.31, P=0.324) and SI (left 1.75 vs. 1.77, P=0.208; right 1.51 vs. 1.54, P=0.121). It has been determined that women with moderate SARS-CoV-2 infections are comparatively less likely to experience adverse prenatal outcomes. A case-control study by Soto-Sanchez et al. [22] assessed the Doppler ultrasonography and placental findings in 57 pregnant women confirmed to have SARS-CoV-2 infection. The study included 32 ultrasound scans in the third trimester, 16 in the second trimester, and nine in the first trimester. For comparison, 110 expectant women (controls) were evaluated, with 19 in the first trimester, 43 in the second, and 48 in the third. The control group exhibited no symptoms and tested negative for SARS-CoV-2 infection. The study examined fetal dimensions, placental characteristics, and Doppler parameters related to the umbilical vein, including blood flow, venous cross-sectional area, and velocity. Pregnant women with SARS-CoV-2 infection had significantly greater placental thickness during the second and third trimesters (53.82 mm [range, 10 to 115 mm], P<0.001). The prevalence of more than four placental lakes was significantly higher in the infected group throughout all three trimesters (28 out of 57 [50.91%]) than in the control group (7 out of 110 [6.36%], P<0.001). Additionally, the average umbilical vein velocity was significantly higher in the infected group during all three trimesters (12.45 cm/s [range, 5.73 to 21 cm/s]) than in the control group (10.81 cm/s [range, 6.31 to 18.80 cm/s], P=0.001). Umbilical vein blood flow was also significantly higher in the infected group, with flow rates of 389.9 mL/min compared to 305.05 mL/min in the control group (P=0.05). The findings from placental and venous Doppler ultrasonography showed significant differences, with increased placental thickness, placental venous lakes, mean umbilical vein velocity, and umbilical vein flow in all three trimesters among expectant women infected with SARS-CoV-2.
Sotiriou et al. [23] conducted a case-control study on placental ultrasonographic findings during SARS-CoV-2 infection. The study involved 40 pregnant women who tested positive for SARS-CoV-2 and required hospitalization, along with 30 pregnant women who tested positive via SARS-CoV-2 RT-PCR but remained at home. The evaluation of placental involvement identified issues such as malperfusion, chorangiosis, deciduitis, and subchorionitis. These findings were observed in over 80% of the cases in the hospitalized group, but only in 25% of the cases in the non-hospitalized group. The researchers concluded that infected women are at a higher risk of complications and suggested that placental damage can be detected earlier through specific ultrasound findings. Soto-Torres et al. [24] performed case-control research on ultrasound and Doppler findings in pregnant women infected with SARS-CoV-2. The study included 106 pregnant women who tested positive for SARS-CoV-2 either at the time of an ultrasound scan or within 1 week of it. Forty-nine of these women were symptomatic, while 57 were asymptomatic. The assessments covered fetal biometry, fetal anatomy, amniotic fluid volume, and Doppler measures, including umbilical and fetal MCA PI, CPR, and BPP. The results showed that women who tested positive for SARS-CoV-2 had a higher occurrence of fetuses with abnormal Doppler assessments (8 out of 106, 7.5% vs. 2 out of 103, 1.9%; P=0.08) and fetuses with abnormal BPP (4 out of 106, 3.8% vs. 0 out of 103, 0%; P=0.14). There were two fetal deaths among the women who tested positive for SARS-CoV-2. Additionally, these women had a significantly higher risk of preterm delivery at or before 35 weeks of gestation than the control group (20.8% vs. 8.7%), with a OR of 2.73 (95% CI, 1.19 to 6.3; P=0.01). This indicates a higher incidence of preterm delivery at ≤35 weeks among SARS-CoV-2-positive women.
Turdybekova et al. [25] conducted a case-control study to compare clinical and placental characteristics in pregnancies affected by SARS-CoV-2 infection versus those without. The study population included 56 women with mild SARS-CoV-2 infection, 39 women with severe infection, and 114 SARS-CoV-2–negative women. The researchers assessed placental abnormalities such as infarction, vascular thrombosis, retroplacental hematoma, aberrant coloration, turbidity, disagreeable odor, placenta mass, and umbilical cord lesions. They found that severe SARS-CoV-2 infection significantly increased the likelihood of placental injury and neonatal hypoxic-ischemic episodes (P<0.001). Turgut et al. [26] carried out a case-control study examining fetal pulmonary artery Doppler parameters in pregnant women who had recovered from COVID-19, comparing them to a control group of 43 healthy pregnant women. The study revealed that women who had recovered from COVID-19 exhibited a higher peak systolic velocity in the main pulmonary artery and lower PIs than those in the control group (P<0.001 and P=0.001). Additionally, the acceleration time, ejection time, and acceleration/ejection time ratio of the fetal main pulmonary artery Doppler were significantly reduced in the COVID-19 recovery group (P<0.001, P=0.036, and P=0.002, respectively). Overall, the Doppler parameters were considerably lower in pregnant women post-COVID-19 recovery than in the healthy controls.
The included studies yielded a range of findings; therefore, the pooled ORs for aberrant placental features and altered Doppler ultrasonography parameters were calculated using primary event data extracted from all the included research. The analysis revealed that pregnant women infected with SARS-CoV-2 were more likely to experience placental abnormalities than the control group, as indicated by a pooled OR of 2.62 (95% CI, 1.66 to 4.13). Additionally, these women were also more likely to exhibit abnormal Doppler parameters than those in the control group, with an overall relative risk of 1.95 (95% CI, 1.16 to 3.27) and a statistically significant P-value of <0.05.
Limitations
This research focuses on the use of specific search criteria, including "placental findings," "Doppler ultrasound parameters," and "SARS-CoV-2-infected pregnant women" across various databases. However, certain limitations should be acknowledged. First, the study was limited to research conducted in English. Second, it is important to recognize the potential selection bias in this analysis, stemming from the exclusion of numerous studies. Lastly, the current meta-analysis included only 10 studies, which exhibit significant heterogeneity and variation. Additionally, with only a small number of patients in each subgroup, further research is necessary to understand the variations observed and how SARS-CoV-2 infection impacts the placenta and Doppler ultrasound parameters in pregnant women.
Conclusion
Based on this meta-analysis, it is concluded that SARS-CoV-2-infected pregnant women are at higher risk of abnormal Doppler ultrasound parameters and placental findings. SARS-CoV-2-infected pregnant women show increased placental thickness, increased placental venous lakes, altered fetoplacental circulation, and an abnormal CPR throughout all three trimesters of pregnancy. However, due to the limited number of case-control studies included, further research with larger sample sizes is necessary to validate these results and strengthen the evidence in the future.
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