ASSOCIATION OF SARS-COV-2 INFECTION WITH RISK AND SEVERITY OF

PREECLAMPSIA AND ITS OUTCOME TO THE NEW BORN: A SYSTEMATIC

REVIEW AND META-ANALYSIS
I Gusti Bagus Mulia Agung Pradnyaandara1, Gusti Ngurah Prana Jagannatha1, I Gde Sastra

Winata2
1
Bachelor of Medicine and Medical Profession, Faculty of Medicine, Udayana University,

Denpasar, Bali, Indonesia;

2
Department of Obstetric and Gynecology, Faculty of Medicine, Udayana University,

Denpasar, Bali, Indonesia.

Objective: Hypertension is one of the comorbidities that most often accompanies SARS-
CoV-2 Infection, but its relationship with preeclampsia and its outcomes are still unclear.
The aim of this study was to determine relationship of SARS-CoV-2 infection to the risk and
severity of preeclampsia, as well as its impact on newborns.
Methods: We performed a systematic search in databases (PubMed, ScienceDirect,
ProQuest, and Cochrane Library) for studies examining impact of SARS-CoV-2 infection on
pregnancy. Included studies were evaluated for risk of bias based on the Newcastle Ottawa
Score. A meta-analysis was conducted using the data extracted from each study. Review
Manager 5.4 was utilized to compute the summary of odds ratios, mean differences, and 95%
confidence intervals (95%CI) for the outcomes. Our outcomes of interest are preeclampsia,
preeclampsia with severe features, eclampsia, fetal distress and still birth. The other
outcomes are preterm birth, instrumental labor, sectio caesaria and birth defect.
Results: We identified 22 observational studies involving 1,025,048 patients. Based on the
analysis, SARS-CoV-2 infection in pregnancy increased the risk of preeclampsia [OR 2.01
(95% CI 1.59-2.53 ;p<0.00001; I2=82%)], and the severity was based on the high prevalence
of preeclampsia with severe features [OR 3.04 (95%CI 1.19-7.78; p=0.02; I 2=91%)] and
eclampsia [OR 17.73 (95%CI 13.83-22.72; p<0.00001; I 2=0%)]. Poor outcome in newborns
in terms of incidence of preterm birth [OR 1.65(95%CI 1.54-1.76; p<0.00001; I 2=86%)],
fetal distress [OR 19.18 (95%CI 17.14-21.45; p<0.00001; I2=99%)] and still birth [OR
2.12(95%CI 1.74-2.59; p<0.00001; I2=0%)], were also significantly associated with SARS-
CoV-2 infection.
Conclusion: SARS-CoV-2 infection during pregnancy increases the risk and severity of
preeclampsia and gives a poor outcome in newborn.
Keyword: COVID-19, newborn, pregnancy, preeclampsia, SARS-CoV-2

Introduction
Preeclampsia is one of the leading causes of maternal death worldwide, which is about
14% of all maternal deaths.1 Preeclampsia caused 5.3% of maternal deaths in the United
States in 2018.2 Preeclampsia has several risk factors, including primiparas, obesity, kidney
disease, chronic hypertension, multiple or mola pregnancies, and pregestational or gestational
diabetes mellitus. Therefore, preeclampsia is known as a multisystem disease. Preeclampsia
is known to result from pathological factors associated with implantation, placental
development, and remodeling of damaged spiral arteries. It causes maternal uteroplacental
and vascular malperfusion accompanied by altered immunoregulation and an inflammatory
response.3-5 In the United States, preeclampsia is the leading cause of maternal death, severe
maternal morbidity, premature rupture of membranes, low birth weight, caesarean section,
prematurity and fetal growth restriction.6,7
Corona Virus Disease 2019 (COVID-19) was declared a global pandemic by WHO in
March 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Pregnant women and infants are a vulnerable population to COVID-19, due to physiological
changes during pregnancy involving the immune and cardiorespiratory systems, which result
in an altered response to SARS-CoV-2 infection in pregnancy. 8 The fetus can be exposed to
SARS-CoV-2 during a critical period of fetal development.9
Several clinical studies suggest that COVID-19 is associated with an increased risk of
preeclampsia and a preeclampsia-like syndrome in pregnant women infected with COVID-19
during pregnancy, but the results remain controversial. 10,11 Therefore, we conducted a
systematic review and meta-analysis to determine the association. between COVID-19 in
pregnancy and the risk and severity of preeclampsia and its outcomes in newborns

Method
A systematic search was conducted in electronic databases (PubMed, ScienceDirect,
ProQuest, and Cochrane Library) for prospective and retrospective observational studies
examining the association of COVID-19 in pregnancy with preeclampsia and newborn
outcome. The keyword search terms we used were the following including: “COVID-19”
“SARS-CoV-2” and “PREEKLAMPSIA” from March 2019 to December 2021. No
publication language filter was applied.
 We included observational studies that assessed the association between SARS-CoV-2
infection during pregnancy and preeclampsia that included data on newborn outcomes and
reported odds ratios (OR) or estimated relative risk (RR) and 95% confidence intervals (CI).
The exposed group was pregnant women with a diagnosis of acute or previous SARS-CoV-2
infection at any stage of pregnancy, which was based on a positive reverse transcriptase-
polymerase chain reaction (RT-PCR) test result or a positive antigen test on samples
collected from the upper respiratory tract. above, or a positive result for anti-SARS-CoV-2
antibody in serum. The unexposed group were pregnant women with negative RT-PCR or
antigen test results in samples collected from the upper respiratory tract, or negative antibody
test results in serum, or those who became pregnant and gave birth before the pandemic. A
study was excluded from this study if (1) the form of the study was a case series or case
report, editorial, commentary, review, without data; (2) only examined the relationship
between SARS-CoV-2 infection and gestational hypertension and did not include specific
data on the prevalence of the preeclampsia category; (3) if risk estimates or CIs are not
reported; (4) the study did not include any newborn outcomes that had been defined in the
study.
The researchers extracted data on the basic characteristics, prevalence and severity of
preeclampsia, as well as newborn outcomes from included journals. Data on basic
characteristics included age, BMI, number of pregnancies, number of deliveries, and
smoking status. Assessment of the risk and severity of preeclampsia includes the overall
prevalence of preeclampsia, severe preeclampsia, and eclampsia. Outcomes of newborns
include stillbirth, premature birth, fetal distress, instrument-assisted birth, caesarean section,
and birth defects. Furthermore, the systematic quality assessment of the included studies was
independently assessed by the investigator with the Newcastle-Ottawa Scale (NOS) which is
preferred for observational studies. Investigations were classified as low quality (<5 points),
medium (5-7 points), and high quality (>7 points).
Categorical variables were analyzed as proportions. Data were collected using the
Mantel-Haenszel fixed effects model with odds risk (OR) as an effect measure with a 95%
confidence interval (CI). Statistical heterogeneity between groups was measured using the
Higgins I2 statistic. In particular, I2=0 indicates no heterogeneity, while we assume high
heterogeneity based on I2 values above 50%. All analyzes were performed using Review
Manager 5.4.1 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2020). P value <
0.05 was considered statistically significant.
Results
Initial searches found 3209 studies. After conducting a full-text evaluation of 107
potentially eligible studies, 22 studies were included in the systematic review and meta-
analysis (Fig. 1).

Figure 1. Flower Chart of the study selection process according to Preferred Reporting Items
for Systematic reviews and Meta-Analyses (PRISMA statements)

Of the included studies, study characteristics are presented in Table 1. All studies were
prospective or retrospective observational studies. In short-term results, all studies included
data on the prevalence of pregnant women who developed preeclampsia with 6 studies
further classifying preeclampsia with severe features, and 2 studies including data on
eclampsia. On newborn outcomes, 10 studies included stillbirth, 20 studies of preterm
delivery, 11 studies of fetal distress, 3 studies of assisted delivery, 20 studies of cesarean
delivery, and 6 studies related to birth defects.
Among the 22 studies,12-33 populations were found to be diverse from Asia, Europe,
America and Africa. 2 studies from papagiorghiou and Villar included populations from
many countries. 1,025,048 patients were included, 15,229 patients had COVID-19 and
1,009,819 patients did not have COVID-19. Among the studies, ages varied from 25 to 33
years and 43,235 of the total population had preeclampsia with a ratio of 1086 COVID-19
patients and 42,149 non-COVID-19 patients.

Table 1. Subject characteristics of the included studies

Assessment of quality and risk of bias was assessed using the New Castle Ottawa
Scale in 22 studies, no study was categorized as having a high risk of bias, all studies were
categorized as moderate quality studies.
Based on the analysis, SARS-CoV-2 infection in pregnancy increases the risk of
preeclampsia, which can be seen from the frequency of women with preeclampsia found to
be significantly more in pregnant women infected with COVID-19 with a relatively narrow
CI, although with high heterogeneity [OR 2.01 (95% CI 1.59-2.53; p<0.00001; I2=82%)].
This result can be seen from the consistency of the findings in almost all studies except the
study of Egerup and Adhikari.21,25 The severity in our study was assessed by looking at the
frequency of patients with severe preeclampsia and the frequency of eclampsia patients based
on the presence or absence of COVID-19 was also found to be significantly higher in patients
with COVID-19 [OR 3.04 (95% CI 1.19 - 7.78; p=0.02; I2=91%)] and [OR17.73 (95% CI
13.83-22.72; p<0.00001; I2=0%)] sequence with low heterogeneity in the parameters of
eclampsia, but it should be noted that only 2 studies included these parameters. (Figure 2.)
 Figure 2. Forest plot of risk and severity of preeclampsia in COVID-19
The mechanism of SARS-CoV-2 infection during pregnancy may be involved in the
pathogenesis of preeclampsia. SARS-CoV-2 enters cells by binding to the cell membrane
angiotensin converting enzyme 2 (ACE2) receptor.34,35 The ACE2 receptor is an important
component that converts angiotensin II to angiotensin 1 to 7. The RAS plays a role in
angiogenesis, trophoblast proliferation, and blood flow. Thus, it is an important regulator of
placental function. The RAS modulates uteroplacental blood flow through a balance between
vasoconstriction and vasodilation pathways.36 SARS-CoV-2 binding to the ACE2 receptor
results in downregulation of the RAS system by decreasing the vasodilatory levels of
angiotensin 1 to 7, resulting in the vasoconstrictive and proinflammatory effects of
angiotensin I, which are thought to play a role. in the pathophysiology of preeclampsia.37,38
 SARS-CoV-2 is known to infect the syncytiotrophoblast and activate an inflammatory
response in the placenta of infected women. 39 Verma et al40 found that SARS-CoV-2
colonizes maternal and fetal cells expressing the ACE2 receptor in the placenta. There is a
decrease in ACE2 receptor expression, and an increase in the production of soluble tyrosine
kinase-1 such as fms (sFlt-1) and a concomitant decrease in proangiogenic factors in infected
placentas. It was also found that serum levels of the sFlt-1 receptor autoantibodies and
angiotensin II type 1 were significantly higher in women with prenatal SARS-CoV2 infection
than in uninfected women. The findings of this study provide a clear mechanism to explain
the association between SARS-CoV-2 infection and preeclampsia, so it is plausible that in
our study women with COVID-19 had a significantly higher frequency and severity of
preeclampsia.
Adverse outcomes in newborns, women with COVID-19 had a significantly higher
frequency of preterm birth with all studies that included these data consistently showing the
same results and analysis showing a relatively narrow CI [OR 1.65 (95% CI) 1.54-1.76;
p<0.00001; I2=86%) ]. In line with these findings, the frequency of fetal distress [OR 19.18
(95% CI 17.14-21.45; p<0.00001; I2=99%)] and stillbirth [OR 2.12 (95% CI 1.74-2.59;
p<0.00001; I2 =0%) ], also significantly higher in patients with SARS-CoV-2 infection, but
not with the incidence of birth defects [OR 1.45 (95% CI 0.96-2.17; p=0.08; I2=0%)] and
delivery by cesarean section [OR 1.75 (95% CI 0.54-5.62; p=0.35; I2=100%) ], where
although COVID-19 tends to increase the risk of both parameters, it does not reach statistical
significance due to the inconsistency of findings in studies that include these parameters.
(Figure 3)
In line with the relationship between COVID-19 and preeclampsia, this study also
found a poor outcome in newborns. Eclampsia/pre-eclampsia contributes to perinatal
mortality. This is due to impaired nutrition and oxygenation of the fetus caused by utero-
placental vascular insufficiency. Although the mechanism is not clearly known.41. Not only
through preeclampsia, COVID-19 is also known to have a direct impact on the fetus. It can
be via vertical intrauterine transmission, via the ACE2 receptor, as well as the breakdown of
the placental blood barrier and the systemic inflammatory response involved in the
pathogenesis of preterm birth and a suboptimal environment for fetal growth and
development, this is in line with the significance of the frequency of preterm delivery, fetal
distress. , stillbirths, in mothers with higher rates of COVID-19. It has been found in
histopathological findings in patients with COVID-19 at delivery, namely fetal placental
vascular malperfusion.42-44
Figure 3. Forest Plot Outcome of Newborns in Preeclampsia with COVID-19
Conclusion:
COVID-19 in pregnancy increases the risk of preeclampsia as well as the severity of
preeclampsia. Preeclampsia together with COVID-19 has the potential to contribute to poor
newborn outcomes, prevention and immediate treatment have the potential to provide a better
outcome for both mother and baby.

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