Clinical Manifestation and Maternal Complications and Neonatal outcomes in Pregnant Women with COVID 19: An Update a Systematic Review and Meta-analysis


 Background Existing evidence indicates that the risk of obstetric and perinatal outcomes is higher in women with coronavirus infection. outbreaks suggest that pregnant women and their fetuses are particularly susceptible to poor outcomes. However, there is little known about pregnancy related complications and co-morbidity in this group of women. Therefore, this, systematic review and meta-analysis performed in order to find out whether COVID-19 may cause different manifestations and outcomes in antepartum and postpartum period or not.Methods We searched databases, including Medline (PubMed), Embase, Scopus, Web of sciences, Cochrane library, Ovid and CINHAL to retrieve all articles reporting the prevalence of maternal and neonatal complications, in addition clinical manifestations, in pregnant women with COVID 19 that published with English language from January to April 2020. Results 11 studies with total 177 pregnant women included in this systematic review.Results show that the pooled prevalence of neonatal mortality, lower birth weight, stillbirth, premature birth, and intrauterine fetal distress in women with COVID 19 were 4% (95% Cl: 1 - 9%), 21% (95% Cl: 11 – 31%), 2% (95% Cl: 1 - 6%), 28% (95% Cl: 12 - 44%), and 15% (95% Cl: 4 - 26%); respectively. Also the pooled prevalence of fever, cough, diarrhea and dyspnea were 56% (95% Cl: 30 - 83%), 30% (95% Cl: 21 - 39%), 9% (95% Cl: 2 - 16%), and 3% (95% Cl: 1 - 6%) in the pregnant women with COVID-19.Conclusion According to this systematic review and meta-analysis, the pregnant women with COVID-19 with or without pneumonia, are at a higher risk of pre-eclampsia, preterm birth, miscarriage and cesarean delivery. Furthermore, the risk of LBW and intrauterine fetal distress seems increased in neonates.


Introduction
The global pandemic due to coronavirus has become a major burden in the world infecting over a million patients (1). There are six different CoV strains in humans of which, severe respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory Syndrome (MERS-CoV) are the most known types (2). Coronavirus is an enveloped and single-strained ribonucleic acid having 9-12 nm-long surface spikes. One of the four major proteins on the envelope binds to angiotensin converting enzyme2 (ACE2) receptor for entering the host cell (3,4). It was rst reported in Wuhan, China, in December 2019, causing a spectrum of symptoms from asymptomatic to death which are mostly nonspeci c. Respiratory signs and symptoms accompanied with some other manifestations such as fever, sore throat, cough, diarrhea, nausea, vomiting are the common symptoms of COVID-19 (5,6). In blood test assay, patients might have lower blood cell counts (Lymphopenia, thrombocytopenia,( and increased C-reactive protein level, erythrocyte sedimentation rate, lactate dehydrogenase, creatinine, and a prolonged prothrombin time (7,8). It can be transmitted through human-to-human contacts mainly by respiratory droplets (9).
According to the knowledge currently available in the literature about the susceptibility of pregnant women to SARS-CoV and MERS-CoV, it seems that there should be a great attention to the coronavirus infection in pregnancy (10). There are several physiological changes during pregnancy which can make the mother more susceptible to severe infections (11). The converted function of cardiorespiratory and immune system, physiologic dyspnea due to increased maternal oxygen demands, the alteration in pulmonary demands can put pregnant women at the risk of severe infection and hypoxic compromise as well as misdiagnosis and mismanagement of routine upper respiratory tract symptoms (12,13). Since there is a great amount of ACE2 receptor expressed in the placenta, the scientists are concerned about the possibility of vertical transmission (14,15).
In this article, we have evaluated several factors such as maternal and neonatal complications, therapeutic managements, signs and symptoms in pregnant women in a systematic review and metaanalysis in order to nd out whether COVID-19 may have a different manifestation and outcome in antepartum and postpartum period or not.

Methods
This systematic review and meta-analysis was performed according to the Meta-Analyses of Observational Studies in Epidemiology (MOOSE) and Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for reviews of analytical observational studies (16, 17).

Search Strategy and Screening
All original published articles were searched in international databases, including Medline (PubMed), Embase, Scopus, Web of science, Cochrane library, Ovid and CINHAL to retrieve all articles reporting the prevalence of maternal and neonatal complications, therapeutic managements, signs and symptoms in pregnant women with COVID 19. Researchers performed a search of these databases, with hand searching through the reference lists and grey literature. We searched in these search engines without language limitations from January to April 2020. The search protocol developed based on four main roots of "Maternal Complications", "Neonatal Complications", "Signs" and "Therapeutic Management".
Reference Manager bibliographic software was used to manage searched citations. Duplicate entries were searched by considering the title of the published papers, authors, the year of publication, and speci cations of the sources types. In questionable records, the texts were compared. We reviewed the primary search results, and after reviewing each article by title and available abstract, some of the articles were eliminated. The evaluation of the papers under consideration was based on the inclusion and exclusion criteria by the two researchers, separately (YM, MS).

Eligibility Criteria
We included all observational studies which assessed the prevalence of maternal and neonatal complications, therapeutic managements, signs and symptoms in pregnant women with COVID 19. We excluded duplicate citations non-peer-reviewed, articles that the abstract and full text was not available, and other languages.

Data Extraction
After three steps of assessment for titles, abstracts and full texts, the full text of each selected article was retrieved for detailed analysis. Data were extracted using a checklist recording authors, publication year, type of study, total of sample, gestational age, cesarean, vaginal delivery, chronic illness, indicators of cesarean, complications of pregnancy, Signs and symptoms (fever on admission, cough, malaise, dyspnea, myalgia, sore Throat, diarrhea, nausea and vomiting, fetal movement, fetal heart rate, vaginal bleeding, premature rupture of membrane, antepartum, post-partum), laboratory tests, imaging, treatment and other parameters (abnormal Laboratory test, imaging, Bio Physical Pro le, maternal mortality, maternal ICU admission, neonatal mortality, intrauterine fetal death, vertical transmission, treatments), and infant characteristics (birth weight, low birth weight, premature birth, Apgar score, intrauterine fetal distress, severe neonatal asphyxia, neonatal death, fetal death or stillbirth). All processes from systematic search to nal data extraction were followed independently by two research experts (YM, MS) (Kappa statistic for agreement for quality assessment; 0.97). Probable discrepancies were resolved by the main investigator.

Risk of Bias
Qualitative evaluation of studies based on the Newcastle-Ottawa Quality Assessment Scale (NOS) (18) was performed by two of the authors (YM and MS). This scale is designed to evaluate the qualitative evaluation of observational studies. NOS examines each study by six items in three groups; selection, comparability, and exposure. Stars are given to each item and the maximum score is 9. In case of differences in the score assigned to the published articles, the external discussion method will be used.
Finally, the articles were categorized as low, moderate and high risk. The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist was also completed for all articles (19, 20).

Statistical analysis
The random effects model was applied to calculate the pooled prevalence with 95% con dence interval (95%CI) with Metaprop order. Heterogeneity across studies was evaluated using I2 value and reported as a percentage (%) to determine the extent of variation between-studies. A forest plot was used to schematically present the meta-analysis results. The Egger's test and funnel plot were used for evaluating the publication bias. In addition, a subgroup analysis was done to identify different sources of heterogeneity. Statistical analysis was performed using STATA 16.0 (Stata Corp, College Station, TX, USA), and statistical signi cance was considered P-Value < 0.05.

Results
Study characteristics 306 articles were initially retrieved on the basis of the search strategies in the online databases. Among these articles, 97 duplicate publications were identi ed and removed. The remained ones were screened according to the titles and abstracts. 11 articles were selected as the nal papers to be analyzed ( Figure  1). The characteristics of 11 selected studies were demonstrated in Table 1. A total number of 177 pregnant women with COVID-19 were evaluated all in 2020 through 8 retrospectives, 1 case control, and 2 case report studies. The factors assessed in these studies involve gestational age, cesarean, vaginal delivery, chronic illness, indicators of cesarean, complications of pregnancy, signs and symptoms (fever on admission, cough, malaise, dyspnea, myalgia, sore throat, diarrhea, nausea and vomiting, fetal movement, fetal heart rate, vaginal bleeding, premature rupture of membrane, antepartum, post-partum), laboratory tests, imaging, treatment and other parameters (abnormal laboratory test, imaging, Bio Physical Pro le, maternal mortality, maternal ICU admission, neonatal mortality, intrauterine fetal death, vertical transmission, treatments), and infant characteristics (birth weight, low birth weight, premature birth, Apgar score, intrauterine fetal distress, severe neonatal asphyxia, neonatal death, fetal death or stillbirth) ( Table 1) The least reported prevalence of fever in pregnant women with COVID 19 was 17% (95% Cl: 2 -33%) in the study by Wang X. et al. and the highest fever as prevalence was recorded 86% (95% Cl: 60-98%) in the retrospective study by Yu. et al. In total, the pooled prevalence of fever has been estimated as 56% (95% Cl: 30 -83%; I 2 = 92.02%; P -Value < 0.01) ( Figure 2 and Table 2). The Meta Regression was used to explore relationship of independent variables (age and gestational age) with the pooled prevalence of primary outcomes. The results of Meta regression showed that the prevalence of fever has not any relationship with age (coe cient: 0.029, P: 0.293, 95% CI: -0.026, 0.032), and gestational age of pregnant women with COVID 19 (coe cient: 0.023, P: 0.451, 95% CI: -0.021, 0.026).
Pooled prevalence of complications in pregnancy and Cesarean indications in pregnant women with COVID 19 Results of this meta-analysis show that the pooled estimate of preeclampsia and fetal distress in women with COVID 19 were 26% (95% Cl: 3 -54%; I 2 = 89.13%; P -Value = 0.00) ( Table 4).

Publication Bias Assessment
The results of Egger's test show no signi cant bias occurred in the publication of the results (Egger's test = 1.15, SE: 0.480, P = 0.216).

Discussion
A total number of 177 pregnant women with COVID-19 were evaluated all in 2020 through 8 retrospective (21-28), 1 case control (29), and 2 case report studies (30, 31). The purpose of this systematic review and meta-analysis was to investigate the prevalence and relationship of several factors associated with COVID-19 in pregnancy and the effect of these factors on the maternal and neonatal outcome. Although a meta-analysis has been already published (32), we tried to have an update on this subject because of the fast rate of publications about the new data on COVID-19. We attempted to nd out the severity of COVID-19 in pregnancy for providing optimum and on time diagnosis to prevent side effects and poor outcomes. In some cases, which the data was completely presented, we could carry out the metaanalysis.
The results of this paper demonstrate that the common signs and symptoms in pregnant women are fever, myalgia, increased CRP, increased LFT and Lymphopenia. As it was mentioned in results, the prevalence of fever, myalgia, sore throat and diarrhea was not related to age and gestational age of pregnant women, while cough and dyspnea had relationship with age and gestational age. About the neonatal factors, the prevalence of premature birth and fetal distress were not correlated with age and gestational age. Among laboratory tests also, Lymphopenia and increased CRP had not any correlation with age and gestational age. All the pregnant women admitted to the hospital had radiological features of COVID-19 pneumonia in CT scan or CXR. Their signs and symptoms were all similar to the nonpregnant population. The prevalence of preterm birth was 28% which is a high rate in comparison with healthy pregnancies. The rate of preeclampsia and cesarean section was more than the general population. The most common adverse perinatal outcome was fetal distress (26%) accompanied with a low rate of fetal death or stillbirth (2%) and neonatal death (4%). We investigated that there is not any clinical evidence of vertical transmission in the newborns, but previous evaluations caused by similar viruses such as SARS and MERS were indicative of vertical transmission (33). Other studies on three newborns showed elevated SARS-CoV IgM antibodies. But the reported nasopharyngeal samples were negative (32, 34). Yang X et al reported an asymptomatic COVID-19 pregnant woman in the late period of pregnancy. They did not nd any intrauterine infection caused by vertical transmission (35). But another study which has evaluated seven pregnant women with severe SARS-CoV-2, has demonstrated that the vertical transmission of COVID-19 infection from mothers during the last days of pregnancy is possible. The method of delivery in this study was C-section. So they concluded that the route of infection was trans-placental. Therefore, there cannot be any advantage for C-section compared to vaginal delivery (36). Rose et al also reported another case of severe COVID-19 during pregnancy. They believe there is a concern for vertical transmission and suggest an exact care for pregnant women as a high risk group (30). So we believe that the possibility of maternal-fetal transmission could not be ruled out completely.
In our systematic review, women suffering from COVID-19 had higher rates of preeclampsia and preterm birth. The fetuses had higher rates of fetal distress and the babies had higher rates of LBW. These data are retrieved from the women in the third trimester of pregnancy. The underlying diseases in pregnant women were gestational hypertension, diabetes and hypothyroidism. One patient needed mechanical ventilation which was not related to any underlying disease. One patient had multi organ dysfunction syndrome (MODS) leading to one stillbirth. One baby had severe neonatal asphyxia. Apgar score was in the normal range in all neonates (except one stillbirth and one asphyxia). Three women had voluntary termination. Two studies had twins, so 4 out of 13 LBW babies were due to twin delivery. But they all had normal infant characteristics without any evidence of COVID-19.
There is a study that has reported two cases of maternal ICU admissions. But these cases had underlying risk factors (high BMI>35) and complicated medical history (37). This can be a con rmation that COVID-19 alone cannot increase the risk maternal and neonatal morbidity. Some other studies have applied Csection for the majority of cases and reported that fetal distress was the major cause of decision for Csection (21, 38). Since fetal distress in our study has not any relationship with age and gestational age of pregnancy, so COVID-19 cannot be a cause of pregnancy termination by C-section.
There is a lack of data about the COVID-19 infection in the rst and second trimester (32). On the basis of the results of this systematic review, there should be a multidisciplinary team of gynecologists, obstetricians, infection disease specialists and neonatologist to decide about the method of delivery (Csection or vaginal delivery). The indications should be evaluated more carefully.

Strengths
This is a comprehensive meta-analysis involving 11 valid publications and evaluating 177 pregnant women on this topic. Most of studies had an appropriate study population. The possibility that some patients were included in more than one report was low. The number of case reports in our assay was low. This leads to a lower risk of publication bias which increases the level of the evidence about our ndings.

Limitations
The major limitations of this systematic review were the poor reports about the exact indications of Csection. We believe that most of C-sections were not necessary. Furthermore, the reported data about the pregnant women whose pregnancy was not terminated during the admission was limited. There was not a clear data about the neonates admitted in NICU. This can cause overestimation or underestimation of the risk of COVID-19 in pregnancy.

Conclusion
According to this systematic review and meta-analysis, the pregnant women with COVID-19 with or without pneumonia, are at a higher risk of preeclampsia, preterm birth, stillbirth and unnecessary cesarean delivery. Furthermore, the babies are at increased risk of LBW and intrauterine fetal distress. Although there cannot be any vertical transmission between mother and the fetus, the evidences show that it is still controversy. Hence, it is recommended to perform complete and exact evaluation of COVID-19 for the pregnant women at the time of admission. Chest CT-scan and RT-PCR testing seems to be necessary in these cases in order to prevent antenatal and postnatal complications and have a better outcome. Since the evidences are increasing, there may be several updates in a soon future.

Declarations
Ethics approval and consent to participate Not applicable because no primary data were collected.

Consent for Publication
Not applicable.

Availability of data and material
Data is available and it can be accessed from the corresponding author with reasonable inquiry.

Competing interests
The authors declare that they have no competing interests.

Funding
None.
Authors' contributions YM conceptualized the idea for this review, formulated the review question, and objectives, assisted with the development of the nal search strategy, contributed to the data analysis/ interpretation, and writing the manuscript. MM, HRB, GM and MM contributed to the writing the manuscript. All authors contributed equally to the formulation of the review question/objectives, development of the search strategy, conducting the searches, data extraction, data analysis/interpretation, and writing the manuscript. All authors read and approved the nal manuscript.        The pooled prevalence of Fever in pregnant women with COVID 19 Figure 3 The pooled prevalence of caught in pregnant women with COVID 19 Page 23/24 The pooled prevalence of Dyspnea in pregnant women with COVID 19 Page 24/24

Figure 5
The pooled prevalence of premature birth in pregnant women with COVID 19 Figure 6 The pooled prevalence of Intrauterine fetal distress in pregnant women with COVID 19