Intrauterine vertical transmission of COVID-19 during pregnancy: A systematic review

Background: COVID-19 infection in pregnancy raised concerns about the risk of intrauterine vertical transmission of the SARS-CoV-2 from mother to fetus. Objectives: To review the current evidence on the possibility of intrauterine vertical transmission potential among COVID19 infected pregnant mothers. Methods: Eligible studies published from December 2019 until August 1, 2020, were searched for from PubMed, PubMed Central, Google scholar, medRxiv, and bioRxiv collection databases using MeSH-compliant keywords including COVID19, pregnancy, intrauterine vertical transmission, Coronavirus 2019, SARS-CoV-2, 2019-nCoV, and maternal-fetal


Introduction
Coronavirus Disease 19 , which is officially named by World Health Organization (WHO) on February 11, 2020 1  8 worldwide to be declared as "a public health emergency of international concern". 3 The virus that causes COVID-19 has been named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. 4 COVID-19 is a highly contagious disease with multiple possible routes of transmission. 5,6 There are many studies, which indicate personto-person transmission of the virus through close contact with infected person or through droplets when the patient coughs or sneezes, 7 or through surfaces touched by an infected person causing a series of respiratory illnesses. 8 Several studies reported that the virus might be present in feces of some patients, which may be a potential route of transmission; however, such route is not a main feature of the epidemic. [9][10][11] Vertical transmission is defined as "mother-tofetus passage of a disease-causing agent (pathogen) during the period immediately before and after birth. Transmission might occur across the placenta, delivery via ingestion or aspiration of cervico-vaginal secretions, or immediately after birth via breastfeeding". 12 SARS-COV-2 is a new strain of corona virus, which is recognized to be pathogenic to humans. The homological modeling indicated that SARS-CoV-2 has a similar structure of the receptorbinding domain to the other two famous strains of corona virus; the SARS-CoV-1 and the Middle-East respiratory syndrome (MERS) coronavirus (MERS-CoV). 13 Previous studies revealed that SARS and MERS infection during pregnancy was associated with adverse maternal and neonatal complications including severe maternal illness and death, spontaneous abortion, preterm delivery, and intrauterine growth restriction. However, the likelihood of vertical transmission occurring with either SARS or MERS was low. 14,15 It remains essential to see whether the risk of COVID-19 vertical transmission is low as that reported for SARS-CoV-1 and MERS infections. Some concerns about the vertical transmission potential of Covid-19 and its impact on newborns were reported. 16

Statistical analysis
The positive rates of the SARS-CoV-2 testing outcomes were estimated. Pooled proportions were calculated with percentages and 95% CI (Confidence interval).
Calculations were done using the MedCalc Statistical Software version 19.3.1. 18

Results
The initial search yielded 152 articles. After elimination of duplicates, review, commentaries, and articles from media, 78 articles were deemed relevant and comprised neonatal outcome data for 1231 neonates whose mothers were infected with COVID-19. Of these, 24 articles that fulfilled the inclusion criteria were eventually selected for analysis 19

Discussion
After primary infection of the mother, vertical transmission occurs via placenta during intrauterine life, during delivery through aspiration of cervico-vaginal secretions, and postpartum through breastfeeding. 43 SARS-CoV-2 was found to have a structure with a receptor domain similar to that of SARS-CoV-1. 13 Therefore, it was assumed that the risk of vertical transmission and pathogenecity of COVID-19 may be similar to that of SARS CoV-1. 44 Previous studies 45,46 showed that in infections caused by similar pathogen of corona virus such as severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), the fetal morbidity is not exclusively caused by vertical transmission. In this review, most of the analyzed studies tend to conclude that the risk of intrauterine vertical transmission of SARS-CoV-2 is possible but uncommon. However, many other studies confirm no evidence of vertical transmission. 47--50 Such inconsistency and uncertainty about definite intrauterine vertical transmission may be due to first; nasopharyngeal, throat, and anal swabs cannot definitely indicate an intrauterine infection. 17 Many studies showed that most women who tested positive for COVID-19 by nasopharyngeal swabs were found to be negative by amniotic fluid and vaginal specimens. 17,51,52 Second; samples of placental tissues, amniotic fluids, and cord blood either not tested for viral particles or showed negative results 20,21,27,53 Third; in many studies, the investigations delayed 1-7 days after delivery. 20,21,41 In such case, the possibility of postnatal and nosocomial infection cannot be excluded. 54 Carosso et al 55 reported an asymptomatic female infant born by vaginal delivery to a covid-19 infected woman. The neonate was tested positive for SARS-C0V-2 by nasopharyngeal swab at delivery but negative after 36 hours. Placental swab on the fetal side was negative by RT-PCR as well as the vaginal swab, but the maternal rectal swab was positive. They concluded that the second negative result could be explained by the low amount of viral RNA in the second sample or due to fecal contamination through the vaginal canal. Fourth; SAR-CoV-1, a corona virus with similar genome consequence was not found to be associated with intrauterine vertical transmission. 14,17,56 Fifth; the infrequent occurrence of placental infection with SARS-CoV-2 may be attributed to the minimal placental expression of angiotensin-converting enzyme 2 (ACR2) receptors, which facilitates the cell entry of the virus, particularly during the first trimester of pregnancy. 57,58 Sixth; the presence of maternal fetal interface barrier, even it is not completely effective, could provide fetal protection against infection, 59,60 furthermore, immune cells in the placenta have antiviral ability. 61 Seventh; some studies, 19,22,62 postulate the probability of intrauterine vertical CVID-19 transmission on the basis of IgM detection in fetal blood. However, due to its structure, IgM antibody cannot usually cross the placental barrier. It was suggested that this could be a possible fetal immune response to the infection. 63 Such evidence is not crucial since placental alterations may allow passage of IgM, or the serological test might be false positive. Eighth, the detection rate by existing methods depends on viral load; therefore, the negative results in placenta or umbilical cord nucleic acid might be false negatives. 44 Ninth, since all the infected women were in their late pregnancies (second or third trimester), it is difficult to have an idea about the dynamics of transmission of infection and the impact on the fetus when mother's infection occurs early in gestation, as there is no explicit data available yet. 32 infected women. In one case, expression of the S protein as well as the N (nucleocapsid) protein in the syncytiotrophoblast was shown. They provided evidence that SARS-CoV-2 can pass across the maternal-fetal interface to infect fetus prior to delivery. However, Hecht et al 58 reported that the best way to prove the infection of placenta is by identifying cellular evidence of viral infection rather than PCR detection of the virus in placental swab. They also indicated that the placenta could be infected by SARS-CoV-2 but this event is rare. Similarly, Penfield et al 66 reported that the existence of viral RNA in placental and membranes samples at time of delivery detected by RT-PCR was not found to be associated with infection of the neonates and not necessarily indicates vertical transmission. In regards to nasopharyngeal swab RT-PCR, which is commonly used for testing for SARS-CoV-2 infection, the pooled proportion of possible vertical transmission was 3.1% (95% CI, 2.2-4.2). This result is in agreement with that reported by Kotlyar et al 67 systematic review and meta-analysis study.

Conclusion
Based on the results of this review, the risk of intrauterine vertical transmission of SARS-CoV-2 is controversial. It can occur but is rare. It was found that the virus could be detected in the placenta; however, the placenta can act as a barrier even if it is not completely effective. Extensive investigations and further studies are needed to examine the mechanisms and the placenta barrier particularly during early pregnancy.