COVID-19 during pregnancy should we really worry from vertical transmission or rather from fetal hypoxia and placental insu ciency? A systematic review and meta -analysis


 Background:COVID-19 is the largest outbreak to strike humanity. The wide scale of fatalities and morbidities lead to a concurrent pandemic of uncertainty in scientific evidence. Conflicting evidences are released on daily basis about the neonatal outcomes of COVID-19 positive mothers. The aim of this study was to use the relevant case reports and series to determine the percentage of newborns who test positive in COVID-19 positive mothers. Secondary outcomes included examining laboratory and placental abnormalities among fetus-mother pairs.Methods:Systematic review was performed on all studies reporting primary data on fetus-mother pairs with COVID-19. Data bases were searched for studies that met our inclusion and exclusion criteria.Results: Final screening revealed 66 studies, from which the primary data of 1787 mother-infant pairs was obtained. Only 2.8% of mother infant pairs were tested positive, and this finding is identical to percentages reported in former coronaviridae outbreaks. Whereas, 20% manifested with intrauterine hypoxia alongside placental abnormalities suggestive of heavy placental vaso-occlusive involvement. Conclusions: These findings suggest that while vertical transmission is unlikely, there appears to be an underlying risk of placental insufficiency due to the prothrombotic tendency observed in COVID-19 infection. Guidelines for proper prophylactic anticoagulation in COVID positive mothers need to be established.

Background COVID-19 (Coronavirus disease 2019), which has been declared a pandemic in March 2020, has caused an unpreceded uncertainty within the scienti c community. Contradictory scienti c evidences are released almost every day, on every aspect of the pandemic from its pathogenesis, to the methods of transmission, and to the possible compassionate use of medications to combat it. Transplacental transmission of COVID- 19, is one of the topics that have raised con icting evidences across the globe. The dilemma about transplacental transmission of coronaviridae is not exclusive to the current outbreak. To our knowledge, nine studies 1-10 from SARS-1 (Severe Acute Respiratory syndrome) and HKCoV (Hong Kong Coronavirus) and MERS (Middle East Respiratory syndrome) outbreaks were reported; ranging from case reports to retrospective case reviews, comprising 71 mother-infant pairs. Table 1 summarizes the ndings of the nine studies. Two cases only have shown vertical transmission, a remarkable nding was the strong evidence in those reports of intrauterine fetal hypoxia possibly due to placental damage or even direct evidence of placental infarctions. Gagnueur et al 6 reported two cases of still birth that was preceded by fetal heart deceleration, whereas, Wong et al and Jeong et al demonstrated placental infarction in three cases. The vascular tropism of COVID-19 has recently gained so much interest, and many of its multi-organ manifestations has been attributed to its endothelial tropism. Such endothelial tropism is accounted for by the high load of Angiotensin Converting Enzyme 2 (ACE2) and Furin, 11,12 which are important viral checkpoints, in the endothelium. Placenta is a vascular organ, whereby Furin play an important role in its differentiation, moreover, ACE2 and Angiotensin 1-7 are heavily expressed in the placenta, making the placenta an important target for the vascular tropic effect of COVID-19. As mentioned earlier, the number of con icting evidences regarding vertical transmission of COVID-19 and the effect of maternal COVID-19 on newborns and their placenta, renders systematic review of the clustered cases available of utmost importance to build stronger evidence the neonatal outcomes of COVID-19. The primary outcome parameter of this systematic review is the percentage of newborns testing positive to COVID-19 mothers, while secondary outcome parameters included the assessment of laboratory abnormalities among COVID-19 mothers, and the placental abnormalities encountered in COVID-19 mothers.

Methods
This systematic review has been conducted in agreement with the guidelines of the PRISMA Statement (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). 13 >>Data Search A computer run has been performed EMBASE, Medline and the Cochrane Central Register (From 1 st November 2019 to 1 st of August 2020). The following terms were included in the search: "COVID-19" OR "SARS-CoV-2" (Severe Acute Respiratory syndrome Coronaviridae 2) AND "Pregnancy" AND "Perinatal". Observational epidemiological studies and case reports addressing the clinical conditions of Mother-fetus pairs. Primary data of patients over 18 years old were considered eligible. Manuscripts that contained only data from pregnant women, or only fetuses, or that did not address the period of delivery, such as puerperium, were disregarded. All data from eligible studies were extracted by 2 independent investigators according to a standard protocol.
Statistical Analysis: Each of the maternal manifestations, neonatal manifestations, placental microscopic and macroscopic changes and laboratory changes in COVID-19 positive newborns was quanti ed and expressed as number (n) and percentages.

Results
The literature search identi ed initially 114 studies, of which 44 studies were excluded, 20 were excluded as they did not tackle the primary outcome parameter of the study. While 24 studies were excluded due to repetition. Total number of studies included was 66 studies, comprising 1787 Mother-infant pair.  The studies included were listed in Table 2, by alphabetical order of the country of origin. Table 3 summarizes the clinical manifestations of included COVID-19 positive mothers and the subsequent percentage of positive newborns.
Out of 1787 mother-infant pairs, only 49 tested positive (2.8%), which is surprisingly identical to the percentage of neonates affected in the reported cases series during the previous three outbreaks caused by Coronaviridae, 2/71 (2.8%) ( Table 1). Most of the affected neonates were asymptomatic (24%). The commonest array of manifestations was those suggestive of intrauterine hypoxia (20%). The sampling time was not reported in 31% of cases which is a non-negligible number putting a huge risk of reporting bias. 42% of positive newborn were tested in the rst 12 hours after delivery while the remainder 27 % of cases were tested after 12 hours, raising suspicion of possible postnatal infection. Table 4 outlines the placental abnormalities in COVID-19 positive mothers. Placental infarction, an evidence of vascular compromise of the villi, was observed in a signi cant number of abnormal placentae (44%%). A lower percentage of positive swabs was retrieved from abnormal placentae accounting for 37% of all abnormal placentae, and 5% of all examined placentae. A closer percentage of placental infarctions was observed in placentae examined from the previous outbreak. Table 5 shows the laboratory abnormalities in COVID-19 positive neonates, the commonest laboratory abnormality in affected neonates is Lymphopenia encountered in 20% of cases.

Discussion
Vertical transmission of COVID-19 follows the same pattern of uncertainty as almost everything concerning COVID-19. New evidences being unraveled everyday make meta-analysis the only possible solution to reach consensus about points of dilemma.
This report is by far the largest systematic review to be implemented in this context, not only regarding the number of mother-infant pairs, but also the targeted outcome parameters. The largest report preceding us is De Sousa et al report 81 .
Our study con rmed the previous impression from the former outbreaks by CoV that transplacental transmission is very unlikely occurring in 2.8% of all positive mothers. A report by Wang and colleagues 82 suggested that viremia is reported to occur in less than 1% of cases.
However, this nding seems to hugely underestimate the burden of viremia in Coronaviridae infections. An old report by Chen et al 83 during rst SARS outbreak showed that RNA of SARS-CoV can be detected in up to 50% of blood samples and can last up to one week.
The commonest laboratory nding in affected neonates was Lymphopenia. This nding goes in agreement with the same pattern of hematologic abnormalities encountered in adult patients. The Programmed cell death receptor 1 secreted from macrophages in the lung environment as well as from resident T cells leads nally to T cell exhaustion with subsequent Lymphopenia encountered affected patients.
The most intriguing nding uncovered in our series is the strong evidence pointing towards placental damage with subsequent intrauterine hypoxia of the fetus. This nding was supported at several stages in our study. As mentioned earlier, 20 % of all infants in whom manifestations have been reported have showed evidence of intrauterine hypoxia. Seven percent of all patients were born preterm due to evidence of fetal deceleration that necessitated pregnancy termination. Histopathological changes of placenta offered a strong reason for the observed neonatal manifestations. Placental changes were more prevalent than COVID-19 positive neonates, 46 vs. 45 respectively, out of which 44% showed evidence of ischemia. Placental changes encountered seemed to mirror the timeline at which infection was detected in COVID-19 positive mothers. 3% of mothers were infected in the 1 st trimester, while defective proliferation and formation of villi was observed in a similar percentage of cases.
Defective formation of villi can be accounted due to the role played by an intracellular enzyme termed Furin in the genesis of placental villi. [84][85][86] AbdelMassih outlined the important interplay between Furin, COVID-19, and the vascular endothelium; an important constituent of the human placenta.
In view of the above ndings, proper hydration and prophylactic anticoagulation should be provided for COVID-19 pregnant women, especially those whose tests suggests strong prothrombotic tendency such elevated D-Dimer, or those whose abdominal ultrasound and fetal     interleukin.