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Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review

Objective  The aim of this study is to summarize currently available evidence on vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Study Design  A systematic review was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis Statement. Results  A total of 22 studies comprising 83 neonates born to mothers diagnosed with coronavirus disease 2019 were included in the present systematic review. Among these neonates, three were confirmed with SARS-CoV-2 infection at 16, 36, and 72 hours after birth, respectively, by nasopharyngeal swab real-time polymerase chain reaction (RT-PCR) tests; another six had elevated virus-specific antibody levels in serum samples collected after birth, but negative RT-PCR test results. However, without positive RT-PCR tests of amniotic fluid, placenta, or cord blood, there is a lack of virologic evidence for intrauterine vertical transmission. Conclusion  There is currently no direct evidence to support intrauterine vertical transmission of SARS-CoV-2. Additional RT-PCR tests on amniotic fluid, placenta, and cord blood are needed to ascertain the possibility of intrauterine vertical transmission. For pregnant women infected during their first and second trimesters, further studies focusing on long-term outcomes are needed. Key Points We review neonates of mothers diagnosed with coronavirus disease 2019 detected by RT-PCR. No direct virologic evidence of vertical transmission has been reported. No evidence that cesarean delivery is safer than vaginal delivery. More RT-PCR tests on amniotic fluid, placenta, and cord blood are recommended.

question are essential for formulating the principles of obstetric care for pregnant women with SARS-CoV-2 infection. Therefore, we conducted this systematic review to summarize the currently available evidence on vertical transmission of SARS-CoV-2.

Materials and Methods
We conducted a systematic review following the guidelines of the Preferred Reporting Items for Systematic Reviews and Metaanalysis Statement. The protocol of this systematic review is registered with Open Science Framework (DOI: 10.17605/OSF.-IO/Y5SR6). A comprehensive literature search of the following databases was performed on April 20, 2020: PubMed, the China National Knowledge Infrastructure, CBMdisc, and Wanfang Data. Two authors independently and systematically searched these databases using the following MeSH terms: "pregnancy," "infant, newborn," "COVID-19," and "severe acute respiratory syndrome coronavirus 2." We also performed a manual search in Google Scholar and the websites of key journals in the related field. Reference lists of included studies were also hand searched for potential eligible studies. Studies were considered for inclusion if they were observational studies or case report/series reporting neonates of mothers diagnosed with COVID-19 by real-time polymerase chain reaction (RT-PCR). There was no restriction on language, but the date of publication was limited to the period from January 1, 2020 to April 20, 2020.
The Newcastle-Ottawa scale was used to assess the quality (risk of bias) of cohort and case-control studies. For case report/series, a modified tool for quality appraisal was used; details can be found in the protocol. All methodological procedures were conducted by two authors independently. Disagreements were resolved by discussion with an expert in the related field.

Results
In the initial search, 197 unique records were identified and the full text of 25 was assessed. In total, 22 studies comprising 83 neonates were included in this review. The flow diagram of the study selection process and the characteristics of included studies are shown in ►Fig. 1 and ►Table 1, respectively. All 22 studies were rated as low quality. Among the 83 neonates, 9 had evidence of SARS-CoV-2 infection (positive RT-PCR results or elevated level of virus-specific antibodies in serum samples). Timelines illustrating the evolution of the results of RT-PCR and antibody tests are shown in ►Fig. 2.
Alzamora et al 5 reported a pregnant woman who developed respiratory failure and underwent a cesarean delivery at 33 weeks of gestation. Neonatal isolation was implemented immediately after birth, without any physical contact with the mother. A nasopharyngeal swab collected from the neonate at 16 hours after birth tested positive for SARS-CoV-2 by RT-PCR, although serum samples were negative for virus-specific immunoglobulin G (IgG) and immunoglobulin M (IgM) using automated chemiluminescence immunoassays. The RT-PCR test repeated 48 hours later for confirmation was also positive.
Similarly, Li et al 6 and Yu et al 7 also reported neonatal infection and the implementation of neonatal isolation measures immediately after birth. In these two cases, the mothers wore an N95 mask during delivery and the newborns were cared for under isolation in a separate pediatric room. RT-PCR test results at 36 hours and 3 days after birth were positive. In these three cases, no amniotic fluid, placenta, or cord blood were collected for RT-PCR tests.
Zeng et al 8 and Dong et al 9 both reported positive detection of virus-specific antibodies in serum samples drawn from the neonates following birth, although serum and throat swab samples tested negative by RT-PCR. Three of seven infants had elevated IgG and IgM levels; another three had elevated IgG levels, while IgM levels were normal. The mothers' vaginal secretions and breastmilk also tested negative by RT-PCR.

Discussion
In terms of virus infection during pregnancy, obstetricians are most concerned about the possibility of vertical transmission from the mother to her fetus. Vertical transmission has been confirmed for many viruses and can lead to adverse perinatal outcomes including miscarriage, fetal growth restriction, preterm birth, and even stillbirth. 10,11 The routes of vertical transmission include intrauterine transmission, transmission during delivery, breast milk transmission, and contact after delivery. 12 Of these, intrauterine vertical transmission is the least likely to be controlled and managed, and is the most important route of mother-to-child transmission that affects the fetus and neonates. Based on the results of the present systematic review, there is currently no direct evidence to suggest that the development of COVID-19 pneumonia in  The latest research suggests that angiotensin-converting enzyme 2 (ACE2) is the SARS-CoV-2 receptor required for cell entry, but the low level of ACE2 expression in cells at the maternal-fetal interface suggest that there are no susceptible cell subsets in these tissues. 13 Moreover, pathological analysis suggests that there are no morphological changes related to the infection in placenta tissues. 14 Therefore, these evidences do not support the possibility of intrauterine vertical transmission.
We noted that currently available data included only expectant mothers infected in their third trimester and due to the uncertainty of the impact of COVID-19 on maternal-fetal and neonatal outcomes, most babies were delivered by cesarean delivery as soon as possible after admission to minimize the risk. However, patients diagnosed in their first and second trimesters were still pregnant when these studies were published. The risk of adverse perinatal outcomes and vertical transmission is unclear, and this issue remains to be clarified by longer follow-up. Compared with the third trimester, maternal virus infection in the first or second trimesters of pregnancy may have different effects. For example, rubella virus infection before 12 weeks of pregnancy causes congenital rubella syndrome in 90% of cases, whereas the incidence is 50% in cases of infection at 13 to 14 weeks of pregnancy and 25% at the end of the second trimester; infection at the third trimester has little influence on the fetus. 15 In terms of breastfeeding, although no positive RT-PCR results have been reported in tests of breast milk, this finding is limited by relatively small sample sizes and short followup time. Expert consensus 16 suggests that infants should not be breastfed by mothers with confirmed or suspected SARS-CoV-2 infection. Indeed, breastfeeding may not be safe until COVID-19 is ruled out or until both mother and neonate clear As there is no evidence to support the possibility of intrauterine vertical transmission, the timing of delivery should not be based solely on the condition that a pregnant patient is infected but should be individualized in each case; that is, obstetricians may consider maternal and fetal wellbeing, gestational age, and other concomitant conditions to determine the time of delivery. 17 In terms of delivery mode, there is a lack of convincing evidence that cesarean delivery is safer. The mode of delivery should be based on routine obstetrical indications, allowing vaginal delivery when possible and reserving cesarean delivery for when obstetrically necessary. 16

Conclusion
The currently available evidence does not support the possibility of intrauterine vertical transmission of SARS-CoV-2 infection during the third trimester of pregnancy. No positive RT-PCR results of tests of amniotic fluid, placenta, cord blood, or breast milk have been reported. For pregnant women infected during their first and second trimesters, further studies focusing on long-term outcomes are needed. We recommend additional RT-PCR testing of amniotic fluid, placenta, and cord blood to confirm these findings.