key: cord-0951555-7mxp3sdy
authors: A, Amouroux; T, Attie-Bitach; J, Martinovic; M, Leruez-Ville; Y, Ville
title: Evidence for and against vertical transmission for SARS-CoV-2 (COVID-19)
date: 2020-05-04
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.04.039
sha: ec61a1cb1b77d02669588971e3c0b7a91ec05651
doc_id: 951555
cord_uid: 7mxp3sdy

Abstract COVID-19 can severely affect pregnant women and the issue of vertical transmission of sars-cov-2 has also emerged. Sars-cov-2 could be recovered by real-time (RT) PCR from nasal and throat swabs, sputum and feces of symptomatic patients including neonates but not from vaginal swabs, amniotic fluid, placenta, cord blood, neonatal blood or breast milk. Viremia was present in 1% of symptomatic adults. We identified 12 articles published between February 10th and April 4th 2020 reporting on 68 deliveries and 71 neonates with maternal infection in the third trimester of pregnancy. Perinatal exposure, including mode of delivery and time interval from delivery to the diagnosis of neonatal infection are crucial in differentiating congenital from perinatal infection. Neonatal infection is usually asymptomatic. Neonatal infection was diagnosed within 48 hours of life in 4 cases. Detection rates of real-time PCR and the interpretation of IgM and IgG antibodies levels in cord and neonatal blood are discussed in relation with the immaturity of the fetal and neonatal immune system.

Transplacental passage of pathogens usually increases with advancing gestational age while the severity of fetal injuries decreases from embryopathy in the first trimester down to fetal infection and immune response driven damage and symptoms in the second and third trimester.

Based upon RT-PCR identification of SARS-CoV-2 virus, early reports from China suggested that intrauterine vertical transmission was unlikely 1 . However, the introduction of serology testing in cord blood and in the neonate's, has raised concerns 2 .

Viruses of the Coronaviridae family possess a single strand, positive-sense RNA genome. Three human coronaviruses cause acute and severe maternal illnesses:

severe acute respiratory syndrome (SARS) and SARS-CoV-2 causes COVID-19 1 .

SARS-CoV-2 strains show 50% and 79% sequence' homology to SARS-CoV and MERS-CoV respectively 1 . A major issue of any published study to date is the relative inaccuracy of currently available diagnostic tests. Indeed, the sensitivity of real time (RT) PCR testing is around 63%, 93% and 29% in nasal swabs, bronchoalveolar lavages and feces of infected individuals 3 . Therefore, testing specimens from multiple sites may improve the detection rate and reduce false-negative diagnoses. Total (Ab) and IgG antibodies seem to be acquired over 2 weeks' in infected individuals from the onset of symptoms and the introduction of SARS-CoV-2 serology is a rapidly evolving field of research and much-needed aid in the management of the pandemic.

The fetus acquires the ability to produce serum immune globulins early in gestation.

Since maternal IgG transfer freely and increasingly across gestation, the fetus and neonate show a repertoire of maternal IgG antibodies. However, maternal IgM does not cross the placenta and IgM in fetal or cord blood reflect the fetal immune response. Anti-SARS-CoV-2 IgM antibodies assays used in perinatal studies from China claim sensitivity and specificity of 70.2%-88.2% and 96.2%-99%, respectively as assessed in only one study and accordingly to the manufacturer ; and both evaluations were published in Chinese 2 . Thus, performance characteristics of the SARS-CoV-2 IgM require further study.

SARS-CoV-2 is thought to be transmitted through respiratory droplets 1 . The viremia is found in 1% of symptomatic patients 3 and is generally low and transient, suggesting that the virus is unlikely to be recovered from the placenta. Few placental samples have been studied to date 4 and none showed the presence of the virus by Table 1 ). Fetal pathologists should nevertheless continue to ensure that standard precautions for any potentially infected biological samples.

Histological examination of 3 placentas did not provide any evidence of placental infection or inflammation, namely no villitis nor chorioamnionitis. In all 3 placentas, vascular villous lesions such as fibrin deposition within and around the villi and infarcts were reported but were likely related to maternal co-morbidities, including preeclampsia 4 . Like SARS-CoV, SARS-CoV-2 also uses angiotensin-converting enzyme 2 (ACE2) as a cell receptor 1 . RNA expression profile of ACE2 in the trophoblast appears very low at between 6 and 14 weeks', as assessed by combined single-cell transcriptome profiles from the early maternal-fetal interface 5 . Therefore, mother-to-fetus transmission of SARS-CoV-2 during first trimester seems unlikely. It is, however, possible that severe maternal respiratory failure and hypoxemia may disrupt uterine placental flow and cause miscarriage.

The dynamic of the pandemic has not allowed for any meaningful cohort following maternal infection in the second trimester of pregnancy to be reported with perinatal outcomes, and the largest numbers relate to cases of infection and delivery in the third trimester of pregnancy.

A total of 71 women were reported having delivered mainly by cesarean section (64/71) 1 to 25 days following symptoms' onset (Supplementary Table 2 ). Vertical Table 1 ) was assessed by RT-PCR in 10 amniotic fluid samples and in 5 placentas; all tested negative.

Of note, maternal serum and vaginal swabs sampled in 3 cases also tested negative and so did breast milk in 10 cases. RT-PCR was also performed in cord blood in 12 cases that tested negative (Supplementary Table 1 ). One newborn delivered by cesarean section who had no contact with her mother, had a positive RT-PCR in a pharyngeal swab collected 36 hours after birth. However, a iatrogenic transmission could not be excluded (Supplementary Table 1 ). In a single series of 33 neonates born to symptomatic COVID-19 mothers, 3 neonates (9%) were symptomatic for COVID-19 with positive RT-PCR in anal and naso-pharyngeal swabs. Symptoms reported at day-2 of life in 2 of the 3 neonates, born at 40 and 40+4 weeks', included lethargy, fever and vomiting with chest X-ray suggestive of pneumonia. The third one who necessitated resuscitation was delivered at 31+4 weeks' and had bacterial sepsis, all symptoms therefore being compatible with sepsis rather than SARS-CoV-2 related infection 6 .

The former 2 cases with early-onset mild symptoms compatible with COVID-19 and positive PCR at day-2 and day-4 bring the strongest argument to date in favor of a vertical transmission. However, both infants were re-sampled on day-6 and RT-PCR performed on multiple site was negative. This is also unexpected in the context of a congenital infection with any pathogen. No outcome data later than day-8 was provided in the article.

One child showed elevated IgM and IgG antibody levels 2 hours after birth.

Nasopharyngeal swabs tested negative on RT-PCR on 5 occasions and both IgM and IgG antibody levels decreased on day 14 and dramatically so for IgM down to the limit of the assay's detection 2 . Another report described potential serological evidence of vertical transmission in 2 of 6 infants from infected mothers 2 . The overall picture resembles that of passive transfer of maternal antibodies, though IgM is known to not cross the placenta and could reflect fetal production following intrauterine infection. However, IgM assays are prone to both false positive and false negative results, but also cross reactivity with non-specific IgM antibodies, presence of rheumatoid factor or incomplete removal of IgG, which may be maternal in origin 2 .

All 

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E009. Time interval between symptom onset and delivery Delivery Number of pregnant women Number of neonates

All authors declare that they did contribute significantly to the review of the litterature and the writing of this manuscript. They certify that this manuscript or data have not been submitted elsewhere Dear Professor Romero, Thank you for considering this viewpoint article for publication in AJOG We have added a Figure and answered all queries Looking forward to hearing from you Sincerely yours Best regards Yves Ville

Amouroux A, MD PhD 1 , Attie-Bitach T, MD PhD 2 , Martinovic J, MD PhD 3 , Leruez-Ville M, MD PhD 4 , Ville Y, MD 5