Vertical Transmission of SARS-CoV-2: A Systematic Review

Transmissão vertical do SARS-CoV-2: Revisão sistemática

Ionara Diniz Evangelista Santos Barcelos Ivan Andrade de Araújo Penna Adriana de Góes Soligo Zelma Bernardes Costa Wellington Paula Martins About the authors

Abstract

Objective

The evaluation of the available evidence on vertical transmission by severe acute respiratory syndrome coronavirus 2 (SARS-CoV)-2.

Data Sources

An electronic search was performed on June 13, 2020 on the Embase, PubMed and Scopus databases using the following search terms: (Coronavirus OR COVID-19 OR COVID19 OR SARS-CoV-2 OR SARS-CoV2 OR SARSCoV2) AND (vertical OR pregnancy OR fetal).

Selection of Studies

The electronic search resulted in a total of 2,073 records. Titles and abstracts were reviewed by two authors (WPM, IDESB), who checked for duplicates using the pre-established criteria for screening (studies published in English without limitation regarding the date or the status of the publication).

Data Collection

Data extraction was performed in a standardized way, and the final eligibility was assessed by reading the full text of the articles. We retrieved data regarding the delivery of the potential cases of vertical transmission, as well as themain findings and conclusions of systematic reviews.

Data Synthesis

The 2,073 records were reviewed; 1,000 duplicates and 896 clearly not eligible records were excluded. We evaluated the full text of 177 records, and identified only 9 suspected cases of possible vertical transmission. The only case with sufficient evidence of vertical transmission was reported in France.

Conclusion

The risk of vertical transmission by SARS-CoV-2 is probably very low. Despite several thousands of affected pregnant women, we have identified only one case that has fulfilled sufficient criteria to be confirmed as a case of vertical transmission. Well-designed observational studies evaluating large samples are still necessary to determine the risk of vertical transmission depending on the gestational age at infection.

Keywords:
vertical transmission; SARS-CoV-2; COVID-19; perinatal outcomes; maternal morbidity

Resumo

Objetivo

Avaliar a evidência disponível acerca da transmissão vertical do coronavírus da síndrome respiratória aguda grave 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, em inglês).

Fontes de Dados

Foi realizada uma busca eletrônica em 13 de junho de 2020 nas plataformas Embase, PubMed e “Scopus utilizando os seguintes termos de busca: (Coronavirus OU COVID-19 OU COVID19 OU SARS-CoV-2 OU SARS-CoV2 OU SARSCoV2) E (vertical OU pregnancy OU fetal).

Seleção dos Estudos

A busca eletrônica resultou em um total de 2.073 registros. Títulos e resumos foram revisados por dois autores (WPM, IDESB), que verificaram a ocorrência de duplicidade e utilizaram critérios preestabelecidos para o rastreamento (estudos publicados em inglês sem limitações quanto à data ou à situação da publicação).

Aquisição dos Dados

A extração de dados foi realizada de forma padrão, e a eligibilidade final foi definida poir meio da leitura do artigo completo. Foram coletados dados dos partos de casos com potencial transmissão vertical, bem como os principais achados e conclusões de revisões sistemáticas.

Síntese dos Dados

Foram revisados os 2.073 registros; 1.000 duplicatas e 896 registros claramente não elegíveis foram excluídos. Avaliamos os artigos completos de 177 registros, e identificamos apenas 9 casos de potencial transmissão vertical. O único caso com evidência suficiente de transmissão vertical foi relatado na França.

Conclusão

O risco de transmissão vertical pelo vírus SARS-CoV-2 é provavelmente muito baixo. Apesar de milhares de gestantes afetadas, identificamos apenas um caso que preencheu critérios suficientes para que fosse confirmado como um caso de transmissão vertical. Estudos observacionais bem desenhados que avaliem grandes amostras ainda são necessários para se determinar o risco de transmissão vertical, a depender da idade gestacional na infecção.

Palavras-chave:
transmissão vertical; SARS-CoV-2; COVID-19; resultados perinatais; morbidade materna

Introduction

At the end of 2019, a new virus was discovered: SARS-CoV-2. It first emerged in China, in the city of Wuhan, and quickly spread throughout the world, causing the coronavirus-19 disease (COVID-19). 11 Karimi-Zarchi M, Neamatzadeh H, Dastgheib SA, Abbasi H, Mirjalili SR, Behforouz A, Ferdosian F, et al. Vertical transmission of Coronavirus Disease 19 (COVID-19) from infected pregnant mothers to neonates: a review. Fetal Pediatr Pathol. 2020;39 (03):246-250. Doi: 10.1080/15513815.2020.1747120
https://doi.org/10.1080/15513815.2020.17...
This virus transmits extraordinarily rapidly. Therefore, pregnant women have become a concern, given their susceptibility to respiratory infections, due to the physiological changes during pregnancy and the restriction of lung expansion. 22 Liu H, Wang LL, Zhao SJ, Kwak-Kim J, Mor G, Liao AH. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139:103122. Doi: 10.1016/j.jri.2020.103122
https://doi.org/10.1016/j.jri.2020.10312...
33 Liu Y, Chen H, Tang K, Guo Y. Clinicalmanifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect. 2020;•••: S0163-4453(20)30109-2. Doi: 10.1016/j.jinf.2020.02.028 [ahead of print]
https://doi.org/10.1016/j.jinf.2020.02.0...

The current coronavirus (SARS-CoV-2), shares many structural similarities with other coronaviruses, like SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). However, SARS-CoV-2 is less virulent, and its performance, as well as that of SARS-CoV, is mediated by the angiotensin-converting enzyme 2 (ACE2) receptor, a component of the renin-angiotensin system present in the lungs, heart, kidneys, and placenta. 44 Li M, Chen L, Zhang J, Xiong C, Li X. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by singlecell transcriptome study. PLoS One. 2020;15(04):e0230295. Doi: 10.1371/journal.pone.0230295
https://doi.org/10.1371/journal.pone.023...
55 Li N, Han L, Peng M, Lv Y, Ouyang Y, Liu K, et al. Maternal and Neonatal Outcomes of Pregnant Women With Coronavirus Disease 2019 (COVID-19) Pneumonia: A Case-Control Study. Clin Infect Dis. 2020;71(16):2035-2041

Affinity with the receptor determines the route of the viral infection, and its identification in the placenta alerts to the possibility of vertical transmission. 66 Zheng QL, Duan T, Jin LP. Single-cell RNA expression profiling of ACE2 and AXL in the humanmaternal-fetal interface. Reprod Dev Med.. 2020;4(01):7-10. Doi: 10.4103/2096-2924.278679
https://doi.org/10.4103/2096-2924.278679...
Although present, the link between SARS-CoV-2 and the ACE2 receptor in the placenta is poorly expressed, which can be a protective factor for vertical transmission. Several studies have been published in recent months describing viral behavior in pregnant women and newborns. However, the impact of COVID-19 during pregnancy and the neonatal period is not yet fully supported by scientific research. 11 Karimi-Zarchi M, Neamatzadeh H, Dastgheib SA, Abbasi H, Mirjalili SR, Behforouz A, Ferdosian F, et al. Vertical transmission of Coronavirus Disease 19 (COVID-19) from infected pregnant mothers to neonates: a review. Fetal Pediatr Pathol. 2020;39 (03):246-250. Doi: 10.1080/15513815.2020.1747120
https://doi.org/10.1080/15513815.2020.17...

A better understanding of the viral pathogenesis in the pregnancy cycle is necessary to enable the monitoring of this group who is considered susceptible to this infection. The present review aims to identify the available evidence regarding the risk of vertical transmission by SARS-CoV-2 to guide family, gestational, and perinatal planning.

Methods

Eligibility Criteria

Observational studies with suspected vertical transmission and systematic reviews assessing the risk of vertical transmission were considered eligible.

Search and Selection of the Studies

We searched the PubMed, Scopus, and Embase databases using the following search terms: (Coronavirus OR COVID-19 OR COVID19 OR SARS-CoV-2 OR SARS-CoV2 OR SARSCoV2) AND (vertical OR pregnancy OR fetal). Titles and abstracts were reviewed by two authors (WPM, IDESB), who checked for duplicates using the pre-established criteria for screening. We limited the search to studies published in English, but there was no limitation regarding the date or the status of the publication. After screening, the full texts of the records considered potentially eligible were retrieved for the final evaluation of eligibility.

Data Collection/Extraction

Data extraction was performed in a standardized way, and final eligibility was assessed by reading the full text of the articles. The studies were characterized according to their design. We retrieved data regarding the delivery of the potential cases of vertical transmission, as well as the main findings and conclusions of systematic reviews and the conclusions from other reviews. The extracted data are presented in tables.

Results

The last electronic search was performed on June 13, 2020, resulting in a total of 2,073 records from the 3 databasis consulted: Embase (n = 698), PubMed (n = 738), and Scopus (n = 637). We excluded 1,000 duplicates, and 1,073 records were screened based on titles and abstracts, resulting in the exclusion of 896 records, as they were not related to the vertical transmission of COVID-19. We evaluated the full text of 177 records ( Fig. 1); out of those, we considered the following studies eligible:

Fig. 1
Flowchart of the selection of studies.

Nine cases of potential vertical transmission were described in ten reports ( Table 1).

  1. - Three reports of the same case of a potential vertical transmission at Tongji Hospital, Wuhan, China. 77 Wang S, Guo L, Chen L, LiuW, Cao Y, Zhang J, Feng L. A case report of neonatal 2019 Coronavirus Disease in China. Clin Infect Dis. 2020;71(15):853-857. Doi: 10.1093/cid/ciaa225
    https://doi.org/10.1093/cid/ciaa225...
    88 Hu X, Gao J, Luo X, Feng L, Liu W, Chen J, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vertical transmission in neonates born to mothers with Coronavirus Disease 2019 (COVID-19) pneumonia. Obstet Gynecol. 2020; 136(01):65-67. Doi: 10.1097/AOG.0000000000003926
    https://doi.org/10.1097/AOG.000000000000...
    99 Yu N, Li W, Kang Q, Xiong Z, Wang S, Lin X, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study. Lancet Infect Dis. 2020;20(05):559-564. Doi:10.1016/S1473-3099(20)30176-6
    https://doi.org/10.1016/S1473-3099(20)30...

  2. - One report of a potential vertical transmission at Renmin Hospital, Wuhan, China. 1010 Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323(18):1846-1848. Doi: 10.1001/jama.2020.4621
    https://doi.org/10.1001/jama.2020.4621...

  3. - One report of a potential vertical transmission at Imam Khomeini Hospital, Sari, Iran. 1111 Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S. Preterm delivery, maternal death, and vertical transmission in a pregnant woman with COVID-19 infection. Prenat Diagn. 2020 [ahead of print]

  4. - One report of two suspect cases at hospital maternity units of the COVID-network in Lombardy and units of Padua and Modena, northern Italy. 1212 Ferrazzi E, Frigerio L, Savasi V, Vergani P, Prefumo F, Barresi S, et al. Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis. BJOG. 2020;127(09): 1116-1121. Doi: 10.1111/1471-0528.16278
    https://doi.org/10.1111/1471-0528.16278...

  5. - One report of a potential vertical transmission at the British American Hospital, Lima, Peru. 1313 AlzamoraMC, Paredes T, Caceres D,Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol. 2020;37(08):861-865. Doi: 10.1055/s-0040-1710050
    https://doi.org/10.1055/s-0040-1710050...

  6. - One report of a potential vertical transmission at Paris Saclay University Hospitals, France. 1414 Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(01):3572. Doi: 10.1038/s41467-020-17436-6
    https://doi.org/10.1038/s41467-020-17436...

  7. - One report of a potential vertical transmission at Saint Barnabas Medical Center, United States. 1515 Mehta H, Ivanovic S, Cronin A, VanBrunt L, Mistry N, Miller R, Yodice P, et al. Novel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: A case report. Case Rep Womens Health. 2020;27:e00220. Doi: 10.1016/j.crwh.2020.e00220
    https://doi.org/10.1016/j.crwh.2020.e002...

  8. - One report of potential vertical transmission at Henan Provincial People's Hospital, China. 1616 Sun M, Xu G, Yang Y, Tao Y, Pian-Smith M, Madhavan V, et al. Evidence of mother-to-newborn infection with COVID-19. Br J Anaesth. 2020;125(02):e245-e247. Doi: 10.1016/j.bja.2020.04.066
    https://doi.org/10.1016/j.bja.2020.04.06...

Table 1
Reports of potential vertical transmission

Seventeen Systematic Reviews ( Box 1)

Box 1
Conclusions from systematic reviews, narrative reviews and large observational studies identified in the present review

We found a total of 17 systematic reviews:

  1. - One systematic review including 79 pregnancies based on 19 studies from China, Saudi Arabia, South Korea, the United Arab Emirates, Jordan, Canada, Hong Kong, and the US. 1717 Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, LiberatiM, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and metaanalysis. Am J Obstet Gynecol MFM. 2020;2(02):100107. Doi: 10.1016/j.ajogmf.2020.100107
    https://doi.org/10.1016/j.ajogmf.2020.10...

  2. - One systematic review including 51 pregnancies based on 6 studies from China. 1818 Della Gatta AN, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease 2019 during pregnancy: a systematic review of reported cases. Am J Obstet Gynecol. 2020;223(01):36-41. Doi: 10.1016/j.ajog.2020.04.013
    https://doi.org/10.1016/j.ajog.2020.04.0...

  3. - One systematic review including 108 pregnancies based on 18 studies from China, Sweden, South Korea, and Honduras. 1919 Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies. Acta Obstet Gynecol Scand. 2020;99(07):823-829. Doi: 10.1111/aogs.13867
    https://doi.org/10.1111/aogs.13867...

  4. - One systematic review not reporting the number of cases, based on 29 studies from China, Iran, France, and the US. 2020 Abdollahpour S, Khadivzadeh T. Improving the quality of care in pregnancy and childbirth with coronavirus (COVID-19): a systematic review. J Matern Fetal Neonatal Med. 2020;•••:1-9. Doi: 10.1080/14767058.2020.1759540 [ahead of print]
    https://doi.org/10.1080/14767058.2020.17...

  5. - One systematic review including 123 cases based on 16 studies from China. 2121 Banaei M, Ghasemi V, Saei Ghare Naz M, Kiani Z, Rashidi-Fakari F, Banaei S, et al. Obstetrics and neonatal outcomes in pregnant women with COVID-19: a systematic review. Iran J Public Health. 2020;49(Suppl 1):38-47

  6. - One systematic review including 222 cases based on 17 studies from China, Australia, Iran, and Spain. 2222 Duran P, Berman S, Niermeyer S, Jaenisch T, Forster T, Ponce de León RG, et al. COVID-19 and newborn health: systematic review. Rev Panam Salud Publica. 2020;44:e54. Doi: 10.26633/RPSP.2020.54
    https://doi.org/10.26633/RPSP.2020.54...

  7. - One systematic review including 385 pregnancies and 256 newborns based on 33 studies from China, Australia, Honduras, Iran, South Korea, Sweden, Turkey, Italy, The Netherlands, and the US. 2323 Elshafeey F, Magdi R, Hindi N, Elshebiny M, Farrag N, Mahdy S, et al. A systematic scoping review of COVID-19 during pregnancy and childbirth. Int J Gynaecol Obstet. 2020;150(01):47-52. Doi: 10.1002/ijgo.13182
    https://doi.org/10.1002/ijgo.13182...

  8. - One systematic review including 46 cases based on 8 studies from China, Belgium, Spain, Iran, and Peru. 2424 Gordon M, Kagalwala T, Rezk K, Rawlingson C, Ahmed MI, Guleri A. Rapid systematic review of neonatal COVID-19 including a case of presumed vertical transmission. BMJ Paediatr Open. 2020;4 (01):e000718. Doi: 10.1136/bmjpo-2020-000718
    https://doi.org/10.1136/bmjpo-2020-00071...

  9. - One systematic review including 538 pregnancies based on 13 studies from China, Italy, and the US. 2525 Huntley BJF, Huntley ES, Di Mascio D, Chen T, Berghella V, Chauhan SP. Rates of maternal and perinatal mortality and vertical transmission in pregnancies complicated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Co-V-2) infection: a systematic review. Obstet Gynecol. 2020;136(02):303-312. Doi: 10.1097/AOG.0000000000004010
    https://doi.org/10.1097/AOG.000000000000...

  10. - One systematic review including 324 pregnancies based on 24 studies from China, Iran, the US, Italy, Spain, Peru, Sweden, Turkey, South Korea, Australia, Canada, and France. 2626 Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review. Ultrasound Obstet Gynecol. 2020;56(01):15-27. Doi: 10.1002/uog.22088
    https://doi.org/10.1002/uog.22088...

  11. - One systematic review including 87 pregnancies based on 9 studies from China and Iran. 2727 Kasraeian M, Zare M, Vafaei H, Asadi N, Faraji A, Bazrafshan K, Roozmeh S. COVID-19 pneumonia and pregnancy; a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2020; •••:1-8. Doi: 10.1080/14767058.2020.1763952 [ahead of print]
    https://doi.org/10.1080/14767058.2020.17...

  12. - One systematic review including 89 pregnancies based on 9 studies from China. 2828 Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(06):1088-1095. Doi: 10.1111/apa.15270
    https://doi.org/10.1111/apa.15270...

  13. - One systematic review including 89 pregnancies based on 9 studies from China. 2929 Muhidin S, Behboodi Moghadam Z, Vizheh M. Analysis of maternal Coronavirus Infections and neonates born to mothers with 2019-nCoV; a systematic review. Arch Acad Emerg Med. 2020;8 (01):e49

  14. - One systematic review including 92 pregnancies based on 9 studies from China. 3030 Smith V, Seo D,Warty R, Payne O, Salih M, Chin KL, et al. Maternal and neonatal outcomes associated with COVID-19 infection: A systematic review. PLoS One. 2020;15(06):e0234187. Doi: 10.1371/journal.pone.0234187
    https://doi.org/10.1371/journal.pone.023...

  15. - One systematic review including 665 pregnancies based on 49 studies from China. 3131 Walker KF, O'Donoghue K, Grace N, Dorling J, Comeau JL, Li W, Thornton JG. Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis. BJOG. 2020;127(11):1324-1336. Doi: 10.1111/1471-0528.16362
    https://doi.org/10.1111/1471-0528.16362...

  16. - One systematic review including 83 neonates based on 22 studies from China, Peru, South Korea, and Spain. 3232 Yang Z, Liu Y. Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review. Am J Perinatol. 2020;37(10):1055-1060. Doi: 10.1055/s-0040-1712161
    https://doi.org/10.1055/s-0040-1712161...

  17. - One systematic review including 114 pregnancies based on 18 studies from China. 3333 Yang Z, Wang M, Zhu Z, Liu Y. Coronavirus disease 2019 (COVID- 19) and pregnancy: a systematic review. J Matern Fetal Neonatal Med. 2020;•••:1-4. Doi: 10.1080/14767058.2020.1759541 [ahead of print]
    https://doi.org/10.1080/14767058.2020.17...

Discussion

Most studies published so far have registered the absence of vertical transmission, few cases of possible vertical transmission, and exceptionally, one case described as confirmed transplacental transmission of SARS-CoV-2 infection. 1414 Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(01):3572. Doi: 10.1038/s41467-020-17436-6
https://doi.org/10.1038/s41467-020-17436...
The identified cases were reported as case reports; therefore, there is a very high risk of selection bias. After defining the eighteen eligible articles, we identified only seven suspected cases of possible vertical transmission: two cases in China, one in Iran, two in Italy, one in Peru, and one in France ( Table 1).

The first are three different reports 77 Wang S, Guo L, Chen L, LiuW, Cao Y, Zhang J, Feng L. A case report of neonatal 2019 Coronavirus Disease in China. Clin Infect Dis. 2020;71(15):853-857. Doi: 10.1093/cid/ciaa225
https://doi.org/10.1093/cid/ciaa225...
88 Hu X, Gao J, Luo X, Feng L, Liu W, Chen J, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vertical transmission in neonates born to mothers with Coronavirus Disease 2019 (COVID-19) pneumonia. Obstet Gynecol. 2020; 136(01):65-67. Doi: 10.1097/AOG.0000000000003926
https://doi.org/10.1097/AOG.000000000000...
99 Yu N, Li W, Kang Q, Xiong Z, Wang S, Lin X, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study. Lancet Infect Dis. 2020;20(05):559-564. Doi:10.1016/S1473-3099(20)30176-6
https://doi.org/10.1016/S1473-3099(20)30...
on the same case report from China that present a methodology bias, since the collection of the newborn's oropharynx swab for the polymerase chain reaction (PCR) test was not performed at the time of delivery, which does not unequivocally guarantee the occurrence of vertical transmission. In the second Chinese case, 1010 Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323(18):1846-1848. Doi: 10.1001/jama.2020.4621
https://doi.org/10.1001/jama.2020.4621...
the diagnosis of possible vertical transmission was made by positive immunoglobulin M (IgM) testing two hours after delivery, but was followed by PCR swab tests that did not identify the virus in the neonate's pharynx. In the reported case from Iran, 1111 Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S. Preterm delivery, maternal death, and vertical transmission in a pregnant woman with COVID-19 infection. Prenat Diagn. 2020 [ahead of print] the virus in the amniotic fluid was identified by PCR during the cesarean section, but there was no positivity in the nasopharynx samples, which suggests the possibility of perioperative contamination. 1111 Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S. Preterm delivery, maternal death, and vertical transmission in a pregnant woman with COVID-19 infection. Prenat Diagn. 2020 [ahead of print] Within the two reported cases in Italy, in which the swab was not performed shortly after birth, the authors themselves suggest the possibility of postpartum transmission. 1212 Ferrazzi E, Frigerio L, Savasi V, Vergani P, Prefumo F, Barresi S, et al. Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis. BJOG. 2020;127(09): 1116-1121. Doi: 10.1111/1471-0528.16278
https://doi.org/10.1111/1471-0528.16278...
The case 1313 AlzamoraMC, Paredes T, Caceres D,Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol. 2020;37(08):861-865. Doi: 10.1055/s-0040-1710050
https://doi.org/10.1055/s-0040-1710050...
reported in Peru showed positivity for the virus by PCR in the sample collected after 16 hours, and in the controls 48 hours later. In this case report, 1313 AlzamoraMC, Paredes T, Caceres D,Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol. 2020;37(08):861-865. Doi: 10.1055/s-0040-1710050
https://doi.org/10.1055/s-0040-1710050...
the patient presented a positive PCR with a short interval between diagnosis and delivery, but the authors did not evaluate different tissues, nor performed serological tests. More recently, there was another report 1515 Mehta H, Ivanovic S, Cronin A, VanBrunt L, Mistry N, Miller R, Yodice P, et al. Novel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: A case report. Case Rep Womens Health. 2020;27:e00220. Doi: 10.1016/j.crwh.2020.e00220
https://doi.org/10.1016/j.crwh.2020.e002...
of a case of a twin pregnancy in a medical center in the United States. Twin A tested positive 72 hours after birth; however, she did not exhibit any symptoms of infection. Twin B tested negative 72 hours after birth. The authors argue that ,because the patient was intubated at the time of delivery, that would make droplet transmission unlikely. Moreover, they claim that, because the babies were delivered via cesarean section, that would eliminate the possibility of fetal contact with maternal feces, which has been reported as a mode of transmission. Maternal contact with the neonates was avoided, they were not breastfed, and appropriate aerosol and contact precautions were taken during their handling in the neonatal intensive care unit (NICU). Due to the aforementioned reasonse, they believe that Twin A tested positive due to vertical transmission. There are crucial limitations to this theory. First, the placenta and umbilical cord blood were not tested for COVID-19, and, second, vertical transmission would have affected both twins, but Twin B, in that case, tested negative. Another article recently published with regards to possible evidence of mother-to-newborn COVID-19 infection reported a case of a neonate that tested positive for SARS-CoV-2 at ay 6 post-partum. In this specific case, obstetricians, anesthesiologists, neonatologists, and nurses wore full personal protective equipment (PPE), including an N95 mask, eye goggles, face shield, and a top-to-bottom tight-fitting gown, entering the operating theaters ∼ 5 minutes before the patients. However, the newborn was discharged home 11h after birth, and tested positive for SARS-CoV-2 on postnatal day (PND) 1. Three days later, his caregiver (his grandmother) also tested positive for SARS-CoV-2. In this case, it is not possible to establish vertical transmission as the route of contamination, once the newborn had contact with other potentially-infected people. 1616 Sun M, Xu G, Yang Y, Tao Y, Pian-Smith M, Madhavan V, et al. Evidence of mother-to-newborn infection with COVID-19. Br J Anaesth. 2020;125(02):e245-e247. Doi: 10.1016/j.bja.2020.04.066
https://doi.org/10.1016/j.bja.2020.04.06...
According to a recently published classification system 3434 Shah PS, Diambomba Y, Acharya G, Morris SK, Bitnun A. Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates. Acta Obstet Gynecol Scand. 2020;99(05):565-568. Doi: 10.1111/aogs.13870
https://doi.org/10.1111/aogs.13870...
for the definition of SARS-CoV-2 infection in pregnant women, fetuses, and neonates, a neonatal congenital infection is considered confirmed if the PCR detects the virus in the amniotic fluid collected before the rupture of the membrane or in the umbilical cord blood or neonatal blood collected within the first 12 hours of birth.

The only case 1414 Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(01):3572. Doi: 10.1038/s41467-020-17436-6
https://doi.org/10.1038/s41467-020-17436...
with sufficient evidence of vertical transmission was reported in France: a pregnant woman, 23 years old, 35 weeks of gestational age, was admitted with fever and severe cough, and diagnosed with SARS-CoV-2 through real-time quantitative PCR (qRT-PCR) analysis (genes E and S) of blood and swab (vaginal and nasopharinx). She delivered through cesarean section due to acute fetal distress, and presented a positive result in the amniotic fluid on the qRT-PCR (genes E and S). In the diagnosis of the newborn, nasopharyngeal and rectal swabs were collected within 1 hour, 3 days, and 18 days of life, and were found positive on the qRT-PCR (genes E and S). Blood and non-bronchoscopic bronchoalveolar lavage fluid collected before extubation (6 hours after delivery) were also positive the on qRT-PCR (genes E and S). According to the study, 1414 Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(01):3572. Doi: 10.1038/s41467-020-17436-6
https://doi.org/10.1038/s41467-020-17436...
the samples were properly collected. Within the first few days of life, the newborn presented neurological symptoms and impairment on a magnetic resonance scan of the central nervous system similar to those described for adults in a previous study. 3535 Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(06):683-690. Doi: 10.1001/jamaneurol.2020.1127
https://doi.org/10.1001/jamaneurol.2020....
The histological examination of the placenta showed a severe inflammatory process, and the qRT-PCR was extremely positive for both SARS-CoV-2 genes, suggesting placental transmission.

Considering the interval between maternal infection and the alleged vertical transmission, the information varies considerably. So far, conventional knowledge dictates that the placenta delays transmission for maternal viral infection; however, a recently-published study demonstrated that the ACE2 and the transmembrane protease serine 2 (TMPRSS2) are expressed in human trophectoderm and placentas throughout the 3 trimesters of pregnancy. 3636 Cui D, Liu Y, Jiang X, Ding C, Poon LC,Wang H, Yang H. Single-cell RNA expression profiling of ACE2 and TMPRSS2 in the human trophectoderm and placenta. Ultrasound Obstet Gynecol. 2020; •••;. Doi: 10.1002/uog.22186 [ahead of print]
https://doi.org/10.1002/uog.22186...
Therefore, the cells of the trophectoderm and the placenta should also be considered target sites for this coronavirus infection. This might suggest that pregnancies complicated with COVID-19 are potentially at risk of intrauterine fetal or placental SARS-CoV-2 infection. 3636 Cui D, Liu Y, Jiang X, Ding C, Poon LC,Wang H, Yang H. Single-cell RNA expression profiling of ACE2 and TMPRSS2 in the human trophectoderm and placenta. Ultrasound Obstet Gynecol. 2020; •••;. Doi: 10.1002/uog.22186 [ahead of print]
https://doi.org/10.1002/uog.22186...
This information was obtained through a bioinformatic analysis, and the immunohistochemical experiments were based on a limited number of samples. Considering the impact of individual heterogeneity, further analyses are required to investigate whether the expression patterns of ACE2 and TMPRSS2 can be extended to the general population.

On the other hand, a recent study 3737 Faure-Bardon V, Isnard P, Roux N, Leruez-Ville M, Molina T, Bessieres B, Ville Y. Anatomical and timely assessment of protein expression of angiotensin-converting enzyme 2, SARS-CoV-2 specific receptor, in fetal and placental tissues: new insight for perinatal counseling. Ultrasound Obstet Gynecol. 2020;•••;. Doi: 10.1002/uog.22178 [ahead of print]
https://doi.org/10.1002/uog.22178...
evaluating the protein expression of ACE2, both in placentas and fetal organs from non-infected pregnancies throughout gestation, has observed the absence of ACE2 expression in the fetal brain and heart. This is reassuring regarding the risk of congenital malformation, but the clinical follow-up of infected pregnant women and their children is required to validate these observations. 3737 Faure-Bardon V, Isnard P, Roux N, Leruez-Ville M, Molina T, Bessieres B, Ville Y. Anatomical and timely assessment of protein expression of angiotensin-converting enzyme 2, SARS-CoV-2 specific receptor, in fetal and placental tissues: new insight for perinatal counseling. Ultrasound Obstet Gynecol. 2020;•••;. Doi: 10.1002/uog.22178 [ahead of print]
https://doi.org/10.1002/uog.22178...
With regards to vertical transmission, what we have observed so far is that the risk is very low. The mechanisms that might be involved in the maternal-fetus transmission are not clear.

Among the systematic reviews that were eligible for the present study, a total of 238 pregnancies and 174 deliveries were evaluated, and only 1 case of suspected vertical transmission, which was also mentioned in the present review (case #7– Table 1), was identified.

Conclusion

The risk of vertical transmission by SARS-CoV-2 is probably very low. Despite millions of confirmed cases of COVID-19 worldwide, which probably include several thousands of pregnant women, we have identified only 1 case that has fulfilled sufficient criteria to be nominated as a confirmed vertical transmission. Well-designed observational studies evaluating large samples are still necessary to determine the risk of vertical transmission depending on the gestational age at infection. Additionally, we also need large observational studies to evaluate whether the infection by SARS-CoV-2 during pregnancy is related to an increased risk of adverse obstetrical outcomes or birth defects.

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Publication Dates

  • Publication in this collection
    24 May 2021
  • Date of issue
    Mar 2021

History

  • Received
    12 Oct 2020
  • Accepted
    06 Nov 2020
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