Is vertical transmission of SARS-CoV-2 possible? Is that the right question?

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Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716.

EXPERT COMMENTARY

Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.^1,2

Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.³ Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,⁴ as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi.

Details of the study

In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.⁵ Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely.

As a caveat to their research, the authors noted that:

transcription levels do not always correlate with protein expression
it is possible that a noncanonical cell-entry mediator facilitates entry
individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2.

Study strengths and limitations

Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m², and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings.

The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.^6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.^8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.¹⁰

The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

While the study by Pique-Regi and colleagues is an important contribution to the literature, it does not satisfactorily answer the question regarding vertical transmission. More research is needed, especially regarding maternal infection in the first and second trimesters, on the effects on placental vasculature (and timing of infection in each trimester), the potential breakdown of the maternal-fetal barrier, and, most important, the clinical courses and outcomes in both mother and infant.

JANE VAN DIS, MD

References

Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinical Medicine. 2020;25:100446.
Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020;324:705-706.
Liu H, Wang LL, Zhao SJ, et al. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139;103122.
Li M, Chen L, Zhang J, et al. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One. 2020;15:e0230295.
Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? eLife. 2020;9:e58716.
Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020;323:1848-1849.
Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323:1846-1848.
Kotlyar A, Grechukhina O, Chen A, et al. Vertical transmission of COVID-19: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;S0002-9378(20)30823-1.
Richtmann R, Torloni MR, Oyamada Otani AR, et al. Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: a case series. Case Rep Womens Health. 2020;e00243.
Wang C, Zhou YH, Yang HX, et al. Intrauterine vertical transmission of SARS-CoV-2: what we know so far. Ultrasound Obstet Gynecol. 2020;55:724-725.

Author and Disclosure Information

Jane van Dis, MD, is an OB Hospitalist, USC Verdugo Hills Hospital, La Cañada Flintridge, California.

The author reports no financial relationships relevant to this article.

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Author and Disclosure Information

Jane van Dis, MD, is an OB Hospitalist, USC Verdugo Hills Hospital, La Cañada Flintridge, California.

The author reports no financial relationships relevant to this article.

Author and Disclosure Information

Jane van Dis, MD, is an OB Hospitalist, USC Verdugo Hills Hospital, La Cañada Flintridge, California.

The author reports no financial relationships relevant to this article.

Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716.

EXPERT COMMENTARY

Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.^1,2

Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.³ Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,⁴ as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi.

Details of the study

In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.⁵ Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely.

As a caveat to their research, the authors noted that:

transcription levels do not always correlate with protein expression
it is possible that a noncanonical cell-entry mediator facilitates entry
individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2.

Study strengths and limitations

Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m², and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings.

The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.^6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.^8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.¹⁰

The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

While the study by Pique-Regi and colleagues is an important contribution to the literature, it does not satisfactorily answer the question regarding vertical transmission. More research is needed, especially regarding maternal infection in the first and second trimesters, on the effects on placental vasculature (and timing of infection in each trimester), the potential breakdown of the maternal-fetal barrier, and, most important, the clinical courses and outcomes in both mother and infant.

JANE VAN DIS, MD

Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716.

EXPERT COMMENTARY

Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.^1,2

Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.³ Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,⁴ as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi.

Details of the study

In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.⁵ Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely.

As a caveat to their research, the authors noted that:

transcription levels do not always correlate with protein expression
it is possible that a noncanonical cell-entry mediator facilitates entry
individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2.

Study strengths and limitations

Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m², and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings.

The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.^6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.^8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.¹⁰

The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

While the study by Pique-Regi and colleagues is an important contribution to the literature, it does not satisfactorily answer the question regarding vertical transmission. More research is needed, especially regarding maternal infection in the first and second trimesters, on the effects on placental vasculature (and timing of infection in each trimester), the potential breakdown of the maternal-fetal barrier, and, most important, the clinical courses and outcomes in both mother and infant.

JANE VAN DIS, MD

References

Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinical Medicine. 2020;25:100446.
Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020;324:705-706.
Liu H, Wang LL, Zhao SJ, et al. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139;103122.
Li M, Chen L, Zhang J, et al. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One. 2020;15:e0230295.
Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? eLife. 2020;9:e58716.
Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020;323:1848-1849.
Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323:1846-1848.
Kotlyar A, Grechukhina O, Chen A, et al. Vertical transmission of COVID-19: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;S0002-9378(20)30823-1.
Richtmann R, Torloni MR, Oyamada Otani AR, et al. Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: a case series. Case Rep Womens Health. 2020;e00243.
Wang C, Zhou YH, Yang HX, et al. Intrauterine vertical transmission of SARS-CoV-2: what we know so far. Ultrasound Obstet Gynecol. 2020;55:724-725.

References

Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinical Medicine. 2020;25:100446.
Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020;324:705-706.
Liu H, Wang LL, Zhao SJ, et al. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139;103122.
Li M, Chen L, Zhang J, et al. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One. 2020;15:e0230295.
Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? eLife. 2020;9:e58716.
Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020;323:1848-1849.
Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323:1846-1848.
Kotlyar A, Grechukhina O, Chen A, et al. Vertical transmission of COVID-19: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;S0002-9378(20)30823-1.
Richtmann R, Torloni MR, Oyamada Otani AR, et al. Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: a case series. Case Rep Womens Health. 2020;e00243.
Wang C, Zhou YH, Yang HX, et al. Intrauterine vertical transmission of SARS-CoV-2: what we know so far. Ultrasound Obstet Gynecol. 2020;55:724-725.