As the pandemic of coronavirus disease 2019 (COVID-19), caused by serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has expanded globally and COVID-19 has been reported in pregnant women, concerns regarding the potential for mother-to-child SARS-CoV-2 transmission have been expressed by clinicians and patients.
For in utero transmission to occur, the pathogen must be present in the blood and be able to cross the placenta to infect the fetus. Viremia secondary to SARS-CoV-2 appears to be uncommon.1 If viremia occurs, allowing the virus to reach the placenta, the presence of angiotensin-converting enzyme 2, the SARS-CoV-2 receptor, in both placenta and fetal tissues suggests transplacental passage and fetal infection may be possible.2 Intrapartum infection can occur through exposure of the infant to infectious virus in maternal blood or secretions during the birth process. SARS-CoV-2 is more often detected in feces than in vaginal secretions, but there is no direct evidence of SARS-CoV-2 transmission from either of these sources.3,4
There are no confirmed cases of maternal–fetal transmission of the other severe coronavirus infections, SARS-CoV-1 and MERS.5 While there have been a small number of cases of neonates with possible vertical SARS-CoV-2 infection reported, diagnosis has generally been based on the detection of SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) in infant naso/oropharyngeal specimens obtained often days after birth. Placental infection has also been reported.6 Confirmation of vertical infection is complex and requires sampling of appropriate tissues and fluids at the time of delivery. Case definitions to define in utero and intrapartum transmission have been proposed, which rely on timing of maternal illness relative to delivery and virologic testing of specimens at birth and intervals thereafter, including placenta, amniotic fluid, vaginal fluid, neonatal blood, and infant respiratory and other secretions.7,8 Detection of SARS-CoV-2 IgM antibody in the infant has been proposed as potential evidence of intrauterine infection, but there are many pitfalls with reliance on an IgM assay.9
This issue of the Journal includes 3 case reports of potential vertical transmission.10–12 These 3 reports present the challenge of applying the available clinical data to proposed definitions of in utero and intrapartum transmission to make an assessment of whether the case represents vertical transmission and, if so, whether it was most likely intrauterine or intrapartum. (Table 1) In all 3 of these cases, there is definitive evidence of ongoing maternal COVID-19 disease (with onset within 10 days prior to delivery) and clear evidence of persistent detection of neonatal SARS-CoV-2 over time. In addition, meticulous procedures—beginning in the delivery room—were undertaken to immediately remove the newborns from their mothers (and families) to prevent postnatal (horizontal) transmission. Despite all of these measures, however, the potential for horizontal transmission, whether from viral contamination of the birthing environment or from another source in the healthcare setting during epidemic surges of COVID-19 cases, remains nearly impossible to exclude.
If these cases represent vertical transmission, were they intrauterine or intrapartum transmissions?
In the case reported by Marzolo et al,10 the infant nasopharyngeal SARS-CoV-2 RT-PCR test at age 12 hours was indeterminate, and thus the earliest documented SARS-CoV-2 RNA detection was not until 36 hours of life. With the additional consideration of the vaginal route of delivery, this case was more likely intrapartum or early horizontal infection than intrauterine transmission. Testing of amniotic fluid, placental tissue, or neonatal (day of birth) blood was not available to refine this assessment.
In the case reported by Demirjian and Singh,11 the SARS-CoV-2 RT-PCR results were negative from nasopharyngeal, stool, urine, and blood specimens obtained from the infant on the day of birth, essentially excluding intrauterine infection. No follow-up specimens were obtained until a nasopharyngeal specimen tested positive on day 3 of life, and no amniotic fluid or placental tissue studies were available. Because the infant was delivered by cesarean section, intrapartum transmission is unlikely. Airborne transmission in the delivery room from the intubated mother or transmission from another horizontal source remain possibilities—and may be more likely than vertical transmission in this case.
Finally, in the case reported by Sisma et al,12 the first infant specimen was obtained by 24 hours of life and that nasopharyngeal specimen was SARS-CoV-2 RT-PCR positive. The evidence for intrauterine infection was strengthened by the histologic, immunohistochemical, and electron microscope findings of the fetal side of the placenta; however, direct SARS-CoV-2 RNA detection was not attempted on the placenta,6 amniotic fluid, or infant blood. Furthermore, rupture of membranes 8 hours prior to birth increases the potential intrapartum exposure risk. Thus, while this case could represent intrauterine or intrapartum infection, the early and persistent SARS-CoV-2 RNA detection in this infant (who developed a febrile respiratory illness compatible with COVID-19), placental tissue findings and careful infection prevention measures suggest intrauterine infection is more likely.
As these cases illustrate, evaluation for vertical—and especially intrauterine—SARS-CoV-2 infection can be challenging, and assessment is often limited by lack of optimal testing of appropriate specimens obtained at specific timepoints. Establishing case definition criteria for in utero, intrapartum and postnatal infection and then implementing standard protocols that facilitate collection, handling, and testing of specimens according to those criteria is critical. Proving that intrauterine infections can occur is a critical step for developing additional research and treatment goals to prevent and manage those infections. This series of cases gets us closer to that critical step, but we strongly encourage clinicians to continue to systematically evaluate infants for potential intrauterine SARS-CoV-2 infection and share their findings in the literature.
Like many prior reports, these cases demonstrate skilled and thorough care of pregnant women with COVID-19 and their infants by medical teams working under difficult circumstances and in the face of many uncertainties about management of this new disease. These cases provide an opportunity to recognize the trust that COVID-19 patients and families put in their healthcare workers and the tremendous dedication of that medical staff—and a special appreciation for the extra efforts made to collect, summarize, and submit their case experiences to advance our understanding of vertical transmission.
1. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323:1843–1844.
2. 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. PLosOne. 2020;15:e020295.
3. Kirtsman M, Diambomba Y, Poutanen SM, et al. Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection. CMAJ. 2020;192:E647–E650.
4. Carosso A, Cosma S, Serafini P, et al. Risk of maternal feacal contamination and how to reduce the potential risk of vertical transmission of SARS-CoV-2 during vaginal delivery. Eur J Obstet Gynecol Reprod Biol. 2020;250:246–249.
5. Schwartz DA, Graham AL. Potential maternal and infant outcomes from coronavirus 2019-nCoV (SARS-CoV-2) infecting pregnant women: Lessons from SARS, MERS, and other human coronavirus infections. Viruses. 2020;12:194.
6. Hosier H, Farhadian SF, Morotti RA, et al. SARS-CoV-2 infection of the placenta [published online ahead of print, 2020 Jun 23]. J Clin Invest. 2020;139569. doi: 10.1172/JCI139569.
7. Blumberg DA, Underwood MA, Hedriana HL, et al. Vertical transmission of SARS-CoV-2: what is the optimal definition? Am J Perinatol. 2020;37:769–772.
8. Shah PS, Diambomba Y, Acharya G, et al. Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates. Acta Obstet Gynecol Scand. 2020;99:565–568.
9. Kimberlin DW, Stagno S. Can SARS-CoV-2 infection be acquired in utero? More definitive evidence is needed. JAMA. 2020 Mar 26 (Online ahead of print).
10. Marzolo R, Aversa S, Prefumo F, et al. Possible coronavirus disease 2019 pandemic and pregnancy: vertical transmission is not excluded. Pediatr Inf Dis J. 2020;39:e262–e262.
11. Demirjian A, Singh C. Probable vertical transmission of SARS-CoV-2 infection. Pediatr Inf Dis J. 2020;39:e257–e260.
12. Sisman J, Jaleel MA, Moreno W, et al. Intrauterine transmission of SARS-COV-2 infection in a preterm infant. Pediatr Inf Dis J. 2020;39:e265–e267.