Data collected from pregnancy outcomes with the presence of SARS-CoV and MERS-CoV infections and those related to inflammatory and thrombotic changes in the placenta indicate that placental and neonatal infections can occur and that maternal infection is associated with placental changes.
Maternal inflammation can cause a variety of consequences throughout the child’s life. Therefore, it can be assumed that the proinflammatory state of SARS-CoV-2 infection during pregnancy may lead to adverse consequences in children. In addition to the potential risk of vertical transmission, SARS-CoV-2 may indirectly lead to perinatal and long-term adverse neurodevelopmental outcomes through maternal immune activation (MIA). Therefore, investigations of inflammatory dysregulation in pregnant women with SARS-CoV-2 and longitudinal studies of developmental outcomes in children exposed to SARS-CoV-2 are necessary to ensure adequate care. Most pregnant women are asymptomatic or have mild disease. However, any infection during pregnancy presents potential risks. A recent study found that 3% of pregnant women with SARS-CoV-2 required intensive care, with cases of preterm labor and perinatal death. Viral infections during pregnancy can lead to many placental and neonatal conditions and can cause villitis and miscarriage, as well as being transmitted to the newborn during labor.
SARS-CoV presents as a disease similar to influenza and pneumonia; Possible complications during pregnancy may include maternal death, hypoxia, disseminated intravascular coagulopathy, intrauterine fetal death, intrauterine growth retardation, premature delivery, and miscarriage. In women who were cured of SARS, the placenta during the first trimester appeared normal, whereas the placentas of women with active SARS infection showed increased intervillous and subchorionic fibrin, attributed to maternal hypoxia or increased thrombotic activity. MERS-CoV emerged in June 2012 in the Arabian Peninsula. Similar to SARS-CoV, MERS-CoV infects the lower respiratory tract, causing severe pneumonia. So far, there have been only 11 cases of MERS-CoV infection of pregnant women. Most MERS-CoV infections have resulted in adverse outcomes ranging from preterm labor to maternal and fetal death. The mortality rate of MERS-CoV infection is similar in pregnant women compared with nonpregnant patients. Given the high mortality rate, it is likely that the infection causes placental changes similar to those seen in SARS-CoV infections.
Most reported cases of SARS-CoV-2 positive pregnancies to document negative polymerase chain reaction (PCR) results for SARS-CoV-2 in the newborn, placenta, cord blood, and vaginal secretions. However, there are cases of infants who tested positive for SARS-CoV-2 after delivery, as well as some infants who had positive IgM antibodies to SARS-CoV-2. The SARS-CoV-2 infection causes inflammatory and vascular changes in the placenta, and these could have deleterious effects on both mother and fetus, and we could even go so far as to talk about neurological inflammation before birth.
Appropriate means for neonatal screening have not yet been established, and serologic testing for SARS-CoV-2 is not stable at this time and consequently, it is difficult to interpret these cases. It appears that the majority of infants born to SARS-CoV-2 positive or convalescent mothers have no viremia, congenital infection, or viral replication in the nasopharynx. There are several cases of possible SARS-CoV-2 infection in both the placenta and the newborn but most with the presence of relatively mild symptoms. Certain evidence suggests that maternal inflammation associated with SARS-CoV-2 may confer a long-term risk of neuropsychiatric disorders in children. Maternal Immune Activation (MIA) has been described as a “neurodevelopmental disease principle” that increases the susceptibility of individuals to interacting genetic and environmental risk factors that may trigger neuro- or psychopathologies later in life. The link between MIA and mood disorders, such as depression and bipolar affective disorder in children, has also been suggested. Regarding the complications of SARS-CoV-2 infection in pregnancy, several cases of fetal loss and preterm delivery due to fetal distress have also been reported in SARS-CoV-2-positive pregnant women; some studies have found that the rate of preterm delivery in SARS-CoV-2-infected patients is higher than in the general pregnant population. Preterm infants born to mothers with SARS-CoV-2 should be closely monitored for short- and long-term complications.
1. COVID-19 map. Johns Hopkins Coronavirus Resource Center Web site.
https://coronavirus.jhu.edu/map.html. Accessed Jul 9, 2020.
2. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine storm’ in COVID-19. J
Infect. 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194613/. Accessed Jun 4, 2020. doi:
3. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission
potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records.
Lancet. 2020;395(10226):809-815. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159281/.
Accessed Jun 3, 2020. doi: 10.1016/S0140-6736(20)30360-3.
4. 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(18):1846-1848.
https://jamanetwork.com/journals/jama/fullarticle/2763853. Accessed Jun 10, 2020. doi:
5. Patanè L, Morotti D, Giunta MR, et al. Vertical transmission of COVID-19: SARS-CoV-2 RNA on
the fetal side of the placenta in pregnancies with COVID-19 positive mothers and neonates at birth.
American Journal of Obstetrics & Gynecology MFM. 2020:100145.
http://dx.doi.org/10.1016/j.ajogmf.2020.100145. doi: 10.1016/j.ajogmf.2020.100145.
6. 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. Accessed Jun 5, 2020.
7. Baud D, Greub G, Favre G, et al. Second-trimester miscarriage in a pregnant woman with SARSCoV-
2 infection. JAMA. 2020;323(21):2198-2200. https://www.ncbi.nlm.nih.gov/pubmed/32352491.
8. Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA. Placental pathology in
COVID-19. Am J Clin Pathol. https://academic.oup.com/ajcp/advancearticle/
doi/10.1093/ajcp/aqaa089/5842018. Accessed Jun 3, 2020. doi: 10.1093/ajcp/aqaa089.
9. Baergen RN, Heller DS. Placental pathology in covid-19 positive mothers: Preliminary findings:
Pediatric and Developmental Pathology. 2020.
10. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in china,
2019. N Engl J Med. 2020;382(8):727-733.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092803/. Accessed Jun 3, 2020.
11. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus
in wuhan, china. Lancet. 2020;395(10223):497-506.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159299/. Accessed Jun 4, 2020.
12. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis,
and angiogenesis in covid-19. N Engl J Med. 2020. Accessed Jun 4, 2020.
13. Wichmann D, Sperhake J, Lütgehetmann M, et al. Autopsy findings and venous
thromboembolism in patients with COVID-19. Ann Intern Med. 2020. Accessed Jun 4, 2020.
14. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019
(COVID-19) outbreak in china: Summary of a report of 72 314 cases from the chinese center for
disease control and prevention. JAMA. 2020;323(13):1239-1242.
https://jamanetwork.com/journals/jama/fullarticle/2762130. Accessed Jun 10, 2020.
15. Andrikopoulou M, Madden N, Wen T, et al. Symptoms and critical illness among obstetric
patients with coronavirus disease 2019 (COVID-19) infection. Obstetrics & Gynecology.
2020;Publish Ahead of Print.
ric.97341.aspx. Accessed Jun 3, 2020.
16. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. COVID-19 infection among asymptomatic and
symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of new
york city hospitals. Am J Obstet Gynecol MFM. 2020:100118. Accessed Jun 10, 2020.
17. Zimmermann P, Curtis N. COVID-19 in children, pregnancy and neonates: A review of epidemiologic and clinical features. The Pediatric Infectious Disease Journal. 2020;39(6):469–477.
a.1.aspx. Accessed Jun 4, 2020.
18. Culler Freeman M, Denison M. Coronaviruses. Nelson textbook of pediatrics, 20th edition.
Elsevier Health Sciences; 2016:1613-1615. Accessed Jun 4, 2020.
19. Gheblawi M, Wang K, Viveiros A, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020;126(10):1456-1474. Accessed Jun 4, 2020.
20. Shang J, Ye G, Shi K, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581(7807):221-224. Accessed Jun 4, 2020.
21. Li M, Chen L, Zhang J, Xiong C, Li X. The SARS-CoV-2 receptor ACE2 expression of maternalfetal interface and fetal organs by single-cell transcriptome study. PLOS ONE. 2020;15(4):e0230295.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230295. Accessed Jun 5, 2020.
22. Ander SE, Diamond MS, Coyne CB. Immune responses at the maternal-fetal interface. Sci Immunol. 2019;4(31). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744611/. Accessed Jun 3,
30. Oliveira GMd, Pascoal-Xavier MA, Moreira DR, et al. Detection of cytomegalovirus, herpes virus
simplex, and parvovirus b19 in spontaneous abortion placentas. J Matern Fetal Neonatal Med.
2019;32(5):768-775. Accessed Jun 10, 2020.
31. León-Juárez M, Martínez-Castillo M, González-García LD, et al. Cellular and molecular
mechanisms of viral infection in the human placenta. Pathogens and disease. 2017;75(7).
32. Marcdante KJ, Kliegman RM. Congenital infections,. In: Nelson essentials of pediatrics. 8th ed. Philadelphia, PA: Elsevier; 2019:259-264. https://www-clinicalkeycom. proxy1.library.jhu.edu/#!/content/book/3-s2.0-B9780323511452003141. Accessed Jun 10, 2020.
33. Blumberg DA, Underwood MA, Hedriana HL, Lakshminrusimha S. Vertical transmission of
SARS-CoV-2: What is the optimal definition? Am J Perinatol. 2020. http://www.thiemeconnect.
de/DOI/DOI?10.1055/s-0040-1712457. Accessed Jun 10, 2020.
34. Cui J, Li F, Shi Z. Origin and evolution of pathogenic coronaviruses. Nature reviews. Microbiology. 2019;17(3):181-192. https://www.ncbi.nlm.nih.gov/pubmed/30531947.
35. 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(2). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077337/. Accessed Jun 2, 2020.
36. Ng WF, Wong SF, Lam A, et al. The placentas of patients with severe acute respiratory syndrome:
A pathophysiological evaluation. Pathology. 2006;38(3):210-218.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131423/. Accessed Jun 3, 2020.
37. de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: Recent insights into emerging coronaviruses. Nature reviews. Microbiology. 2016;14(8):523-534.
38. Lambelet V, Vouga M, Pomar L, et al. Sars-CoV-2 in the context of past coronaviruses epidemics: Consideration for prenatal care. Prenatal Diagnosis. ;n/a(n/a).
https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.5759. Accessed Jun 3, 2020.
39. Jeong SY, Sung SI, Sung J, et al. MERS-CoV infection in a pregnant woman in Korea. J Korean
Med Sci. 2017;32(10):1717-1720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592190/.
Accessed Jun 3, 2020.
40. Chen Y, Peng H, Wang L, et al. Infants born to mothers with a new coronavirus (COVID-19).
Front Pediatr. 2020;8. https://www.frontiersin.org/articles/10.3389/fped.2020.00104/full. Accessed
Jun 5, 2020.
41. Li N, Han L, Peng M, et al. Maternal and neonatal outcomes of pregnant women with COVID-19
pneumonia: A case-control study. Clin Infect Dis. https://academic.oup.com/cid/advancearticle/
42. Peng Z, Wang J, Mo Y, et al. Unlikely SARS-CoV-2 vertical transmission from mother to child:
A case report. Journal of Infection and Public Health. 2020;13(5):818-820.
43. Baergen RN, Heller DS. Placental pathology in covid-19 positive mothers: Preliminary findings: Pediatric and Developmental Pathology. 2020.
https://journals.sagepub.com/doi/10.1177/1093526620925569. Accessed Jun 5, 2020.
44. Pereira A, Cruz‐Melguizo S, Adrien M, Fuentes L, Marin E, Perez‐Medina T. Clinical course of
coronavirus disease-2019 in pregnancy. Acta Obstetricia et Gynecologica Scandinavica. ;n/a(n/a).
https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1111/aogs.13921. Accessed Jun 10, 2020.
45. Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia.
JAMA. 2020;323(18):1848-1849. https://jamanetwork.com/journals/jama/fullarticle/2763854. Accessed Jun 5, 2020.
46. Sun B, Feng Y, Mo X, et al. Kinetics of SARS-CoV-2 specific IgM and IgG responses in COVID-
19 patients. Emerging Microbes & Infections. 2020;9(1):940-948.
https://doi.org/10.1080/22221751.2020.1762515. Accessed Jun 10, 2020.
47. Long Q, Liu B, Deng H, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19.
Nature medicine. 2020:1-4. https://www.ncbi.nlm.nih.gov/pubmed/32350462.
48. Schoenmakers S, Snijder P, Verdijk R, et al. SARS-CoV-2 placental infection and inflammation
leading to fetal distress and neonatal multi-organ failure in an asymptomatic woman. medRxiv. 2020.
49. Hosier H, Farhadian S, Morotti R, et al. SARS-CoV-2 infection of the placenta. medRxiv. 2020.
50. Eloundou SN, Lee J, Wu D, et al. Placental malperfusion in response to intrauterine inflammation
and its connection to fetal sequelae. PLoS One. 2019;14(4).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447225/. Accessed Jun 9, 2020.
51. Gronvall GP, Connell NP, Kobokovich AM, et al. Developing a national strategy for serology
(antibody testing) in the united states. Johns Hopkins Center for Health Security Web site. https://www.centerforhealthsecurity.org/our-work/publications/developing-a-national-strategy-for- Serology-antibody-testing-in-the-US. Updated 2020. Accessed Jun 9, 2020.
52. Britt W. Cytomegalovirus. In: Remington and Klein’s infectious diseases of the fetus and newborn
infant. 8th ed. Philadelphia, PA: Elsevier/Saunders; 2016:724-781. https://www-clinicalkeycom.
proxy1.library.jhu.edu/#!/content/book/3-s2.0- B9780323241472000249?scrollTo=%23hl0002513. Accessed Jun 9, 2020.
53. Afran L, Knight MG, Nduati E, Urban BC, Heyderman RS, Rowland‐Jones SL. HIV-exposed
uninfected children: A growing population with a vulnerable immune system? Clinical & Experimental Immunology. 2014;176(1):11-22. https://onlinelibrary.wiley.com/doi/abs/10.1111/cei.12251. Accessed Jun 10, 2020.
54. Evans C, Jones CE, Prendergast AJ. HIV-exposed, uninfected infants: New global challenges in
the era of paediatric HIV elimination. The Lancet Infectious Diseases. 2016;16(6):e92-e107.https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)00055-4/abstract. Accessed Jun
10, 2020. doi: 10.1016/S1473-3099(16)00055-4.
55. Sharma BK, Kakker NK, Bhadouriya S, Chhabra R. Effect of TLR agonist on infections bronchitis virus replication and cytokine expression in embryonated chicken eggs. Mol Immunol.
2020;120:52-60. Accessed Jun 10, 2020. doi: 10.1016/j.molimm.2020.02.001.
56. Pierce-Williams RAM, Burd J, Felder L, et al. Clinical course of severe and critical COVID-19 in hospitalized pregnancies: A US cohort study. Am J Obstet Gynecol MFM. 2020:100134. Accessed
Jun 12, 2020.
57. Sarapultsev A, Sarapultsev P. Immunological environment shifts during pregnancy may affect the
risk of developing severe complications in COVID-19 patients. Am J Reprod Immunol. 2020:e13285.
Accessed Jun 11, 2020.
58. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J
Med. 2000;342(20):1500-1507. Accessed Jun 10, 2020. doi: 10.1056/NEJM200005183422007.
59. Al-Haddad BJS, Oler E, Armistead B, et al. The fetal origins of mental illness. Am J Obstet Gynecol. 2019;221(6):549-562. Accessed Jun 11, 2020.
60. Mor G, Cardenas I. The immune system in pregnancy: A unique complexity. Am J Reprod Immunol. 2010;63(6):425-433. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025805/. Accessed Jun 10, 2020.
61. Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN. The role of cytokines in mediating effects of prenatal infection on the fetus: Implications for schizophrenia. Mol Psychiatry. 2006;11(1):47-55. Accessed Jun 11, 2020. doi: 10.1038/sj.mp.4001748.
62. Gilmore JH, Fredrik Jarskog L, Vadlamudi S, Lauder JM. Prenatal infection and risk for
schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development. Neuropsychopharmacology. 2004;29(7):1221-1229. Accessed Jun 11, 2020. doi: 10.1038/sj.npp.1300446.
63. Presicce P, Park C, Senthamaraikannan P, et al. IL-1 signaling mediates intrauterine inflammation
and chorio-decidua neutrophil recruitment and activation. JCI Insight. 2018;3(6). Accessed Jun 11,
2020. doi: 10.1172/jci.insight.98306.
64. Cardenas I, Means RE, Aldo P, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol. 2010;185(2):1248-
1257. Accessed Jun 10, 2020. doi: 10.4049/jimmunol.1000289.
65. Gantert M, Been JV, Gavilanes AWD, Garnier Y, Zimmermann LJI, Kramer BW.
Chorioamnionitis: A multiorgan disease of the fetus? J Perinatol. 2010;30 Suppl:21. Accessed Jun 12, 2020.
66. Mitra S, Aune D, Speer CP, Saugstad OD. Chorioamnionitis as a risk factor for retinopathy of prematurity: A systematic review and meta-analysis. Neonatology. 2014;105(3):189-199. Accessed
Jun 12, 2020.
67. Chen C, Chou H. Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury in
rat offspring. Pediatr Res. 2019;86(2):174-180. Accessed Jun 12, 2020. doi: 10.1038/s41390-019-
68. Gover A, Chau V, Miller SP, et al. Prenatal and postnatal inflammation in relation to cortisol
levels in preterm infants at 18 months corrected age. J Perinatol. 2013;33(8):647-651. Accessed Jun
12, 2020. doi: 10.1038/jp.2013.24.
69. Hudalla H, Karenberg K, Kuon R, Pöschl J, Tschada R, Frommhold D. LPS-induced maternal inflammation promotes fetal leukocyte recruitment and prenatal organ infiltration in mice. Pediatr
Res. 2018;84(5):757-764. Accessed Jun 12, 2020.
80. Meyer U, Feldon J, Schedlowski M, Yee BK. Immunological stress at the maternal-fetal interface: A link between neurodevelopment and adult psychopathology. Brain Behav Immun.
2006;20(4):378-388. Accessed Jun 10, 2020.
81. Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel H-. Elevated
maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014;19(2):259- 264. Accessed Jun 11, 2020. doi: 10.1038/mp.2012.197.
82. Zhang J, Luo W, Huang P, Peng L, Huang Q. Maternal C-reactive protein and cytokine levels during pregnancy and the risk of selected neuropsychiatric disorders in offspring: A systematic review
and meta-analysis. J Psychiatr Res. 2018;105:86-94. Accessed Jun 11, 2020.
83. Wu C, Yang W, Wu X, et al. Clinical manifestation and laboratory characteristics of SARS-CoV-
2 infection in pregnant women. Virologica Sinica. 2020:1-6.
84. Kayem G, Alessandrini V, Azria E, et al. A snapshot of the covid-19 pandemic among pregnant women in france. J Gynecol Obstet Hum Reprod. 2020:101826. Accessed Jun 12, 2020. doi: