Synthesis and systematic review of reported neonatal SARS-CoV-2 infections

Abstract

A number of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have been reported in neonates. Here, we aim to clarify the transmission route, clinical features and outcomes of these infections. We present a meta-analysis of 176 published cases of neonatal SARS-CoV-2 infections that were defined by at least one positive nasopharyngeal swab and/or the presence of specific IgM. We report that 70 and 30% of infections are due to environmental and vertical transmission, respectively. Our analysis shows that 55% of infected neonates developed COVID-19; the most common symptoms were fever (44%), gastrointestinal (36%), respiratory (52%) and neurological manifestations (18%), and lung imaging was abnormal in 64% of cases. A lack of mother-neonate separation from birth is associated with late SARS-CoV-2 infection [OR 4.94 (95% CI: 1.98-13.08), p=0.0002; adjusted OR 6.6 (95% CI: 2.6-16), p<0.0001], while breastfeeding is not [OR 0.35 (95% CI: 0.09-1.18), p=0.10; adjusted OR 2.2 (95% CI: 0.7-6.5), p=0.148]. Our findings add to the literature on neonatal SARS-CoV-2 infections.

Raschetti R., Vivanti A.J., Vauloup-Fellous C., et al. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections. Nat Commun. 2020; 11:5164. DOI: https://doi.org/10.1038/s41467-020-18982-9

References

1. World Health Organization (WHO). WHO Director-General’s opening remarks at the media briefing on COVID-19: 11 March 2020. URL: https:// www.who.int/dg/speeches/detail/who-directorgeneral-s-opening-remarks-at-themedia-briefingon-covid-19-11-march-2020

2. Imperial College COVID-19 Response Team, et al. Suppression of a SARSCoV-2 outbreak in the Italian municipality of Vo’. Nature. 2020; 584: 425-9.

3. Oran D.P., Topol E.J. Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review. Ann Intern Med. 2020; 173: 362-7.

4. Guan W., et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020; 382: 1708-20.

5. Grant M.C., et al. The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): a systematic review and meta-analysis of 148 studies from 9 countries. PLoS One. 2020; 15: e0234765.

6. Domingo P., et al. The four horsemen of a viral Apocalypse: the pathogenesis of SARS-CoV-2 infection (COVID-19). EBioMedicine. 2020; 58: 102887.

7. Jain V., Yuan J.-M. Predictive symptoms and comorbidities for severe COVID-19 and intensive care unit admission: a systematic review and metaanalysis. Int J Public Health. 2020; 65: 533-46.

8. Williamson E.J., et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020; 584: 430-6.

9. De Luca D., et al. The EPICENTRE (ESPNIC Covid pEdiatric Neonatal Registry) initiative: background and protocol for the international SARS-CoV-2 infections registry. Eur J Pediatr. 2020; 179: 1271-8.

10. Castagnoli R., et al. Severe acute respiratory syndrome corona-virus 2 (SARSCoV-2) infection in children and adolescents: a systematic review. JAMA Pediatr. 2020; 174 (9): 882-9. DOI: https://doi.org/10.1001/jamapediatrics.2020.1467

11. Gotzinger F., et al. COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. Lancet Child Adolesc Health. 2020; 4: 653-61.

12. Lu X., et al. SARS-CoV-2 infection in children. N Engl J Med. 2020; 382: 1663-5.

13. Algarroba G.N., et al. Visualization of SARS-CoV-2 virus invading the human placenta using electron microscopy. Am J Obstet Gynecol. 2020; 223: 275-8.

14. Hosier H., et al. SARS-CoV-2 infection of the placenta. J Clin Invest. 2020; 130: 4947-53.

15. Egloff C., Vauloup-Fellous C., Picone O., Mandelbrot L., Roques P. Evidence and possible mechanisms of rare maternal-fetal transmission of SARS-CoV-2. J Clin Virol. 2020; 128: 104447.

16. Shah P.S., Diambomba Y., Acharya G., Morris S.K., Bitnun A. Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates. Acta Obstet Gynecol Scand. 2020; 99: 565-8.

17. Abasse S., et al. Neonatal COVID-19 Pneumonia: report of the first case in a preterm neonate in Mayotte, an Overseas Department of France. Child (Basel). 2020; 7: E87.

18. Aghdam M.K., Jafari N., Eftekhari K. Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report. Infect Dis. 2020; 52: 427-9.

19. Alonso Diaz C., Lopez Maestro M., Moral Pumarega M.T., Flores Anton B., Pallas Alonso C.R. Primer caso de infeccion neonatal por SARS-CoV-2 en Espana. An Pediatr (Barc). 2020; 92: 237-8.

20. Alzamora M.C., et al. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol. 2020; 37: 861-5.

21. Ayed A., et al. Maternal and perinatal characteristics and outcomes of pregnancies complicated with COVID-19 in Kuwait. medRxiv. 2020. DOI: https://doi.org/10.1101/2020.07.10.20150623

22. Banerjee S., Guha A., Das A., Nandy M., Monda R. A preliminary report of COVID-19 in children in India. Indian Pediatr. 2020; 28: 097475591600217.

23. Barbero P., et al. SARS-CoV-2 in pregnancy: characteristics and outcomes of hospitalized and non-hospitalized women due to COVID-19. J Matern Fetal Neonatal Med. 2020; 20: 1-7.

24. Buonsenso D., et al. Neonatal late onset infection with Severe Acute Respiratory Syndrome Coronavirus 2. Am J Perinatol. 2020; 37: 869-72.

25. Carosso A., et al. Pre-labor anorectal swab for SARS-CoV-2 in COVID-19 pregnant patients: is it time to think about it? Eur J Obstet Gynecol Reprod Biol. 2020; 249: 98-9.

26. Chacon-Aguilar R., et al. COVID-19: fever syndrome and neurological symptoms in a neonate. An Pediatr (Barc). 2020; 92: 373-4.

27. Coronado Munoz A., et al. Late-onset neonatal sepsis in a patient with COVID-19. N Engl J Med. 2020; 382: e49.

28. Demirjian A., et al. Probable vertical transmission of SARS-CoV-2 infection. Pediatr Infect Dis J. 2020; 39: 257-60.

29. Dong L., et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020; 323: 1846-8.

30. Dumpa V., Kamity R., Vinci A.N., Noyola E., Noor A. Neonatal Coronavirus 2019 (COVID-19) infection: a case report and review of literature. Cureus. 2020; 12: e8165.

31. Eghbalian F., Esfahani A.M., Jenabi E. COVID-19 virus in a 6-day-old girl neonate: a case report. Clin Pediatr (Phila). 2020; 22: 9922820946010.

32. Feng, X.Y., Tao X.W., Zeng L.K., Wang W.Q., Li G. Application of pulmonary ultrasound in the diagnosis of COVID-19 pneumonia in neonates. Zhonghua Er Ke Za Zhi. 2020; 58: 347-50.

33. Fenizia C., et al. In-utero mother-to-child SARS-CoV-2 transmission: viral detection and fetal immune response. medRxiv. 2020. DOI: https://doi.org/10.1101/2020.07.09.20149591

34. Ferrazzi E.M., et al. COVID-19 obstetrics task force, Lombardy, Italy: executive management summary and short report of outcome. Int J Gynaecol Obstet. 2020; 149: 377-8.

35. Garazzino S., et al. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020. Eur Surveill. 2020; 25: 2000600.

36. Gonzalez Brabin A., Iglesias-Bouzas M.I., Nieto-Moro M., Martinez de Azagra-Garde A., Garcia-Salido A. [Neonatal apnea as initial manifestation of SARS-CoV-2 infection]. An. Pediatr. 2020; 93: 215-6.

37. Gordon M., et al. Rapid systematic review of neonatal COVID-19 including a case of presumed vertical transmission. BMJ Paediatr Open. 2020; 4: e000718.

38. Gregorio-Hernandez R., Escobar-Izquierdo A.B., Cobas-Pazos J., Martfnez-Gimeno A. Point-of-care lung ultrasound in three neonates with COVID-19. Eur J Pediatr. 2020; 179: 1279-85.

39. Grog R., et al. Detection of SARS-CoV-2 in human breastmilk. Lancet. 2020; 395: 1757-8.

40. Han M.S., et al. Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2. Clin Infect Dis. 2020; 16: ciaa447.

41. Hantoushzadeh S., et al. Maternal death due to COVID-19 disease. Am J Obstet Gynecol. 2020; 223: 109.e1-16.

42. Hasan M.S., Ali M.A., Huq U. Outcome of COVID-19 with co-existing surgical emergencies in children: our initial experiences and recommendations. medRxiv. 2020 DOI: https://doi.org/10.1101/2020.08.01.20166371

43. Hu X., et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vertical transmission in neonates born to mothers with Corona-virus Disease 2019 (COVID-19) pneumonia. Obstet Gynecol. 2020; 136: 65-7.

44. Ibarra-Rios D., Villanueva-Garcia D., Martinez-Garcia A., Marquez-Gonzales O. Lung ultrasound and neonatal COVID-19 pneumonia: a case report. Res Sq. 2020. DOI: https://doi.org/10.21203/rs.3.rs-33182/v1

45. Kanburoglu M.K., Altuntas O., Cicek A.C. The challenges of contact tracing in a case of early neonatal sepsis with COVID-19. Indian J Pediatr. 2020; 87: 647.

46. Kayem G., et al. A snapshot of the COVID-19 pandemic among pregnant women in France. J Gynecol Obstet Hum Reprod. 2020; 49: 101826.

47. Kirtsman M., et al. Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection. CMAJ. 2020; 192: E647-50.

48. Knight M., et al. Characteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV-2 infection in the UK: a national cohort study using the UK Obstetric Surveillance System (UKOSS). BMJ. 2020; 369: m2107.

49. Kulkarni R., et al. Early-onset symptomatic neonatal COVID-19 infection with high probability of vertical transmission. Infection. 2020; 2: 1-5.

50. LHuillier A.G., Torriani G., Pigny F., Kaiser L., Eckerle I. Shedding of infectious SARS-CoV-2 in symptomatic neonates, children and adolescents. Emerg Infect Dis. 2020. DOI: https://doi.org/10.3201/eid2610.202403

51. Lorenz N., et al. Neonatal early-onset infection with SARS-CoV-2 in a newborn presenting with encephalitic symptoms. Pediatr Infect Dis J. 2020; 39: e212.

52. Martfnez-Perez O., et al. Association between mode of delivery among pregnant women with COVID-19 and maternal and neonatal outcomes in Spain. JAMA. 2020; 324: 296-9.

53. Marzollo R., et al. Possible coronavirus disease 2019 pandemic and pregnancy: vertical transmission is not excluded. Pediatr Infect Dis J. 2020; 39: e261-2.

54. Meredith L.W., et al. Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study. Lancet Infect Dis. 2020. URL: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30562-4/fulltext

55. Meslin P., et al. Coronavirus disease 2019 in newborns and very young infants: a series of six patients in France. Pediatr Infect Dis J. 2020; 39: e145-7.

56. Mithal L.B., Machut K.Z., Muller W.J., Kociolek L.K. SARS-CoV-2 infection in infants less than 90 days old. J Pediatr. 2020; 224: 150-2.

57. Needleman J.S., Hanson A.E. COVID-19-associated apnea and circumoral cyanosis in a 3-week-old. BMC Pediatr. 2020; 20: 382.

58. Ng K.F., Bandi S., Bird P.W., WeiTze Tang J. COVID-19 in neonates and infants: progression and recovery. Pediatr Infect Dis J. 2020; 39: e140-2.

59. Oncel M.Y., et al. A multicenter study on epidemiological and clinical characteristics of 125 newborns born to women infected with COVID-19 by Turkish Neonatal Society. Eur J Pediatr. 2020; 10: 1-10.

60. Paret M., et al. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress. Clin Infect Dis. 2020; 17: ciaa452.

61. Patane L., et al. Vertical transmission of coronavirus disease 2019: severe acute respiratory syndrome coronavirus 2 RNA on the fetal side of the placenta in pregnancies with coronavirus disease 2019-positive mothers and neonates at birth. Am J Obstet Gynecol MFM. 2020; 2: 100145.

62. Patil U.P., et al. Newborns of COVID-19 mothers: short-term outcomes of colocating and breastfeeding from the pandemic’s epicenter. J Perinatol. 2020; 40 (10): 1455-8. URL: https://doi.org/10.1038/s41372-020-0765-3

63. Pierce-Williams R.A.M., et al. Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study. Am J Obstet Gynecol MFM. 2020; 2: 100145.

64. Piersigilli F., et al. COVID-19 in a 26-week preterm neonate. Lancet Child Adolesc. Health. 2020; 4: 476-8.

65. Precit M.R., et al. A case report of neonatal acute respiratory failure due to Severe Acute Respiratory Syndrome Coronavirus-2. J Pediatr Infect Dis Soc. 2020; 9: 390-2.

66. Salik I., Mehta B. Tetralogy of Fallot palliation in a COVID-19 positive neonate. J Clin Anesth. 2020; 66: 109914.

67. Salvatori G., et al. Managing COVID-19-positive maternal-infant dyads: an Italian experience. Breastfeed. Med. 2020; 15: 347-8.

68. Savasi V.M., et al. Clinical findings and disease severity in hospitalized pregnant women with Coronavirus Disease 2019 (COVID-19). Obstet Gynecol. 2020; 136: 252-8.

69. Schwartz D.A., et al. Spectrum of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections with varying test results, clinical findings and outcomes. J Matern Fetal Neonatal Med. 2020; 12: 1-10.

70. Siddhi P.S., et al. COVID-19 in a preterm-leading to remodelling of care. Indian J Pediatr. 2020; 87: 759.

71. Sinelli M.T., et al. Early neonatal SARS-CoV-2 Infection manifesting with hypoxemia requiring respiratory support. Pediatrics. 2020; 146: e20201121.

72. Sisman J., et al. Intrauterine transmission of SARS-CoV-2 infection in a preterm infant. Pediatr Infect Dis J. 2020; 39: e265-7.

73. Sola A., Rodriguez S., Cardetti M., Davila C. COVID-19 perinatal en America Latina. Rev Panam Salud Publica. 2020; 44: e47.

74. Sun D., et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr. 2020; 16: 251-9.

75. Sun M., et al. Evidence of mother-to-newborn infection with COVID-19. Br J Anaesth. 2020; 125: e245-7.

76. Verma S., et al. Outcomes of maternal-newborn dyads after maternal SARSCoV-2. Pediatrics. 2020; 31: e2020005637.

77. Vivanti A., et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020; 11: 3572.

78. Wang J., Wang D., Chen G.-C., Tao X.-W., Zeng L.-K. [SARS-CoV-2 infection with gastrointestinal symptoms as the first manifestation in a neonate]. Zhongguo Dang Dai Er Ke Za Zhi. 2020; 22: 211-4.

79. Wang X., et al. A case of 2019 Novel Coronavirus in a pregnant woman with preterm delivery. Clin Infect Dis. 2020; 71: 844-6.

80. Wardell H., Campbell J.I., Van der Pluym C., Dixit A. SARS-CoV-2 infection in febrile neonates. J Pediatr Infect Dis Soc. 2020; 9: piaa084.

81. White A., et al. Neonates hospitalized with community-acquired SARS-CoV-2 in a Colorado Neonatal Intensive Care Unit. Neonatology. 2020; 4: 1-5.

82. Wu Y.-T., et al. Neonatal outcome in 29 pregnant women with COVID-19: A retrospective study in Wuhan, China. PLoS Med. 2020; 17: e1003195.

83. Xia W., et al. Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults. Pediatr Pulmonol. 2020; 55: 1169-74.

84. Xiao F., et al. Children with SARS-CoV-2 infection during an epidemic in China (outside of Hubei province). Ann Transl Med. 2020; 8: 849.

85. Yu Z., et al. Transport, diagnosis and treatment of a newborn with severe SARS-CoV-2 infection: a case report. China J Evid Based Pediatr. 2020; 15: 37-41.

86. Zamaniyan M., et al. Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission. Prenat Diagn. 2020; 40 (2): 5713. DOI: https://doi.org/10.1002/pd.5713

87. Zeng H., et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020; 323: 1848-9.

88. Zeng L., et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China. JAMA Pediatr. 2020; 174: 722-5.

89. Zeng L.K., et al. [First case of neonate infected with novel coronavirus pneumonia in China]. Zhonghua Er Ke Za Zhi. 2020; 58: 279-80.

90. Zhang Z.-J., et al. Novel Coronavirus Infection in newborn babies under 28 days in China. Eur Respir J. 2020; 55: 2000697.

91. Valdes G., et al. Distribution of Angiotensin-(1-7) and ACE2 in human placentas of normal and pathological pregnancies. Placenta. 2006; 27: 200-7.

92. 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 single-cell transcriptome study. PLoS One. 2020; 15: e0230295.

93. Baud D., et al. Second-trimester miscarriage in a pregnant woman with SARSCoV-2 infection. JAMA. 2020; 323: 2198-200.

94. Shah B.A., Padbury J.F. Neonatal sepsis: an old problem with new insights. Virulence. 2014; 5: 170-8.

95. De Luca D., et al. The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity. Lancet Respir Med. 2017; 5: 657-66.

96. Wang L., et al. Chinese expert consensus on the perinatal and neonatal management for the prevention and control of the 2019 novel coronavirus infection (first edition). Ann Transl Med. 2020; 8: 47.

97. Yeo K.T., et al. Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19. Acta Paediatr. 2020; July 27. DOI: https://doi.org/10.1111/apa.15495

98. He X., et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020; 26: 672-5.

99. Salvatore C.M., et al. Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study. Lancet Child Adolesc Health. 2020; 4 (10): 721-7.

100. Chen H., 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: 809-15.

101. Harrison W., Goodman D. Epidemiologic trends in neonatal intensive care, 2007-2012. JAMA Pediatr. 2015; 169: 855-62.

102. De Luca D. Managing neonates with respiratory failure due to SARS-CoV-2. Lancet Child Adolesc Health. 2020; 4: E8.

103. Murad M.H., Sultan S., Haffar S., Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018; 23: 60-3.

104. Andrews J.C., et al. GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation’s direction and strength. J Clin Epidemiol. 2013; 66: 726-35.

105. Gagnier J.J., et al. The CARE guidelines: consensus-based clinical case report guideline development. J Clin Epidemiol. 2014; 67: 46-51.

106. Majumder M.S., Mandl K.D. Early in the epidemic: impact of preprints on global discourse about COVID-19 transmissibility. Lancet Glob Health. 2020; 8: e627-30.

107. Moher D., Liberati A., Tetzlaff J., Altman D.G.; the PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6: e1000097.

108. World Health Organization. Coronavirus disease (COVID-19) Technical Guidance: Laboratory Testing for 2019-nCoV in Humans. 2020. URL: https://apps.who.int/iris/bitstream/handle/10665/331329/WHO-COVID-19-laboratory-2020.4-eng.pdf

109. Stroup D.F. Meta-analysis of observational studies in epidemiology: a proposal for reporting. meta-analysis of observational studies in pidemiology (MOOSE) group. JAMA. 2000; 283: 2008-12.

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

CHIEF EDITOR
CHIEF EDITOR
Degtyarev Dmitriy Nikolaevich
Doctor of Medical Sciences, Professor, Deputy Director for Scientific Research of the V.I. Kulakov Obstetrics, Gynecology and Perinatology National Medical Research Center of Ministry of Healthсаre of the Russian Federation, Head of the Chair of Neonatology at the Clinical Institute of Children's Health named after N.F. Filatov, I.M. Sechenov First Moscow State Medical University, Chairman of the Ethics Committee of the Russian Society of Neonatologists, Moscow, Russian Federation

ORCID iD 0000-0001-8975-2425

Journals of «GEOTAR-Media»